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S Y, K L M, Harithpriya K, Zong C, Sahabudeen S, Ichihara G, Ramkumar KM. Disruptive multiple cell death pathways of bisphenol-A. Toxicol Mech Methods 2025; 35:430-443. [PMID: 39815394 DOI: 10.1080/15376516.2024.2449423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/26/2024] [Accepted: 12/30/2024] [Indexed: 01/18/2025]
Abstract
Endocrine-disrupting chemicals (EDCs) significantly contribute to health issues by interfering with hormonal functions. Bisphenol A (BPA), a prominent EDC, is extensively utilized as a monomer and plasticizer in producing polycarbonate plastic and epoxy resins, making it one of the highest-demanded chemicals in commercial use. This is the major component used in plastic products, including bottles, containers, storage items, and food serving ware. Exposure of BPA happens through oral, respiratory, transdermal routes and eye contact. As an EDC, BPA disrupts hormonal binding, leading to various health problems, such as cancers, reproductive abnormalities, metabolic syndrome, immune dysfunction, neurological effects, cardiovascular problems, respiratory issues, and obesity. BPA mimics the hormone estrogen but exhibits a weak affinity for estrogen receptors. This weak binding affinity triggers multiple cell death pathways, including necroptosis, pyroptosis, apoptosis, ferroptosis, and autophagy, across different cell types. Numerous clinical, in-vitro, and in-vivo experiments have demonstrated that BPA exposure results in unfavorable health effects. This review highlights the mechanisms of cell death pathways initiated through BPA exposure and the associated negative health consequences. The extensive use of BPA and its frequent detection in environmental and biological models underscore the urgent need for further investigation into its effects and the development of safe alternatives. Addressing the health risks posed by BPA involves a comprehensive approach that includes reducing exposure and finding novel substitutes to lessen its detrimental impact on humans.
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Affiliation(s)
- Yukta S
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, India
| | - Milan K L
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, India
| | - Kannan Harithpriya
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, India
| | - Cai Zong
- Department of Occupational and Environmental Health, Faculty of Pharmaceutical Science, Tokyo University of Science, Tokyo, Japan
| | - S Sahabudeen
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, India
| | - Gaku Ichihara
- Department of Occupational and Environmental Health, Faculty of Pharmaceutical Science, Tokyo University of Science, Tokyo, Japan
| | - K M Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, India
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Ren XM, Wang J, Zhao F, Zhang P, Zhang Z, Yang Z, He H, Xu Z, Huang B, Pan X. 6:2 fluorotelomer sulfonate as a safer alternative to PFOS: Comparative cytotoxicity and oxidative stress mechanisms in pancreatic β-cells (INS-1 model). Toxicol In Vitro 2025; 105:106034. [PMID: 39978700 DOI: 10.1016/j.tiv.2025.106034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 02/10/2025] [Accepted: 02/17/2025] [Indexed: 02/22/2025]
Abstract
Previous studies suggest that 6:2 fluorotelomer sulfonate (6:2 FTSA) exhibits lower hepatotoxicity and reduced reproductive and developmental toxicity compared to perfluorooctane sulfonate (PFOS), indicating it may offer a safer alternative. This study aimed to investigate whether 6:2 FTSA is safer than PFOS in terms of its cytotoxic effects on pancreatic β-cells. Using rat insulinoma cells (INS-1) as a model of pancreatic β-cells, we compared the effects of 6:2 FTSA and PFOS in both their acid (6:2 FTSA-H, PFOS-H) and potassium salt forms (6:2 FTSA-K, PFOS-K) on cell viability through Cell Counting Kit-8 (CCK-8) assays, Trypan Blue staining, and apoptosis assays. Results indicated that 6:2 FTSA was less toxic to INS-1 cells than PFOS (6:2 FTSA-H < PFOS-H; 6:2 FTSA-K < PFOS-K), the LOECs of 6:2 FTSA-H, 6:2 FTSA-K, PFOS-H, and PFOS-K were 150 μM, 150 μM, 20 μM, and 10 μM under FBS free conditions, respectively. To further explore whether these compounds induce cell death via oxidative stress, we measured intracellular reactive oxygen species (ROS) levels, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) levels. All four compounds induced oxidative stress in INS-1 cells, with oxidative stress levels corresponding to cytotoxicity, suggesting β-cell death may occur via an oxidative stress mechanism. In conclusion, this study supports the notion that 6:2 FTSA is a safer alternative to PFOS, particularly regarding risks related to pancreatic β-cell cytotoxic effects. While the in vitro experiments in this study provide valuable preliminary information on the compounds' effects on cells and their mechanisms, they cannot fully capture the complexity of the in vivo environment. Therefore, future research should include in vivo experiments to validate the findings from the in vitro studies and comprehensively evaluate the actual effects of the compounds in living organisms.
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Affiliation(s)
- Xiao-Min Ren
- Faculty of Environmental Science and Engineering. Kunming University of Science and Technology, Kunming 650500, China
| | - Jianying Wang
- Faculty of Environmental Science and Engineering. Kunming University of Science and Technology, Kunming 650500, China
| | - Fenqing Zhao
- Faculty of Environmental Science and Engineering. Kunming University of Science and Technology, Kunming 650500, China
| | - Pingping Zhang
- Faculty of Environmental Science and Engineering. Kunming University of Science and Technology, Kunming 650500, China
| | - Zhenghuan Zhang
- Faculty of Environmental Science and Engineering. Kunming University of Science and Technology, Kunming 650500, China
| | - Zhongneng Yang
- Faculty of Environmental Science and Engineering. Kunming University of Science and Technology, Kunming 650500, China
| | - Huan He
- Faculty of Environmental Science and Engineering. Kunming University of Science and Technology, Kunming 650500, China
| | - Zhixiang Xu
- Faculty of Environmental Science and Engineering. Kunming University of Science and Technology, Kunming 650500, China
| | - Bin Huang
- Faculty of Environmental Science and Engineering. Kunming University of Science and Technology, Kunming 650500, China
| | - Xuejun Pan
- Faculty of Environmental Science and Engineering. Kunming University of Science and Technology, Kunming 650500, China.
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Lin Y, Ni X, Zhu L, Lin Y, Peng C, Lei Z, Wang Y, Wang H, You X, Li J, Shen H, Wei J. Multi-miRNAs-Mediated Hepatic Lepr Axis Suppression: A Pparg-Dicer1 Pathway-Driven Mechanism in Spermatogenesis for the Intergenerational Transmission of Paternal Metabolic Syndrome. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410831. [PMID: 39792613 PMCID: PMC11884570 DOI: 10.1002/advs.202410831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 12/14/2024] [Indexed: 01/12/2025]
Abstract
Bisphenol A (BPA) is an "environmental obesogen" and this study aims to investigate the intergenerational impacts of BPA-induced metabolic syndrome (MetS), specifically focusing on unraveling mechanisms. Exposure to BPA induces metabolic disorders in the paternal mice, which are then transmitted to offspring, leading to late-onset MetS. Mechanistically, BPA upregulates Srebf1, which in turn promotes the Pparg-dependent transcription of Dicer1 in spermatocytes, increasing the levels of multiple sperm microRNAs (miRNAs). Several of these miRNAs are highly expressed in a synchronized manner in liver of the offspring. miR149-5p, miR150-5p, and miR700-5p target a specific region in the Lepr 3'UTR, termed "SMITE" ("Several MiRNAs Targeting Elements"), to negatively regulate Lepr. These inherited anti-Lepr miRNAs, also referred to inherited anti-Lepr miRNAs (IAL-miRs), modulate hepatic steatosis, and insulin signaling through the Lepr regulatory Igfbp2, Egfr, and Ampk. Furthermore, IAL-miRs inhibit Ccnd1 not only via binding to "SMITE" but also via Lepr-Igfbp2 axis, which contribute to hepatocyte senescence. These pathological processes interact in a self-reinforcing cycle, worsening MetS in the paternal BPA-exposed offspring. The findings reveal mechanism wherein lipid metabolism reprogramming in spermatocytes-induced perturbations of sperm miRNAs, triggered by BPA, leads to intergenerational inheritance of paternal MetS through suppression of the hepatic Lepr axis in the offspring.
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Affiliation(s)
- Yi Lin
- State Key Laboratory of Vaccines for Infectious Diseases， Xiang An Biomedicine Laboratory， National Innovation Platform for Industry‐Education Integration in Vaccine ResearchSchool of Public HealthXiamen UniversityXiamen361102China
| | - Xiuye Ni
- State Key Laboratory of Vaccines for Infectious Diseases， Xiang An Biomedicine Laboratory， National Innovation Platform for Industry‐Education Integration in Vaccine ResearchSchool of Public HealthXiamen UniversityXiamen361102China
| | - Lin Zhu
- State Key Laboratory of Vaccines for Infectious Diseases， Xiang An Biomedicine Laboratory， National Innovation Platform for Industry‐Education Integration in Vaccine ResearchSchool of Public HealthXiamen UniversityXiamen361102China
| | - Yilong Lin
- Department of Basic Medical SciencesSchool of MedicineXiamen UniversityXiamen361102China
| | - Cai Peng
- Department of Basic Medical SciencesSchool of MedicineXiamen UniversityXiamen361102China
| | - Zhao Lei
- State Key Laboratory of Vaccines for Infectious Diseases， Xiang An Biomedicine Laboratory， National Innovation Platform for Industry‐Education Integration in Vaccine ResearchSchool of Public HealthXiamen UniversityXiamen361102China
| | - Yihui Wang
- State Key Laboratory of Vaccines for Infectious Diseases， Xiang An Biomedicine Laboratory， National Innovation Platform for Industry‐Education Integration in Vaccine ResearchSchool of Public HealthXiamen UniversityXiamen361102China
| | - Huan Wang
- State Key Laboratory of Vaccines for Infectious Diseases， Xiang An Biomedicine Laboratory， National Innovation Platform for Industry‐Education Integration in Vaccine ResearchSchool of Public HealthXiamen UniversityXiamen361102China
| | - Xiang You
- Department of Basic Medical SciencesSchool of MedicineXiamen UniversityXiamen361102China
| | - Juan Li
- Department of Basic Medical SciencesSchool of MedicineXiamen UniversityXiamen361102China
| | - Heqing Shen
- State Key Laboratory of Vaccines for Infectious Diseases， Xiang An Biomedicine Laboratory， National Innovation Platform for Industry‐Education Integration in Vaccine ResearchSchool of Public HealthXiamen UniversityXiamen361102China
| | - Jie Wei
- Department of Basic Medical SciencesSchool of MedicineXiamen UniversityXiamen361102China
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Celik MN, Yesildemir O. Endocrine Disruptors in Child Obesity and Related Disorders: Early Critical Windows of Exposure. Curr Nutr Rep 2025; 14:14. [PMID: 39775248 PMCID: PMC11706864 DOI: 10.1007/s13668-024-00604-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2024] [Indexed: 01/11/2025]
Abstract
PURPOSE OF REVIEW Endocrine disruptors (EDs) can mimic or interfere with hormones in the body, leading to non-communicable diseases, such as obesity, diabetes, and metabolic syndrome. Susceptibility to EDs increases during prenatal and postnatal life, a critical time window. This review aims to summarize the latest evidence on the relation of early life exposure to some EDs with obesity and the other metabolic disorders. RECENT FINDINGS: There is increasing evidence that early life exposure to EDs may impair adipogenesis by increasing the number and size of adipocytes, thereby increasing susceptibility to obesity in childhood. It is stated that exposure to EDs during the prenatal and postnatal period may raise the risk of type 2 diabetes in adulthood by disrupting glucose, lipid, and insulin homeostasis in the offspring. They can also accelerate the development of type 1 diabetes through various mechanisms, like immunomodulation, gut microbiota, and vitamin D pathways. There is a growing understanding that ED exposure during critical stages of life could play an important role in the development of obesity and metabolic disorders. We suggest setting national goals, global standards, and policies to reduce environmental exposure to pregnant and lactating women, and babies, considered sensitive populations.
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Affiliation(s)
- Mensure Nur Celik
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Ondokuz Mayıs University, Samsun, Turkey.
| | - Ozge Yesildemir
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Bursa Uludag University, Bursa, Turkey
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Sun W, Lei Y, Jiang Z, Wang K, Liu H, Xu T. BPA and low-Se exacerbate apoptosis and mitophagy in chicken pancreatic cells by regulating the PTEN/PI3K/AKT/mTOR pathway. J Adv Res 2025; 67:61-69. [PMID: 38311007 PMCID: PMC11725106 DOI: 10.1016/j.jare.2024.01.029] [Citation(s) in RCA: 46] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 12/09/2023] [Accepted: 01/25/2024] [Indexed: 02/06/2024] Open
Abstract
INTRODUCTION Bisphenol A (BPA) is a widespread environmental pollutant which has serious toxic effects on organisms. One of the crucial trace elements is selenium (Se), whose shortage can harm biological tissues and enhance the toxicity of contaminants, in which apoptosis and autophagy are core events. OBJECTIVES An in vivo model was established to investigate the effects of BPA and low-Se on chicken pancreatic tissue, and identify the possible potential molecular mechanism. METHODS A total of 80 1-day-old broiler chickens (Xinghua Chicken Farm, Harbin, China) were stochastically divided into 4 groups (n = 20/group): Control group, BPA group, low-Se group, and low-Se + BPA group. Pancreatic tissue was collected at day 42 to detect changes in markers. RESULTS First, the data showed that BPA and low-Se exposure gave rose to structural abnormalities in pancreatic tissue, oxidative stress, mitochondrial dysfunction and homeostasis imbalance, apoptosis and mitophagy. In addition, the co-exposure of BPA and low-Se caused the most serious damage to pancreatic tissue. In terms of mechanism, it was found that apoptosis and mitophagy induced by BPA and low-Se were related to the activation of PTEN/PI3K/AKT/mTOR pathway. CONCLUSION In summary, the study found that BPA and low-Se exacerbated mitochondria damage, apoptosis and mitophagy by regulating the PTEN/PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Wenying Sun
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Yutian Lei
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Zhihui Jiang
- Henan Beiai Natural Product Application and Development Engineering Research Center, Anyang Institute of Technology, Anyang 455000, Henan, PR China
| | - Kun Wang
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Huanyi Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China
| | - Tong Xu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, PR China.
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Sadek KM, Khalifa NE, Alshial EE, Abdelnour SA, Mohamed AAR, Noreldin AE. Potential hazards of bisphenol A on the male reproductive system: Induction of programmed cell death in testicular cells. J Biochem Mol Toxicol 2024; 38:e23844. [PMID: 39252451 DOI: 10.1002/jbt.23844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 08/10/2024] [Accepted: 08/29/2024] [Indexed: 09/11/2024]
Abstract
A common industrial chemical known as bisphenol A (BPA) has been linked to endocrine disruption and can interfere with hormonal signaling pathways in humans and animals. This comprehensive review aims to explore the detrimental consequences of BPA on reproductive organ performance and apoptosis induction, shedding light on the emerging body of evidence from laboratory animal studies. Historically, most studies investigating the connection between BPA and reproductive tissue function have mainly leaned on laboratory animal models. These studies have provided crucial insights into the harmful effects of BPA on several facets of reproduction. This review consolidates an increasing literature that correlates exposure to BPA in the environment with a negative impact on human health. It also integrates findings from laboratory studies conducted on diverse species, collectively bolstering the mounting evidence that environmental BPA exposure can be detrimental to both humans and animals, particularly to reproductive health. Furthermore, this article explores the fundamental processes by which BPA triggers cell death and apoptosis in testicular cells. By elucidating these mechanisms, this review aids a deeper understanding of the complex interactions between BPA and reproductive tissues.
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Affiliation(s)
- Kadry M Sadek
- Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
| | - Norhan E Khalifa
- Department of Physiology, Faculty of Veterinary Medicine, Matrouh University, Matrouh, Egypt
| | - Eman E Alshial
- Department of Biochemistry, Faculty of Science, Damanhour University, Damanhour, Egypt
| | - Sameh A Abdelnour
- Department of Animal Production, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
| | - Amany A-R Mohamed
- Departmentof Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Ahmed E Noreldin
- Department of Histology and Cytology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt
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Huang C, Chen X, Ouyang Z, Meng L, Liu J, Pang Q, Fan R. Bisphenol a accelerates the glucolipotoxicity-induced dysfunction of rat insulinoma cell lines: An implication for a potential risk of environmental bisphenol a exposure for individuals susceptible to type 2 diabetes. Toxicol In Vitro 2024; 99:105866. [PMID: 38844119 DOI: 10.1016/j.tiv.2024.105866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/21/2024] [Accepted: 06/03/2024] [Indexed: 06/11/2024]
Abstract
Epidemiological studies have suggested a correlation between bisphenol A (BPA) and type 2 diabetes (T2DM). The effects of BPA on β-cell dysfunction may reveal the risks from an in vitro perspective. We used the rat insulinoma (INS-1) cell lines (a type of β-cells) to set up normal or damaged models (DM), which were exposed to various concentrations of BPA (0.001, 0.01, 0.1, 1, 10 and 100 μM). An increase in reactive oxygen species (ROS) and apoptosis, and a decrease in cell viability were observed in INS-1 cells exposed to high doses of BPA for 48 h. Interestingly, exposure to lower doses of BPA for 24 h resulted in increased ROS levels and apoptosis rates in INS-1 in the DM group, along with decreased cell viability, suggesting that BPA exerts toxicity to INS-1 cells, particularly to the DM group. Insulin levels and Glut2 expression, glucose consumption, intracellular Ca2+ and insulin secretion were increased in INS-1 cells after 48 h exposure to high dose of BPA. Stronger effects were observed in the DM group, even those exposed to low doses of BPA for 24 h. Moreover, BPA inhibited high glucose-stimulated insulin secretion in these cells. Our research suggests that low doses of BPA exacerbate the dysfunction caused by glucolipotoxicity, implying environmental BPA exposure poses a risk for individuals with prediabetes or T2DM.
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Affiliation(s)
- Chengmeng Huang
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Guangdong Provincial Engineering Technology Research Center for Drug and Food Biological Resources Processing and Comprehensive Utilization, School of Life Sciences, South China Normal University, Guangzhou 510631, China
| | - Xiaolin Chen
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Guangdong Provincial Engineering Technology Research Center for Drug and Food Biological Resources Processing and Comprehensive Utilization, School of Life Sciences, South China Normal University, Guangzhou 510631, China
| | - Zedong Ouyang
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Guangdong Provincial Engineering Technology Research Center for Drug and Food Biological Resources Processing and Comprehensive Utilization, School of Life Sciences, South China Normal University, Guangzhou 510631, China
| | - Lingxue Meng
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Guangdong Provincial Engineering Technology Research Center for Drug and Food Biological Resources Processing and Comprehensive Utilization, School of Life Sciences, South China Normal University, Guangzhou 510631, China
| | - Jian Liu
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Guangdong Provincial Engineering Technology Research Center for Drug and Food Biological Resources Processing and Comprehensive Utilization, School of Life Sciences, South China Normal University, Guangzhou 510631, China
| | - Qihua Pang
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Guangdong Provincial Engineering Technology Research Center for Drug and Food Biological Resources Processing and Comprehensive Utilization, School of Life Sciences, South China Normal University, Guangzhou 510631, China.
| | - Ruifang Fan
- Guangzhou Key Laboratory of Subtropical Biodiversity and Biomonitoring, Guangdong Provincial Engineering Technology Research Center for Drug and Food Biological Resources Processing and Comprehensive Utilization, School of Life Sciences, South China Normal University, Guangzhou 510631, China.
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Aysin F. Bisphenol A promotes cell death in healthy respiratory system cells through inhibition of cell proliferation and induction of G2/M cell cycle arrest. ENVIRONMENTAL TOXICOLOGY 2024; 39:3264-3273. [PMID: 38459623 DOI: 10.1002/tox.24203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 02/05/2024] [Accepted: 02/15/2024] [Indexed: 03/10/2024]
Abstract
Bisphenol A (BPA) is a substance that can harm the environment and human health by interfering with the normal functioning of the body's hormonal system. It is commonly found in various plastic-based products such as cosmetics, canned foods, beverage containers, and medical equipment and as well as it can also be absorbed by inhalation. There have been limited studies on the effects of BPA on lung fibroblasts, and it is still unclear how high levels of BPA can impact respiratory system cells, particularly the lungs and trachea. In this research, we aimed to investigate the cell cycle disruption potential of BPA on respiratory system cells by examining healthy trachea and lung cells together for the first time. The findings indicated that BPA exposure can alter the healthy cells' morphology, leading to reduced cellular viability that has been assessed by MTT and SRB assays. BPA treatment was able to activate caspase3 as expected, which could cause apoptosis in treated cells. Although the highest dose of BPA did not increase the apoptotic rate of rat trachea cells, it remarkably caused them to become necrotic (52.12%). In addition to quantifying the induction of apoptosis and necrosis by BPA, cell cycle profiles were also determined using flow cytometry. Thereby, BPA treatment unexpectedly inhibited the cell cycle's progression by causing G2/M cell cycle arrest in both lung and tracheal cells, which hindered cell proliferation. The findings of the study suggested that exposure to BPA could lead to serious respiratory problems, even respiratory tract cancers via alterations in the cell cycle.
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Affiliation(s)
- Ferhunde Aysin
- Department of Biology, Faculty of Science, Atatürk University, Erzurum, Turkey
- East Anatolia High Technology Application and Research Center (DAYTAM), Atatürk University, Erzurum, Turkey
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Johnson L, Sarosiek KA. Role of intrinsic apoptosis in environmental exposure health outcomes. Trends Mol Med 2024; 30:56-73. [PMID: 38057226 DOI: 10.1016/j.molmed.2023.11.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/31/2023] [Accepted: 11/06/2023] [Indexed: 12/08/2023]
Abstract
Environmental exposures are linked to diseases of high public health concern, including cancer, neurodegenerative disorders, and autoimmunity. These diseases are caused by excessive or insufficient cell death, prompting investigation of mechanistic links between environmental toxicants and dysregulation of cell death pathways, including apoptosis. This review describes how legacy and emerging environmental exposures target the intrinsic apoptosis pathway to potentially drive pathogenesis. Recent discoveries reveal that dynamic regulation of apoptosis may heighten the vulnerability of healthy tissues to exposures in children, and that apoptotic signaling can guide immune responses, tissue repair, and tumorigenesis. Understanding how environmental toxicants dysregulate apoptosis will uncover opportunities to deploy apoptosis-modulating agents for the treatment or prevention of exposure-linked diseases.
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Affiliation(s)
- Lissah Johnson
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA
| | - Kristopher A Sarosiek
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Laboratory for Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute/Harvard Cancer Center, Boston, MA, USA.
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Ryu DY, Pang WK, Adegoke EO, Rahman MS, Park YJ, Pang MG. Bisphenol-A disturbs hormonal levels and testis mitochondrial activity, reducing male fertility. Hum Reprod Open 2023; 2023:hoad044. [PMID: 38021376 PMCID: PMC10681812 DOI: 10.1093/hropen/hoad044] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/09/2023] [Indexed: 12/01/2023] Open
Abstract
STUDY QUESTION How does bisphenol-A (BPA) influence male fertility, and which mechanisms are activated following BPA exposure? SUMMARY ANSWER BPA exposure causes hormonal disruption and alters mitochondrial dynamics and activity, ultimately leading to decreased male fertility. WHAT IS KNOWN ALREADY As public health concerns following BPA exposure are rising globally, there is a need to understand the exact mechanisms of BPA on various diseases. BPA exposure causes hormonal imbalances and affects male fertility by binding the estrogen receptors (ERs), but the mechanism of how it mediates the hormonal dysregulation is yet to be studied. STUDY DESIGN SIZE DURATION This study consisted of a comparative study using mice that were separated into a control group and a group exposed to the lowest observed adverse effect level (LOAEL) (n = 20 mice/group) after a week of acclimatization to the environment. For this study, the LOAEL established by the US Environmental Protection Agency of 50 mg/kg body weight (BW)/day of BPA was used. The control mice were given corn oil orally. Based on the daily variations in BW, both groups were gavaged every day from 6 to 11 weeks (6-week exposure). Before sampling, mice were stabilized for a week. Then, the testes and spermatozoa of each mouse were collected to investigate the effects of BPA on male fertility. IVF was carried out using the cumulus-oocyte complexes from female hybrid B6D2F1/CrljOri mice (n = 3) between the ages of eight and twelve weeks. PARTICIPANTS/MATERIALS SETTING METHODS Signaling pathways, apoptosis, and mitochondrial activity/dynamics-related proteins were evaluated by western blotting. ELISA was performed to determine the levels of sex hormones (FSH, LH, and testosterone) in serum. Hematoxylin and eosin staining was used to determine the effects of BPA on histological morphology and stage VII/VIII testicular seminiferous epithelium. Blastocyst formation and cleavage development rate were evaluated using IVF. MAIN RESULTS AND THE ROLE OF CHANCE BPA acted by binding to ERs and G protein-coupled receptors and activating the protein kinase A and mitogen-activated protein kinase signaling pathways, leading to aberrant hormone levels and effects on the respiratory chain complex, ATP synthase and protein-related apoptotic pathways in testis mitochondria (P < 0.05). Subsequently, embryo cleavage and blastocyst formation were reduced after the use of affected sperm, and abnormal morphology of seminiferous tubules and stage VII and VIII seminiferous epithelial cells (P < 0.05) was observed. It is noteworthy that histopathological lesions were detected in the testes at the LOAEL dose, even though the mice remained generally healthy and did not exhibit significant changes in BW following BPA exposure. These observations suggest that testicular toxicity is more than a secondary outcome of compromised overall health in the mice due to systemic effects. LARGE SCALE DATA Not applicable. LIMITATIONS REASONS FOR CAUTION Since the protein expression levels in the testes were validated, in vitro studies in each testicular cell type (Leydig cells, Sertoli cells, and spermatogonial stem cells) would be required to shed further light on the exact mechanism resulting from BPA exposure. Furthermore, the BPA doses employed in this study significantly exceed the typical human exposure levels in real-life scenarios. Consequently, it is imperative to conduct experiments focusing on the effects of BPA concentrations more in line with daily human exposures to comprehensively assess their impact on testicular toxicity and mitochondrial activity. WIDER IMPLICATIONS OF THE FINDINGS These findings demonstrate that BPA exposure impacts male fertility by disrupting mitochondrial dynamics and activities in the testes and provides a solid foundation for subsequent investigations into the effects on male reproductive function and fertility following BPA exposure, and the underlying mechanisms responsible for these effects. In addition, these findings suggest that the LOAEL concentration of BPA demonstrates exceptional toxicity, especially when considering its specific impact on the testes and its adverse consequences for male fertility by impairing mitochondrial activity. Therefore, it is plausible to suggest that BPA elicits distinct toxicological responses and mechanistic endpoints based on the particular concentration levels for each target organ. STUDY FUNDING/COMPETING INTERESTS This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2018R1A6A1A03025159). No competing interests are declared.
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Affiliation(s)
- Do-Yeal Ryu
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Republic of Korea
| | - Won-Ki Pang
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Republic of Korea
| | - Elikanah Olusayo Adegoke
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Republic of Korea
| | - Md Saidur Rahman
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Republic of Korea
| | - Yoo-Jin Park
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Republic of Korea
| | - Myung-Geol Pang
- Department of Animal Science & Technology and BET Research Institute, Chung-Ang University, Anseong, Republic of Korea
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11
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Khan NG, Tungekar B, Adiga D, Chakrabarty S, Rai PS, Kabekkodu SP. Alterations induced by Bisphenol A on cellular organelles and potential relevance on human health. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023; 1870:119505. [PMID: 37286138 DOI: 10.1016/j.bbamcr.2023.119505] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 04/29/2023] [Accepted: 05/26/2023] [Indexed: 06/09/2023]
Abstract
Bisphenol A (BPA) is a chemical partially soluble in water and exists in a solid state. Its structural similarity with estrogen makes it an endocrine-disrupting chemical. BPA can disrupt signaling pathways at very low doses and may cause organellar stress. According to in vitro and in vivo studies, BPA interacts with various cell surface receptors to cause organellar stress, producing free radicals, cellular toxicity, structural changes, DNA damage, mitochondrial dysfunction, cytoskeleton remodeling, centriole duplication, and aberrant changes in several cell signaling pathways. The current review summarizes the impact of BPA exposure on the structural and functional aspects of subcellular components of cells such as the nucleus, mitochondria, endoplasmic reticulum, lysosome, ribosome, Golgi apparatus, and microtubules and its consequent impact on human health.
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Affiliation(s)
- Nadeem G Khan
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Bushra Tungekar
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Divya Adiga
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Sanjiban Chakrabarty
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India; Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Padmalatha S Rai
- Department of Biotechnology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India; Center for DNA Repair and Genome Stability (CDRGS), Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
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12
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Xu L, Cheng F, Bu D, Li X. The Effects of Prolonged Basic Amino Acid Exposures on Mitochondrial Enzyme Gene Expressions, Metabolic Profiling and Insulin Secretions and Syntheses in Rat INS-1 β-Cells. Nutrients 2023; 15:4026. [PMID: 37764809 PMCID: PMC10538135 DOI: 10.3390/nu15184026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 09/09/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
In order to investigate the chronic effects of basic amino acids (BAA) on β-cell metabolism and insulin secretion, INS-1 β-cells were randomly assigned to cultures in standard medium (Con), standard medium plus 10 mM L-Arginine (Arg), standard medium plus 10 mM L-Histidine (His) or standard medium plus 10 mM L-Lysine (Lys) for 24 h. Results showed that insulin secretion was decreased by the Arg treatment but was increased by the His treatment relative to the Con group (p < 0.05). Higher BAA concentrations reduced the high glucose-stimulated insulin secretions (p < 0.001), but only Lys treatment increased the intracellular insulin content than that in the Con group (p < 0.05). Compared with Arg and Lys, the His treatment increased the mitochondrial key enzyme gene expressions including Cs, mt-Atp6, mt-Nd4l and Ogdh, and caused a greater change in the metabolites profiling (p < 0.05). The most significant pathways affected by Arg, His and Lys were arginine and proline metabolism, aminoacyl-tRNA biosynthesis and pyrimidine metabolism, respectively. Regression analysis screened 7 genes and 9 metabolites associated with insulin releases during BAA stimulations (p < 0.05). Together, different BAAs exerted dissimilar effects on β-cell metabolism and insulin outputs.
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Affiliation(s)
- Lianbin Xu
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Fengqi Cheng
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Dengpan Bu
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao 266109, China
| | - Xiuli Li
- College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, China
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13
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Huang RG, Li XB, Wang YY, Wu H, Li KD, Jin X, Du YJ, Wang H, Qian FY, Li BZ. Endocrine-disrupting chemicals and autoimmune diseases. ENVIRONMENTAL RESEARCH 2023; 231:116222. [PMID: 37224951 DOI: 10.1016/j.envres.2023.116222] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 04/10/2023] [Accepted: 05/21/2023] [Indexed: 05/26/2023]
Abstract
Endocrine-disrupting chemicals (EDCs) widely exist in people's production and life which have great potential to damage human and animal health. Over the past few decades, growing attention has been paid to the impact of EDCs on human health, as well as immune system. So far, researchers have proved that EDCs (such as bisphenol A (BPA), phthalate, tetrachlorodibenzodioxin (TCDD), etc.) affect human immune function and promotes the occurrence and development of autoimmune diseases (ADs). Therefore, in order to better understand how EDCs affect ADs, we summarized the current knowledge about the impact of EDCs on ADs, and elaborated the potential mechanism of the impact of EDCs on ADs in this review.
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Affiliation(s)
- Rong-Gui Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Xian-Bao Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Yi-Yu Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Hong Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Kai-Di Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Xue Jin
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Yu-Jie Du
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Hua Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | | | - Bao-Zhu Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China.
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14
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Milanović M, Milošević N, Milić N, Stojanoska MM, Petri E, Filipović JM. Food contaminants and potential risk of diabetes development: A narrative review. World J Diabetes 2023; 14:705-723. [PMID: 37383596 PMCID: PMC10294057 DOI: 10.4239/wjd.v14.i6.705] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 03/03/2023] [Accepted: 04/13/2023] [Indexed: 06/14/2023] Open
Abstract
The number of people diagnosed with diabetes continues to increase, especially among younger populations. Apart from genetic predisposition and lifestyle, there is increasing scientific and public concern that environmental agents may also contribute to diabetes. Food contamination by chemical substances that originate from packaging materials, or are the result of chemical reactions during food processing, is generally recognized as a worldwide problem with potential health hazards. Phthalates, bisphenol A (BPA) and acrylamide (AA) have been the focus of attention in recent years, due to the numerous adverse health effects associated with their exposure. This paper summarizes the available data about the association between phthalates, BPA and AA exposure and diabetes. Although their mechanism of action has not been fully clarified, in vitro, in vivo and epidemiological studies have made significant progress toward identifying the potential roles of phthalates, BPA and AA in diabetes development and progression. These chemicals interfere with multiple signaling pathways involved in glucose and lipid homeostasis and can aggravate the symptoms of diabetes. Especially concerning are the effects of exposure during early stages and the gestational period. Well-designed prospective studies are needed in order to better establish prevention strategies against the harmful effects of these food contaminants.
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Affiliation(s)
- Maja Milanović
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad 21000, Serbia
| | - Nataša Milošević
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad 21000, Serbia
| | - Nataša Milić
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad 21000, Serbia
| | - Milica Medić Stojanoska
- Faculty of Medicine, Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Center of Vojvodina, University of Novi Sad, Novi Sad 21000, Serbia
| | - Edward Petri
- Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Novi Sad 21000, Serbia
| | - Jelena Marković Filipović
- Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Novi Sad 21000, Serbia
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15
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Martínez-Pinna J, Sempere-Navarro R, Medina-Gali RM, Fuentes E, Quesada I, Sargis RM, Trasande L, Nadal A. Endocrine disruptors in plastics alter β-cell physiology and increase the risk of diabetes mellitus. Am J Physiol Endocrinol Metab 2023; 324:E488-E505. [PMID: 37134142 PMCID: PMC10228669 DOI: 10.1152/ajpendo.00068.2023] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/27/2023] [Accepted: 04/28/2023] [Indexed: 05/05/2023]
Abstract
Plastic pollution breaks a planetary boundary threatening wildlife and humans through its physical and chemical effects. Of the latter, the release of endocrine disrupting chemicals (EDCs) has consequences on the prevalence of human diseases related to the endocrine system. Bisphenols (BPs) and phthalates are two groups of EDCs commonly found in plastics that migrate into the environment and make low-dose human exposure ubiquitous. Here we review epidemiological, animal, and cellular studies linking exposure to BPs and phthalates to altered glucose regulation, with emphasis on the role of pancreatic β-cells. Epidemiological studies indicate that exposure to BPs and phthalates is associated with diabetes mellitus. Studies in animal models indicate that treatment with doses within the range of human exposure decreases insulin sensitivity and glucose tolerance, induces dyslipidemia, and modifies functional β-cell mass and serum levels of insulin, leptin, and adiponectin. These studies reveal that disruption of β-cell physiology by EDCs plays a key role in impairing glucose homeostasis by altering the mechanisms used by β-cells to adapt to metabolic stress such as chronic nutrient excess. Studies at the cellular level demonstrate that BPs and phthalates modify the same biochemical pathways involved in adaptation to chronic excess fuel. These include changes in insulin biosynthesis and secretion, electrical activity, expression of key genes, and mitochondrial function. The data summarized here indicate that BPs and phthalates are important risk factors for diabetes mellitus and support a global effort to decrease plastic pollution and human exposure to EDCs.
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Affiliation(s)
- Juan Martínez-Pinna
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Elche, Spain
- Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain
| | - Roberto Sempere-Navarro
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Elche, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Regla M Medina-Gali
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Elche, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Esther Fuentes
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Elche, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Ivan Quesada
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Elche, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Robert M Sargis
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Leonardo Trasande
- Department of Pediatrics, New York University Grossman School of Medicine, New York, New York, United States
- Department of Population Health, New York University Grossman School of Medicine, New York, New York, United States
- Wagner School of Public Service, New York University, New York, New York, United States
| | - Angel Nadal
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Elche, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
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16
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Liu J, Lin Y, Peng C, Jiang C, Li J, Wang W, Luo S, Fu P, Lin Z, Liang Y, Shen H, Lin Y, Wei J. Bisphenol F induced hyperglycemia via activation of oxidative stress-responsive miR-200 family in the pancreas. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 255:114769. [PMID: 36924560 DOI: 10.1016/j.ecoenv.2023.114769] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 03/06/2023] [Accepted: 03/09/2023] [Indexed: 06/18/2023]
Abstract
Bisphenol F (BPF), BPS and BPAF are gaining popularity as main substitutes to BPA, but there is no clear evidence that these compounds disrupt glycemic homeostasis in the same way. In this study, four bisphenols were administered to C57BL/6 J mice, and showed that the serum insulin was elevated in the BPA and BPS exposed mice, whereas BPF exposed mice exhibited lower serum insulin and higher blood glucose. BPF decreased oxidized glutathione/reduced glutathione ratio (GSSG/GSH) and N6-methyladenosine (m6A) levels, which was responsible for pancreatic apoptosis in mice. Additionally, the downregulation of Nrf2 and the aberrant regulation of the p53-lncRNA H19 signaling pathway further increased miR-200 family in the BPF-exposed pancreas. The miR-200 family directly suppressed Mettl14 and Xiap by targeting their 3' UTR, leading to islet apoptosis. Antioxidant treatment not only elevated m6A levels and insulin contents but also suppressed the miR-200 family in the pancreas, ultimately improving BPF-induced hyperglycemia. Taken together, miR-200 family could serve as a potential oxidative stress-responsive regulator in the pancreas. And moreover, we demonstrated a novel toxicological mechanism in that BPF disrupted the Keap1-Nrf2 redox system to upregulate miR-141/200b/c which controlled pancreatic insulin production and apoptosis via Mettl14 and Xiap, respectively. As the major surrogates of BPA in various applications, BPF was also diabetogenic, which warrants attention in future research.
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Affiliation(s)
- Jintao Liu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Yilong Lin
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Cai Peng
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Chunyang Jiang
- Department of Thoracic Surgery, Tianjin Union Medical Center, Nankai University, 190 Jieyuan Road, Hongqiao District, Tianjin 300121, China
| | - Juan Li
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Wenyu Wang
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Shuyue Luo
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Pengbin Fu
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Zhenxin Lin
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China
| | - Yujie Liang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Heqing Shen
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
| | - Yi Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
| | - Jie Wei
- Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen 361102, China.
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17
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Kowalczyk M, Piwowarski JP, Wardaszka A, Średnicka P, Wójcicki M, Juszczuk-Kubiak E. Application of In Vitro Models for Studying the Mechanisms Underlying the Obesogenic Action of Endocrine-Disrupting Chemicals (EDCs) as Food Contaminants-A Review. Int J Mol Sci 2023; 24:ijms24021083. [PMID: 36674599 PMCID: PMC9866663 DOI: 10.3390/ijms24021083] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 12/29/2022] [Accepted: 01/04/2023] [Indexed: 01/09/2023] Open
Abstract
Obesogenic endocrine-disrupting chemicals (EDCs) belong to the group of environmental contaminants, which can adversely affect human health. A growing body of evidence supports that chronic exposure to EDCs can contribute to a rapid increase in obesity among adults and children, especially in wealthy industrialized countries with a high production of widely used industrial chemicals such as plasticizers (bisphenols and phthalates), parabens, flame retardants, and pesticides. The main source of human exposure to obesogenic EDCs is through diet, particularly with the consumption of contaminated food such as meat, fish, fruit, vegetables, milk, and dairy products. EDCs can promote obesity by stimulating adipo- and lipogenesis of target cells such as adipocytes and hepatocytes, disrupting glucose metabolism and insulin secretion, and impacting hormonal appetite/satiety regulation. In vitro models still play an essential role in investigating potential environmental obesogens. The review aimed to provide information on currently available two-dimensional (2D) in vitro animal and human cell models applied for studying the mechanisms of obesogenic action of various industrial chemicals such as food contaminants. The advantages and limitations of in vitro models representing the crucial endocrine tissue (adipose tissue) and organs (liver and pancreas) involved in the etiology of obesity and metabolic diseases, which are applied to evaluate the effects of obesogenic EDCs and their disruption activity, were thoroughly and critically discussed.
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Affiliation(s)
- Monika Kowalczyk
- Laboratory of Biotechnology and Molecular Engineering, Department of Microbiology, Prof. Wacław Dąbrowski Institute of Agricultural and Food Biotechnology—State Research Institute, 02-532 Warsaw, Poland
| | - Jakub P. Piwowarski
- Microbiota Lab, Department of Pharmacognosy and Molecular Basis of Phytotherapy, Medical University of Warsaw, 02-097 Warsaw, Poland
- Correspondence: (J.P.P.); (E.J.-K.)
| | - Artur Wardaszka
- Laboratory of Biotechnology and Molecular Engineering, Department of Microbiology, Prof. Wacław Dąbrowski Institute of Agricultural and Food Biotechnology—State Research Institute, 02-532 Warsaw, Poland
| | - Paulina Średnicka
- Laboratory of Biotechnology and Molecular Engineering, Department of Microbiology, Prof. Wacław Dąbrowski Institute of Agricultural and Food Biotechnology—State Research Institute, 02-532 Warsaw, Poland
| | - Michał Wójcicki
- Laboratory of Biotechnology and Molecular Engineering, Department of Microbiology, Prof. Wacław Dąbrowski Institute of Agricultural and Food Biotechnology—State Research Institute, 02-532 Warsaw, Poland
| | - Edyta Juszczuk-Kubiak
- Laboratory of Biotechnology and Molecular Engineering, Department of Microbiology, Prof. Wacław Dąbrowski Institute of Agricultural and Food Biotechnology—State Research Institute, 02-532 Warsaw, Poland
- Correspondence: (J.P.P.); (E.J.-K.)
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18
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Yang R, Zheng J, Qin J, Liu S, Liu X, Gu Y, Yang S, Du J, Li S, Chen B, Dong R. Dibutyl phthalate affects insulin synthesis and secretion by regulating the mitochondrial apoptotic pathway and oxidative stress in rat insulinoma cells. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 249:114396. [PMID: 36508788 DOI: 10.1016/j.ecoenv.2022.114396] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 12/02/2022] [Accepted: 12/05/2022] [Indexed: 06/17/2023]
Abstract
Dibutyl phthalate (DBP) is a typical phthalate (PAEs). The environmental health risks of DBP have gradually attracted attention due to the common use in the production of plastics, cosmetics and skin care products. DBP was associated with diabetes, but its mechanism is not clear. In this study, an in vitro culture system of rat insulinoma (INS-1) cells was established to explore the effect of DBP on insulin synthesis and secretion and the potential mechanisms. INS-1 cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum and treated with 15, 30, 60 and 120 μmol/L of DBP and dimethyl sulfoxide (vehicle, < 0.1%) for 24 h. The contents of insulin in the intracellular fluid and the extracellular fluid of the cells were measured. The results showed that insulin synthesis and secretion in INS-1 cells were significantly decreased in 120 μmol/L DBP group. The apoptosis rate and mitochondrial membrane potential of INS-1 cells were measured by flow cytometry with annexin V-FITC conjugate and PI, and JC-1, respectively. The results showed that DBP caused an increase in the apoptosis rate and a significant decrease in the mitochondrial membrane potential in INS-1 cells in 60 μmol/L and 120 μmol/L DBP group. The results of western blot showed that the expression of Bax/Bcl-2, caspase-3, caspase-9 and Cyt-C were significantly increased. Meanwhile, the level of oxidative stress in INS-1 cells was detected by fluorescent probes DCFH-DA and western blot. With the increase of DBP exposure, the oxidative stress levels (MDA, GSH/GSSG) were increased; and the antioxidant index (SOD) levels were decreased. Our experimental results provide reliable evidence that DBP induced apoptosis and functional impairment in INS-1 cells through the mitochondrial apoptotic pathway and oxidative stress. Therefore, we hypothesized that interference with these two pathways could be considered in the development of preventive protection measures.
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Affiliation(s)
- Ruoru Yang
- School of Public Health, Institute of Nutrition, Key Lab of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China.
| | | | - Jin Qin
- Affiliated cancer hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450003, China.
| | - Shaojie Liu
- School of Public Health, Institute of Nutrition, Key Lab of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China.
| | - Xinyuan Liu
- School of Public Health, Institute of Nutrition, Key Lab of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China.
| | - Yiying Gu
- School of Public Health, Institute of Nutrition, Key Lab of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China.
| | - Shuyu Yang
- Nutrilite Health Institute, Shanghai 200023, China.
| | - Jun Du
- Nutrilite Health Institute, Shanghai 200023, China.
| | - Shuguang Li
- School of Public Health, Institute of Nutrition, Key Lab of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China.
| | - Bo Chen
- School of Public Health, Institute of Nutrition, Key Lab of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China.
| | - Ruihua Dong
- School of Public Health, Institute of Nutrition, Key Lab of Public Health Safety of the Ministry of Education, Fudan University, Shanghai 200032, China.
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19
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Amin MAS, Sonpol HMA, Gouda RHE, Aboregela AM. Bisphenol A enhances apoptosis, fibrosis, and biochemical fluctuations in the liver of adult male rats with possible regression after recovery. Anat Rec (Hoboken) 2023; 306:213-225. [PMID: 35773941 DOI: 10.1002/ar.25032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 06/12/2022] [Accepted: 06/17/2022] [Indexed: 01/29/2023]
Abstract
Bisphenol A (BPA) is an environmental contaminant that might be harmful. Human exposure to BPA can occur during the fetal and postnatal periods and extends throughout life. This study aimed to estimate the effects of oral administration of BPA on rat liver and assess the possibility of recovery after cessation. Adult male albino rats were orally administered with BPA (50 mg/kg body weight) for 8 weeks, and then one group was left to recover for 4 weeks. Histological, immunohistochemical, biochemical, and quantitative real-time polymerase chain reaction assessments were performed. Loss of hepatic architecture, vascular dilatation congestion, and exudation, as well as cellular vacuolation, fat accumulation, and pyknotic nuclei were detected. Furthermore, inflammatory infiltration, localized metaplasia, and excessive collagen deposition in the portal triad were observed. Expression of Bcl-2-associated X protein and transforming growth factor beta 1 was prominent, denoting apoptosis and fibrosis. After the administration of BPA, serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, cholesterol, triglycerides, and low-density lipoproteins were enhanced. Additionally, total protein, albumin, and high-density lipoproteins decreased. After a recovery for 4 weeks, hepatic cellular and vascular pathologies returned to normal, except for some inflammatory infiltration. Regarding biochemical affection, most of the parameters were directed toward normal during recovery. However, most of them were still significantly different from controls. This explored BPA hepatotoxicity from structural and functional aspects, and the possible spontaneous reversibility was confirmed. However, the precise mechanisms underlying hepatotoxicity or recovery need more in-depth investigations.
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Affiliation(s)
| | - Hany M A Sonpol
- Human Anatomy and Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.,Basic Medical Sciences Department, College of Medicine, University of Bisha, Bisha, Kingdom of Saudi Arabia
| | - Rehab Hassan Elbanna Gouda
- Medical Biochemistry Unit, Zagazig Scientific and Medical Research Center, Zagazig University, Zagazig, Egypt
| | - Adel Mohamed Aboregela
- Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.,Basic Medical Sciences Department, College of Medicine, University of Bisha, Bisha, Kingdom of Saudi Arabia
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20
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Screening of Metabolism-Disrupting Chemicals on Pancreatic α-Cells Using In Vitro Methods. Int J Mol Sci 2022; 24:ijms24010231. [PMID: 36613676 PMCID: PMC9820113 DOI: 10.3390/ijms24010231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/07/2022] [Accepted: 12/20/2022] [Indexed: 12/25/2022] Open
Abstract
Metabolism-disrupting chemicals (MDCs) are endocrine disruptors with obesogenic and/or diabetogenic action. There is mounting evidence linking exposure to MDCs to increased susceptibility to diabetes. Despite the important role of glucagon in glucose homeostasis, there is little information on the effects of MDCs on α-cells. Furthermore, there are no methods to identify and test MDCs with the potential to alter α-cell viability and function. Here, we used the mouse α-cell line αTC1-9 to evaluate the effects of MDCs on cell viability and glucagon secretion. We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 µM): bisphenol-A (BPA), tributyltin (TBT), perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS), and dichlorodiphenyldichloroethylene (DDE). Using two different approaches, MTT assay and DNA-binding dyes, we observed that BPA and TBT decreased α-cell viability via a mechanism that depends on the activation of estrogen receptors and PPARγ, respectively. These two chemicals induced ROS production, but barely altered the expression of endoplasmic reticulum (ER) stress markers. Although PFOA, TPP, TCS, and DDE did not alter cell viability nor induced ROS generation or ER stress, all four compounds negatively affected glucagon secretion. Our findings suggest that αTC1-9 cells seem to be an appropriate model to test chemicals with metabolism-disrupting activity and that the improvement of the test methods proposed herein could be incorporated into protocols for the screening of diabetogenic MDCs.
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21
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Nayak D, Adiga D, Khan NG, Rai PS, Dsouza HS, Chakrabarty S, Gassman NR, Kabekkodu SP. Impact of Bisphenol A on Structure and Function of Mitochondria: A Critical Review. REVIEWS OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY 2022; 260:10. [DOI: 10.1007/s44169-022-00011-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 10/26/2022] [Indexed: 04/02/2024]
Abstract
AbstractBisphenol A (BPA) is an industrial chemical used extensively to manufacture polycarbonate plastics and epoxy resins. Because of its estrogen-mimicking properties, BPA acts as an endocrine-disrupting chemical. It has gained attention due to its high chances of daily and constant human exposure, bioaccumulation, and the ability to cause cellular toxicities and diseases at extremely low doses. Several elegant studies have shown that BPA can exert cellular toxicities by interfering with the structure and function of mitochondria, leading to mitochondrial dysfunction. Exposure to BPA results in oxidative stress and alterations in mitochondrial DNA (mtDNA), mitochondrial biogenesis, bioenergetics, mitochondrial membrane potential (MMP) decline, mitophagy, and apoptosis. Accumulation of reactive oxygen species (ROS) in conjunction with oxidative damage may be responsible for causing BPA-mediated cellular toxicity. Thus, several reports have suggested using antioxidant treatment to mitigate the toxicological effects of BPA. The present literature review emphasizes the adverse effects of BPA on mitochondria, with a comprehensive note on the molecular aspects of the structural and functional alterations in mitochondria in response to BPA exposure. The review also confers the possible approaches to alleviate BPA-mediated oxidative damage and the existing knowledge gaps in this emerging area of research.
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22
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In vitro biochemical assessment of mixture effects of two endocrine disruptors on INS-1 cells. Sci Rep 2022; 12:20102. [PMID: 36418342 PMCID: PMC9684134 DOI: 10.1038/s41598-022-20655-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 09/16/2022] [Indexed: 11/24/2022] Open
Abstract
4-tert-Octylphenol (4-tOP) is a component of non-ionic surfactants alkylphenol polyethoxylates while triclosan (TCS) is an antibacterial present in personal care products. Both compounds can co-exist in environmental matrices such as soil and water. The mixture effects of these micropollutants in vitro remains unknown. INS-1 cells were exposed to 20 µM or 30 µM 4-tOP and 8 µM or 12.5 µM TCS as well as equimolar mixture of the chemicals (Mix) in total concentration of 12.5 µM or 25 µM for 48 h. Mitochondrial related parameters were investigated using high content analytical techniques. The cytotoxicity of the chemicals (IC50) varied according to TCS > Mix > 4-tOP. Increased glucose uptake and loss of mitochondrial membrane potential were recorded in TCS and Mix treated cells. Fold values of glucose-galactose assay varied according to dinitrophenol > TCS > 4-tOP > Mix in decreasing order of mitochondrial toxicity. The loss of the intracellular Ca2+ influx by all the test substances and Mix was not substantial whereas glibenclamide and diazoxide increased the intracellular Ca2+ influx when compared with the Blank. The recorded increase in Ca2+ influx by diazoxide which contrasted with its primary role of inhibiting insulin secretion need be re-investigated. It is concluded that the toxic effects of TCS and Mix but not 4-tOP on INS-1 cells was mitochondria-mediated.
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23
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Kurşunoğlu NE, Sarer Yurekli BP. Endocrine disruptor chemicals as obesogen and diabetogen: Clinical and mechanistic evidence. World J Clin Cases 2022; 10:11226-11239. [PMID: 36387809 PMCID: PMC9649566 DOI: 10.12998/wjcc.v10.i31.11226] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/19/2022] [Accepted: 09/27/2022] [Indexed: 02/05/2023] Open
Abstract
Obesity is becoming an inevitable pandemic all over the world. The World Obesity Federation predicts in the 2022 World Obesity Atlas that one billion people worldwide, including 1 in 5 women and 1 in 7 men, will be living with obesity by 2030. Moreover, the prevalence of diabetes is increasing worldwide, and diabetes is becoming more of a public health problem. Increased insulin resistance due to obesity and deficiency in insulin secretion are the two main causes of type 2 diabetes mellitus (T2DM). An exogenous chemical or mixture of chemicals that interferes with any aspect of hormone action was defined as endocrine-disrupting chemicals (EDCs). Bisphenol A (BPA), the first known EDC, was synthesized and was considered to be estrogenic. Global production of BPA has increased progressively from 5 to 8 million tons (MT) between 2010 and 2016. Furthermore, researchers estimated that the production should reach 10.2 MT by 2022. The human population is exposed to EDCs in daily life in such forms as pesticides/herbicides, industrial and household products, plastics, detergents, and personal care products. The term obesogen was used for chemicals that promote weight gain and obesity by increasing the number of adipocytes and fat storage in existing adipocytes, changing the energy balance, and finally regulating appetite and satiety. Besides the obesogenic effect, EDCs can cause T2DM through alteration in ß cell function and morphology and insulin resistance. In this review, we provide clinical and mechanistic evidence regarding EDCs as obesogen and diabetogen. However, those studies are not enough methodologically to indicate causality. In this respect, randomized clinical trials are needed to investigate the association between obesogen, diabetogen and the related metabolic clinical picture.
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24
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Kourmaeva E, Sabry R, Favetta LA. Bisphenols A and F, but not S, induce apoptosis in bovine granulosa cells via the intrinsic mitochondrial pathway. Front Endocrinol (Lausanne) 2022; 13:1028438. [PMID: 36387888 PMCID: PMC9650025 DOI: 10.3389/fendo.2022.1028438] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/13/2022] [Indexed: 11/13/2022] Open
Abstract
With the gradual decline in global fertility rates, there is a need to identify potential contributing factors, their mechanisms of actions and investigate possible solutions to reverse the trend. Endocrine disrupting compounds (EDCs), such as bisphenol A (BPA), are environmental toxicants that are known to negatively impact reproductive functions. As such, the use of BPA in the manufacturing industry has slowly been replaced by analogs, including bisphenol S (BPS) and bisphenol F (BPF), despite limited knowledge available regarding their impact on health and their safety. The following study investigates the effects of BPA, BPS and BPF at a concentration of 0.5 μg/mL and 50 μg/mL on bovine granulosa cell apoptosis, with the ultimate goal of determining how they may impact oocyte competence and, thus, overall fertility. The underlying hypothesis is that bisphenols disrupt the granulosa cell environment surrounding the oocyte inducing excessive apoptosis via the intrinsic mitochondrial pathway. To test this hypothesis, apoptosis was measured following a time- and dose-dependent exposure to all three bisphenols by flowcytometry paired with annexin V/PI staining as well as by quantification of key genes belonging to the intrinsic apoptotic pathway both at the mRNA and protein levels. The results of this study report that BPA and BPF reduce cell viability through reduced cell counts and increased apoptosis. This increase is due, in part, to the induction of apoptotic genes of the intrinsic pathway of apoptosis. Additionally, this study also suggests that BPS may not act on the intrinsic mitochondrial apoptotic pathway in bovine granulosa cells. Overall, this study allows us to establish potential apoptotic pathways activated by bisphenols as well as compare the relative apoptotic activities of BPA to its most widespread analogs.
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Affiliation(s)
| | | | - Laura A. Favetta
- Reproductive Health and Biotechnology Laboratory, Department of Biomedical Science, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada
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25
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Morimoto S, Solís‐Lemus E, Jiménez‐Vivanco J, Castellanos‐Ruiz D, Díaz‐Díaz E, Mendoza‐Rodríguez CA. Maternal perinatal exposure to bisphenol S induces an estrogenic like effect in glucose homeostasis in male offspring. ENVIRONMENTAL TOXICOLOGY 2022; 37:2189-2200. [PMID: 35596937 PMCID: PMC9543293 DOI: 10.1002/tox.23585] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/28/2022] [Accepted: 05/06/2022] [Indexed: 05/27/2023]
Abstract
Bisphenol S (BPS) has been introduced into the industry as a safer alternative to bisphenol A (BPA). However, the recent studies have reported a possible association between BPS and disturbed glucose homeostasis, indicating that it may be a risk factor for type 1 and type 2 diabetes mellitus, obesity, and gestational diabetes mellitus. Nevertheless, the role of BPS in glucose metabolism remains controversial. In this study, we investigated the glucose metabolism of male Wistar rats born from dams that were BPS-exposed (groups: BPS-L (0.05 mg/kg/day), BPS-H (20 mg/kg/day)) during pregnancy and lactation. We observed that both BPS treated groups of animals presented a significant decrease in anogenital distance/weight1/3 , as compared to control animals, although no alterations in testosterone levels were observed. Furthermore, the BPS-L group presented a significant decrease in body weight from postnatal day (PND) 21 to adult stage. In addition, a significant increase in glucose tolerance, pancreatic β-cell proliferation, the frequency of small islets, and the average β-cell size at PND 36 was observed in this group. However, no changes in insulin serum levels and percentage of β-cells were recorded. Furthermore, these changes were not preserved at the adult stage (PND 120). The results suggest that the administration of low doses of BPS during the perinatal period induced an estrogenic like effect, with males apparently becoming more female-like in their responses to a glucose challenge.
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Affiliation(s)
- Sumiko Morimoto
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránCiudad de MéxicoMexico
| | - Edgar Solís‐Lemus
- Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de MéxicoCiudad de MéxicoMexico
| | - Jesica Jiménez‐Vivanco
- Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de MéxicoCiudad de MéxicoMexico
| | - Dafne Castellanos‐Ruiz
- Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de MéxicoCiudad de MéxicoMexico
| | - Eulises Díaz‐Díaz
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránCiudad de MéxicoMexico
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26
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Adverse Effects of Bisphenol A on the Liver and Its Underlying Mechanisms: Evidence from In Vivo and In Vitro Studies. BIOMED RESEARCH INTERNATIONAL 2022; 2022:8227314. [PMID: 36017387 PMCID: PMC9398799 DOI: 10.1155/2022/8227314] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 07/06/2022] [Accepted: 07/28/2022] [Indexed: 11/17/2022]
Abstract
BPA is a known endocrine-disrupting agent that is capable of binding to the estrogen receptor and has exhibited adverse effects in many laboratory animal and in vitro studies. Moreover, it also been shown to have estrogenic, antiandrogenic, inflammatory, and oxidative properties. The widespread presence of BPA in the environment presents a considerable threat to humans. BPA has been shown to be leached into the human ecosystem, where it is commonly found in food products consumed by humans. Although the concentration is relatively low, its prolonged consumption may cause a variety of deleterious health effects. The liver is an important organ for metabolizing and detoxifying toxic metabolites to protect organisms from potentially toxic chemical insults. BPA that is ingested will be eliminated by the liver. However, it has also induced hepatoxicity and injury via various mechanisms. To find research demonstrating the effects of BPA on kidney, a number of databases, including Google Scholar, MEDLINE, PubMed, and the Directory of Open Access Journals, were searched. Thus, this review summarizes the research on the relationship between BPA and its effects on the liver-derived from animals and cellular studies. The underlying mechanism of liver injury caused by BPA is also elucidated.
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27
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Ferreira Azevedo L, Masiero MM, Cherkaoui S, Hornos Carneiro MF, Barbosa F, Zamboni N. The alternative analog plasticizer BPS displays similar phenotypic and metabolomic responses to BPA in HepG2 and INS-1E cells. Food Chem Toxicol 2022; 167:113266. [PMID: 35779701 DOI: 10.1016/j.fct.2022.113266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/30/2022] [Accepted: 06/24/2022] [Indexed: 10/17/2022]
Abstract
Bisphenols A (BPA) and S (BPS) are endocrine-disrupting chemicals that affect energy metabolism, leading to impairment of glucose and lipid homeostasis. We aimed at identifying metabolic pathways regulated by both compounds in human liver cells and rat pancreatic β-cells that could impair energy homeostasis regulation. We assessed the effects on growth, proliferation, and viability of hepatocarcinoma (HepG2) and insulinoma (INS-1E) cells exposed to either BPA or BPS in a full range concentration between 0.001 and 100 μM. Both the dose and duration of exposure caused a differential response on growth and viability of both cells. Effects were more pronounced on HepG2, as these cells exhibited non-linear dose-responses following exposure to xenobiotics. For INS-1E, effect was observed only at the highest concentration. In addition, we profiled their intracellular state by untargeted metabolomics at 24, 48, and 72 h of exposure. This analysis revealed time- and dose-dependently molecular changes for HepG2 and INS-1E that were similar between BPA and BPS. Both increased levels of inflammatory mediators, such as metabolites pertaining to linolenic and linoleic acid metabolic pathway. In summary, this study shows that BPS also disrupts molecular functions in cells that regulate energy homeostasis, displaying similar but less pronounced responses than BPA.
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Affiliation(s)
- L Ferreira Azevedo
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. Café s/n, 14040-903, Ribeirão Preto, SP, Brazil; Institute of Molecular Systems Biology, ETH Zürich, Otto-Stern-Weg 3, 8093, Zürich, Switzerland.
| | - Mauro Miguel Masiero
- Institute of Molecular Systems Biology, ETH Zürich, Otto-Stern-Weg 3, 8093, Zürich, Switzerland; PhD Program in Systems Biology, Life Science Zürich, 8057, Zürich, Switzerland.
| | - S Cherkaoui
- Institute of Molecular Systems Biology, ETH Zürich, Otto-Stern-Weg 3, 8093, Zürich, Switzerland; PhD Program in Systems Biology, Life Science Zürich, 8057, Zürich, Switzerland; Division of Metabolism, University Children's Hospital Zürich and Children's Research Center, University of Zürich, Switzerland; Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Center, Université Paris-Saclay, INSERM U1015, Villejuif, France.
| | - M F Hornos Carneiro
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. Café s/n, 14040-903, Ribeirão Preto, SP, Brazil; Department of Pharmacy, Faculty of Chemistry and Pharmacy, Pontificia Universidad Católica de Chile, Santiago, 7820436, Chile.
| | - F Barbosa
- Department of Clinical Analyses, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. Café s/n, 14040-903, Ribeirão Preto, SP, Brazil.
| | - N Zamboni
- Institute of Molecular Systems Biology, ETH Zürich, Otto-Stern-Weg 3, 8093, Zürich, Switzerland.
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28
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Babiloni-Chust I, Dos Santos RS, Medina-Gali RM, Perez-Serna AA, Encinar JA, Martinez-Pinna J, Gustafsson JA, Marroqui L, Nadal A. G protein-coupled estrogen receptor activation by bisphenol-A disrupts the protection from apoptosis conferred by the estrogen receptors ERα and ERβ in pancreatic beta cells. ENVIRONMENT INTERNATIONAL 2022; 164:107250. [PMID: 35461094 DOI: 10.1016/j.envint.2022.107250] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/12/2022] [Accepted: 04/15/2022] [Indexed: 06/14/2023]
Abstract
17β-estradiol protects pancreatic β-cells from apoptosis via the estrogen receptors ERα, ERβ and GPER. Conversely, the endocrine disruptor bisphenol-A (BPA), which exerts multiple effects in this cell type via the same estrogen receptors, increased basal apoptosis. The molecular-initiated events that trigger these opposite actions have yet to be identified. We demonstrated that combined genetic downregulation and pharmacological blockade of each estrogen receptor increased apoptosis to a different extent. The increase in apoptosis induced by BPA was diminished by the pharmacological blockade or the genetic silencing of GPER, and it was partially reproduced by the GPER agonist G1. BPA and G1-induced apoptosis were abolished upon pharmacological inhibition, silencing of ERα and ERβ, or in dispersed islet cells from ERβ knockout (BERKO) mice. However, the ERα and ERβ agonists PPT and DPN, respectively, had no effect on beta cell viability. To exert their biological actions, ERα and ERβ form homodimers and heterodimers. Molecular dynamics simulations together with proximity ligand assays and coimmunoprecipitation experiments indicated that the interaction of BPA with ERα and ERβ as well as GPER activation by G1 decreased ERαβ heterodimers. We propose that ERαβ heterodimers play an antiapoptotic role in beta cells and that BPA- and G1-induced decreases in ERαβ heterodimers lead to beta cell apoptosis. Unveiling how different estrogenic chemicals affect the crosstalk among estrogen receptors should help to identify diabetogenic endocrine disruptors.
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Affiliation(s)
- Ignacio Babiloni-Chust
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Elche, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Reinaldo S Dos Santos
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Elche, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Regla M Medina-Gali
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Elche, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Atenea A Perez-Serna
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Elche, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - José-Antonio Encinar
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Elche, Spain
| | - Juan Martinez-Pinna
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Elche, Spain; Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Alicante, Spain
| | - Jan-Ake Gustafsson
- Department of Cell Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA; Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
| | - Laura Marroqui
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Elche, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain
| | - Angel Nadal
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, Elche, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Spain.
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29
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Anastasiou IA, Eleftheriadou I, Tentolouris A, Sarantis P, Angelopoulou A, Katsaouni A, Mourouzis I, Karamouzis MV, Gorgoulis V, Pantos C, Tentolouris N. Low concentrations of bisphenol A promote the activation of the mitochondrial apoptotic pathway on Beta-TC-6 cells via the generation of intracellular reactive oxygen species and mitochondrial superoxide. J Biochem Mol Toxicol 2022; 36:e23099. [PMID: 35593412 DOI: 10.1002/jbt.23099] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 04/03/2022] [Accepted: 05/11/2022] [Indexed: 11/10/2022]
Abstract
Τhe natural history of type 2 diabetes mellitus is characterized by a progressive loss of pancreatic beta cell function and insulin resistance. Bisphenol A (BPA) is an endocrine-disrupting chemical that is used widely in industry; people are exposed to BPA and its products daily. Studies have delineated that BPA alters the function of pancreatic beta cells. Herein, we examined the effect of low doses of BPA on pancreatic beta cell viability and apoptosis and we tried to elucidate the mechanisms involved in these processes. Beta-TC-6 (ATCC® CRL-11506™) cells were cultured with a medium containing the following dilutions of BPA: 0.002, 0.02, 0.1, 0.2, 2 μΜ up to 72 h. We examined the viability and adenosine triphosphate (ATP) levels of cells. Then, we measured apoptosis, cell cycle, and insulin levels. We quantified the levels of proteins implicated in the mitochondrial pathway of apoptosis; and finally, we quantified the intracellular reactive oxygen species and mitochondrial superoxide. We found that the exposure of Beta-TC-6 cells to BPA results in a decrease in cell viability, ATP levels, and an increase in insulin levels. We found an increase in apoptosis levels and a decrease in cell cycle levels. In addition, we provide evidence of the levels of apoptotic proteins. Finally, we found an increase in the cellular reactive oxygen species and mitochondrial superoxide production. Exposure to low concentrations of BPA triggers the mitochondrial pathway of apoptosis via the generation of intracellular reactive oxygen species and mitochondrial superoxide on Beta-TC-6 cells in a dose-dependent way.
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Affiliation(s)
- Ioanna A Anastasiou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Ioanna Eleftheriadou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Anastasios Tentolouris
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Andriani Angelopoulou
- Laboratory of Histology-Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanasia Katsaouni
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Iordanis Mourouzis
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Michalis V Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Vasilios Gorgoulis
- Laboratory of Histology-Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Constantinos Pantos
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolaos Tentolouris
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
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30
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Dos Santos RS, Medina-Gali RM, Babiloni-Chust I, Marroqui L, Nadal A. In Vitro Assays to Identify Metabolism-Disrupting Chemicals with Diabetogenic Activity in a Human Pancreatic β-Cell Model. Int J Mol Sci 2022; 23:ijms23095040. [PMID: 35563431 PMCID: PMC9102687 DOI: 10.3390/ijms23095040] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/21/2022] [Accepted: 04/29/2022] [Indexed: 11/22/2022] Open
Abstract
There is a need to develop identification tests for Metabolism Disrupting Chemicals (MDCs) with diabetogenic activity. Here we used the human EndoC-βH1 β-cell line, the rat β-cell line INS-1E and dispersed mouse islet cells to assess the effects of endocrine disruptors on cell viability and glucose-stimulated insulin secretion (GSIS). We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 µM). Bisphenol-A (BPA) and tributyltin (TBT) were used as controls while four other chemicals, namely perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS) and dichlorodiphenyldichloroethylene (DDE), were used as “unknowns”. Regarding cell viability, BPA and TBT increased cell death as previously observed. Their mode of action involved the activation of estrogen receptors and PPARγ, respectively. ROS production was a consistent key event in BPA-and TBT-treated cells. None of the other MDCs tested modified viability or ROS production. Concerning GSIS, TBT increased insulin secretion while BPA produced no effects. PFOA decreased GSIS, suggesting that this chemical could be a “new” diabetogenic agent. Our results indicate that the EndoC-βH1 cell line is a suitable human β-cell model for testing diabetogenic MDCs. Optimization of the test methods proposed here could be incorporated into a set of protocols for the identification of MDCs.
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Affiliation(s)
- Reinaldo Sousa Dos Santos
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, 03202 Elche, Spain; (R.S.D.S.); (R.M.M.-G.); (I.B.-C.); (L.M.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Regla María Medina-Gali
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, 03202 Elche, Spain; (R.S.D.S.); (R.M.M.-G.); (I.B.-C.); (L.M.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Ignacio Babiloni-Chust
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, 03202 Elche, Spain; (R.S.D.S.); (R.M.M.-G.); (I.B.-C.); (L.M.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Laura Marroqui
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, 03202 Elche, Spain; (R.S.D.S.); (R.M.M.-G.); (I.B.-C.); (L.M.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Angel Nadal
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández de Elche, 03202 Elche, Spain; (R.S.D.S.); (R.M.M.-G.); (I.B.-C.); (L.M.)
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Correspondence:
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Al-Abdulla R, Ferrero H, Soriano S, Boronat-Belda T, Alonso-Magdalena P. Screening of Relevant Metabolism-Disrupting Chemicals on Pancreatic β-Cells: Evaluation of Murine and Human In Vitro Models. Int J Mol Sci 2022; 23:ijms23084182. [PMID: 35457000 PMCID: PMC9025712 DOI: 10.3390/ijms23084182] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/05/2022] [Accepted: 04/07/2022] [Indexed: 02/01/2023] Open
Abstract
Endocrine-disrupting chemicals (EDCs) are chemical substances that can interfere with the normal function of the endocrine system. EDCs are ubiquitous and can be found in a variety of consumer products such as food packaging materials, personal care and household products, plastic additives, and flame retardants. Over the last decade, the impact of EDCs on human health has been widely acknowledged as they have been associated with different endocrine diseases. Among them, a subset called metabolism-disrupting chemicals (MDCs) is able to promote metabolic changes that can lead to the development of metabolic disorders such as diabetes, obesity, hepatic steatosis, and metabolic syndrome, among others. Despite this, today, there are still no definitive and standardized in vitro tools to support the metabolic risk assessment of existing and emerging MDCs for regulatory purposes. Here, we evaluated the following two different pancreatic cell-based in vitro systems: the murine pancreatic β-cell line MIN6 as well as the human pancreatic β-cell line EndoC-βH1. Both were challenged with the following range of relevant concentrations of seven well-known EDCs: (bisphenol-A (BPA), bisphenol-S (BPS), bisphenol-F (BPF), perfluorooctanesulfonic acid (PFOS), di(2-ethylhexyl) phthalate (DEHP), cadmium chloride (CdCl2), and dichlorodiphenyldichloroethylene (DDE)). The screening revealed that most of the tested chemicals have detectable, deleterious effects on glucose-stimulated insulin release, insulin content, electrical activity, gene expression, and/or viability. Our data provide new molecular information on the direct effects of the selected chemicals on key aspects of pancreatic β-cell function, such as the stimulus-secretion coupling and ion channel activity. In addition, we found that, in general, the sensitivity and responses were comparable to those from other in vivo studies reported in the literature. Overall, our results suggest that both systems can serve as effective tools for the rapid screening of potential MDC effects on pancreatic β-cell physiology as well as for deciphering and better understanding the molecular mechanisms that underlie their action.
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Affiliation(s)
- Ruba Al-Abdulla
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, 03202 Elche, Spain; (R.A.-A.); (H.F.); (S.S.); (T.B.-B.)
| | - Hilda Ferrero
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, 03202 Elche, Spain; (R.A.-A.); (H.F.); (S.S.); (T.B.-B.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
| | - Sergi Soriano
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, 03202 Elche, Spain; (R.A.-A.); (H.F.); (S.S.); (T.B.-B.)
- Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, 03690 Alicante, Spain
| | - Talía Boronat-Belda
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, 03202 Elche, Spain; (R.A.-A.); (H.F.); (S.S.); (T.B.-B.)
| | - Paloma Alonso-Magdalena
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, 03202 Elche, Spain; (R.A.-A.); (H.F.); (S.S.); (T.B.-B.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), 28029 Madrid, Spain
- Correspondence:
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Tian M, Xia P, Gou X, Yan L, Yu H, Zhang X. CRISPR screen identified that UGT1A9 was required for bisphenols-induced mitochondria dyshomeostasis. ENVIRONMENTAL RESEARCH 2022; 205:112427. [PMID: 34861229 DOI: 10.1016/j.envres.2021.112427] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 11/07/2021] [Accepted: 11/20/2021] [Indexed: 06/13/2023]
Abstract
Exposure to bisphenols chemicals could cause various adverse health effects, including non-alcoholic fatty liver disease (NAFLD), which have been associated with cellular mitochondria stress. However, the biological mechanism underlying the mitochondria stress-mediated cell death by bisphenols was poorly understood. Here, CRISPR screens were performed to identify the critical genes which were involved in cell death caused by exposure to four bisphenols (BPA, BPB, BPE and BPS). Results of CRISPR screens showed that UGT1A9 was the primary genetic factor facilitating cell death induced by all of the four bisphenols. Systematic toxicological tests demonstrated that UGT1A9 was required for BPA-induced mitochondria dyshomeostasis in vitro and in vivo, and UGT1A9-mediated mitochondria dyshomeostasis was an important cause of facilitating cell death. Liver injury caused by exposure to BPA in wild-type mice was accompanied with suppression of mitophagy and increased expression of C-Caspase 3, but UGT1A9 knockout attenuated these adverse effects induced by BPA. Finally, molecular epidemiology analysis suggested that the five genetic variants of UGT1A9 could be potential genetic risk factors of NAFLD when people were exposed to BPA. The biological mechanism uncovered here provided mechanistic evidence for identification of susceptible populations of liver injury associated with exposure to BPA.
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Affiliation(s)
- Mingming Tian
- State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, People's Republic of China
| | - Pu Xia
- State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, People's Republic of China
| | - Xiao Gou
- State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, People's Republic of China
| | - Lu Yan
- State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, People's Republic of China
| | - Hongxia Yu
- State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, People's Republic of China
| | - Xiaowei Zhang
- State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, People's Republic of China.
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Singh RD, Koshta K, Tiwari R, Khan H, Sharma V, Srivastava V. Developmental Exposure to Endocrine Disrupting Chemicals and Its Impact on Cardio-Metabolic-Renal Health. FRONTIERS IN TOXICOLOGY 2022; 3:663372. [PMID: 35295127 PMCID: PMC8915840 DOI: 10.3389/ftox.2021.663372] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 05/10/2021] [Indexed: 01/12/2023] Open
Abstract
Developmental origin of health and disease postulates that the footprints of early life exposure are followed as an endowment of risk for adult diseases. Epidemiological and experimental evidence suggest that an adverse fetal environment can affect the health of offspring throughout their lifetime. Exposure to endocrine disrupting chemicals (EDCs) during fetal development can affect the hormone system homeostasis, resulting in a broad spectrum of adverse health outcomes. In the present review, we have described the effect of prenatal EDCs exposure on cardio-metabolic-renal health, using the available epidemiological and experimental evidence. We also discuss the potential mechanisms of their action, which include epigenetic changes, hormonal imprinting, loss of energy homeostasis, and metabolic perturbations. The effect of prenatal EDCs exposure on cardio-metabolic-renal health, which is a complex condition of an altered biological landscape, can be further examined in the case of other environmental stressors with a similar mode of action.
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Affiliation(s)
- Radha Dutt Singh
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - Kavita Koshta
- Systems Toxicology and Health Risk Assessment Group, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research, Lucknow, India.,Academy of Scientific and Innovative Research, New Delhi, India
| | - Ratnakar Tiwari
- Feinberg Cardiovascular and Renal Research Institute, Feinberg School of Medicine, Northwestern University Chicago, Chicago, IL, United States
| | - Hafizurrahman Khan
- Systems Toxicology and Health Risk Assessment Group, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research, Lucknow, India
| | - Vineeta Sharma
- Systems Toxicology and Health Risk Assessment Group, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research, Lucknow, India
| | - Vikas Srivastava
- Systems Toxicology and Health Risk Assessment Group, Council of Scientific and Industrial Research-Indian Institute of Toxicology Research, Lucknow, India.,Academy of Scientific and Innovative Research, New Delhi, India
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Martyniuk CJ, Martínez R, Navarro-Martín L, Kamstra JH, Schwendt A, Reynaud S, Chalifour L. Emerging concepts and opportunities for endocrine disruptor screening of the non-EATS modalities. ENVIRONMENTAL RESEARCH 2022; 204:111904. [PMID: 34418449 PMCID: PMC8669078 DOI: 10.1016/j.envres.2021.111904] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/22/2021] [Accepted: 08/16/2021] [Indexed: 05/15/2023]
Abstract
Endocrine disrupting chemicals (EDCs) are ubiquitous in the environment and involve diverse chemical-receptor interactions that can perturb hormone signaling. The Organization for Economic Co-operation and Development has validated several EDC-receptor bioassays to detect endocrine active chemicals and has established guidelines for regulatory testing of EDCs. Focus on testing over the past decade has been initially directed to EATS modalities (estrogen, androgen, thyroid, and steroidogenesis) and validated tests for chemicals that exert effects through non-EATS modalities are less established. Due to recognition that EDCs are vast in their mechanisms of action, novel bioassays are needed to capture the full scope of activity. Here, we highlight the need for validated assays that detect non-EATS modalities and discuss major international efforts underway to develop such tools for regulatory purposes, focusing on non-EATS modalities of high concern (i.e., retinoic acid, aryl hydrocarbon receptor, peroxisome proliferator-activated receptor, and glucocorticoid signaling). Two case studies are presented with strong evidence amongst animals and human studies for non-EATS disruption and associations with wildlife and human disease. This includes metabolic syndrome and insulin signaling (case study 1) and chemicals that impact the cardiovascular system (case study 2). This is relevant as obesity and cardiovascular disease represent two of the most significant health-related crises of our time. Lastly, emerging topics related to EDCs are discussed, including recognition of crosstalk between the EATS and non-EATS axis, complex mixtures containing a variety of EDCs, adverse outcome pathways for chemicals acting through non-EATS mechanisms, and novel models for testing chemicals. Recommendations and considerations for evaluating non-EATS modalities are proposed. Moving forward, improved understanding of the non-EATS modalities will lead to integrated testing strategies that can be used in regulatory bodies to protect environmental, animal, and human health from harmful environmental chemicals.
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Affiliation(s)
- Christopher J Martyniuk
- Department of Physiological Sciences and Center for Environmental and Human Toxicology, College of Veterinary Medicine, University of Florida, Gainesville, FL, 32611, USA.
| | - Rubén Martínez
- Institute of Environmental Assessment and Water Research, IDAEA-CSIC, Barcelona, Catalunya, 08034, Spain
| | - Laia Navarro-Martín
- Institute of Environmental Assessment and Water Research, IDAEA-CSIC, Barcelona, Catalunya, 08034, Spain
| | - Jorke H Kamstra
- Institute for Risk Assessment Sciences, Department of Population Health Sciences, Faculty of Veterinary Medicine, Utrecht University, the Netherlands
| | - Adam Schwendt
- Division of Experimental Medicine, School of Medicine, Faculty of Medicine and Biomedical Sciences, McGill University, 850 Sherbrooke Street, Montréal, Québec, H3A 1A2, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin Cote Ste Catherine, Montréal, Québec, H3T 1E2, Canada
| | - Stéphane Reynaud
- Univ. Grenoble-Alpes, Univ. Savoie Mont Blanc, CNRS, LECA, 38000, Grenoble, France
| | - Lorraine Chalifour
- Division of Experimental Medicine, School of Medicine, Faculty of Medicine and Biomedical Sciences, McGill University, 850 Sherbrooke Street, Montréal, Québec, H3A 1A2, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin Cote Ste Catherine, Montréal, Québec, H3T 1E2, Canada
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Chiang YW, Su CH, Sun HY, Chen SP, Chen CJ, Chen WY, Chang CC, Chen CM, Kuan YH. Bisphenol A induced apoptosis via oxidative stress generation involved Nrf2/HO-1 pathway and mitochondrial dependent pathways in human retinal pigment epithelium (ARPE-19) cells. ENVIRONMENTAL TOXICOLOGY 2022; 37:131-141. [PMID: 34664771 DOI: 10.1002/tox.23384] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 09/23/2021] [Accepted: 10/03/2021] [Indexed: 05/21/2023]
Abstract
Bisphenol A (BPA) is an estrogen-like compound, and an environmental hormone, that is commonly used in daily life. Therefore, it may enter the human body through food or direct contact, causing BPA residues in blood and urine. Because most studies focused on the analysis of BPA in reproductive cells or tissues, regarding evidence the effect of BPA on human retinal pigment epithelium (ARPE-19) cells unavailable. Accordingly, the present study explored the cytotoxicity of BPA on ARPE-19 cells. After BPA treatment, the expression of Bcl-XL an antiapoptotic protein, in the mitochondria decreased, and the expression of Bax, a proapoptotic protein increased. Then the mitochondrial membrane potential was affected. BPA changed in mitochondrial membrane potential led to the release of cytochrome C, which activated caspase-9 to promote downstream caspase-3 leading to cytotoxicity. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) pathway play a major role in age-related macular degeneration. Our results showed that expression of HO-1 and Nrf2 suppressed by BPA. Superoxide dismutase and catalase, which Nrf2 downstream antioxidants, were degraded by BPA. AMP-activated kinase (AMPK), which can regulate the phosphorylation of Nrf2, and the phosphorylation of AMPK expression was reduced by BPA. Finally, BPA-induced ROS generation and cytotoxicity were reduced by N-acetyl-l-cysteine. Taken together, these results suggest that BPA induced ARPE-19 cells via oxidative stress, which was associated with down regulated Nrf2/HO-1 pathway, and the mitochondria dependent apoptotic signaling pathway.
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Affiliation(s)
- Yun-Wei Chiang
- Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan
- Department of Optometry, Central Taiwan University of Science and Technology, Taichung, Taiwan
| | - Chun-Hung Su
- Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
- Department of Internal Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Han-Yin Sun
- Department of Optometry, Chung Shan Medical University, Taichung, Taiwan
- Department of Ophthalmology, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Shih-Pin Chen
- Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
- Department of Internal Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Chun-Jung Chen
- Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Wen-Ying Chen
- Department of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Chia-Che Chang
- Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
- Department of Biotechnology, Asia University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, Taichung, Taiwan
- Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Chuan-Mu Chen
- Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan
| | - Yu-Hsiang Kuan
- Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung, Taiwan
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Yahia D, Hamdy H, Salem DA, Afifi S. Effects of bisphenol A on pancreas and thyroid gland of young and adult female Sprague Dawlеy rats. BULGARIAN JOURNAL OF VETERINARY MEDICINE 2022. [DOI: 10.15547/bjvm.2020-0102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Bisphenol A (BPA), a chemical involved in formation of plastic vessels, is one of the most widespread endocrine disrupting chemicals. The study was designed to investigate the effect of BPA on pancreas and thyroid gland of young and adult female Sprague Dawley rats. The rats were exposed to 330 mg/kg BPA orally every other day for 12 weeks; control rats were exposed orally to ethyl alcohol and corn oil. Samples were collected at 4, 8 and 12 weeks for hormonal, biochemical assays and histopathological examination. The insulin hormone in exposed young rats was decreased, but its level in adult ones was increased; the biochemical assay for blood sugar level showed a significant increase in young rats and decrease in adult ones. T3 hormone was increased in treated young and adult rats; T4 hormone was increased in treated adults, while calcium level was decreased in treated adult rats. The histopathological findings of pancreas revealed vacuolation in its endocrine parts in young rats, while in adult ones there was intralobular fatty infiltration - a typical picture of diabetes. The thyroid gland in treated young female rats showed increased cellularity of parafollicular cells; moreover there was parafollicular haemorrhage, and in adult ones - desquamation in lining epithelium of follicular cells. In conclusion, exposure of young and adult female rats to BPA resulted in changes in the pancreatic and thyroid gland cells manifested by morphological, hormonal and biochemical parameters.
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Affiliation(s)
- D. Yahia
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt
| | - H. Hamdy
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, New Valley University, New Valley, Egypt
| | - D. A. Salem
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt
| | - S. Afifi
- Department of Pathology and Clinical Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt
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Wang J, Guo Y, Geng X, Hu J, Yan M, Sun Y, Zhang K, Qu L, Li Z. Quantitative Structure-Activity Relationship Enables the Rational Design of Lipid Droplet-Targeting Carbon Dots for Visualizing Bisphenol A-Induced Nonalcoholic Fatty Liver Disease-like Changes. ACS APPLIED MATERIALS & INTERFACES 2021; 13:44086-44095. [PMID: 34516075 DOI: 10.1021/acsami.1c13157] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Lipid droplets (LDs) play indispensable roles in numerous physiological processes; hence, the visualization of the dynamic behavior of LDs in living cells is of great importance in physiological and pathological research. In this article, the quantitative structure-activity relationship (QSAR) theory was employed as an effective design strategy for the development of organelle-targeting carbon dots (CDs). The lipid-water partition coefficient (Log P) of the QSAR was adopted as a key parameter to predict the cellular uptake and subcellular localization of CDs in live cells. By carefully adjusting the molecular structure and lipophilicity of the precursors, p-phenylenediamine-derivatized nucleolus-targeting hydrophilic CDs were converted to lipophilic CDs [4-piperidinoaniline (PA) CDs] with inherent LD-targeting performance. The PA CDs were able to indicate the dynamic behavior of LDs and visualize the changes of bisphenol A-induced nonalcoholic fatty liver disease-like changes in a cellular model. The QSAR strategy of CDs demonstrated here is expected to be increasingly exploited as a powerful design tool for developing various organelle-targeting CDs.
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Affiliation(s)
- Junli Wang
- College of Chemistry, Green Catalysis Center, Henan Joint International Research Laboratory of Green Construction of Functional Molecules and Their Bioanalytical Applications, Zhengzhou Key Laboratory of Functional Nanomaterial and Medical Theranostic, Zhengzhou University, Zhengzhou 450001, China
| | - Yifei Guo
- College of Chemistry, Green Catalysis Center, Henan Joint International Research Laboratory of Green Construction of Functional Molecules and Their Bioanalytical Applications, Zhengzhou Key Laboratory of Functional Nanomaterial and Medical Theranostic, Zhengzhou University, Zhengzhou 450001, China
| | - Xin Geng
- College of Chemistry, Green Catalysis Center, Henan Joint International Research Laboratory of Green Construction of Functional Molecules and Their Bioanalytical Applications, Zhengzhou Key Laboratory of Functional Nanomaterial and Medical Theranostic, Zhengzhou University, Zhengzhou 450001, China
| | - Jingyu Hu
- College of Chemistry, Green Catalysis Center, Henan Joint International Research Laboratory of Green Construction of Functional Molecules and Their Bioanalytical Applications, Zhengzhou Key Laboratory of Functional Nanomaterial and Medical Theranostic, Zhengzhou University, Zhengzhou 450001, China
| | - Minmin Yan
- College of Chemistry, Green Catalysis Center, Henan Joint International Research Laboratory of Green Construction of Functional Molecules and Their Bioanalytical Applications, Zhengzhou Key Laboratory of Functional Nanomaterial and Medical Theranostic, Zhengzhou University, Zhengzhou 450001, China
| | - Yuanqiang Sun
- College of Chemistry, Green Catalysis Center, Henan Joint International Research Laboratory of Green Construction of Functional Molecules and Their Bioanalytical Applications, Zhengzhou Key Laboratory of Functional Nanomaterial and Medical Theranostic, Zhengzhou University, Zhengzhou 450001, China
| | - Ke Zhang
- Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States
| | - Lingbo Qu
- College of Chemistry, Green Catalysis Center, Henan Joint International Research Laboratory of Green Construction of Functional Molecules and Their Bioanalytical Applications, Zhengzhou Key Laboratory of Functional Nanomaterial and Medical Theranostic, Zhengzhou University, Zhengzhou 450001, China
| | - Zhaohui Li
- College of Chemistry, Green Catalysis Center, Henan Joint International Research Laboratory of Green Construction of Functional Molecules and Their Bioanalytical Applications, Zhengzhou Key Laboratory of Functional Nanomaterial and Medical Theranostic, Zhengzhou University, Zhengzhou 450001, China
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Ge Y, Ren F, Chen L, Hu D, Wang X, Cui Y, Suo Y, Zhang H, He J, Yin Z, Ning H. Bisphenol A exposure induces apoptosis and impairs early embryonic development in Xenopus laevis. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2021; 280:116901. [PMID: 33773307 DOI: 10.1016/j.envpol.2021.116901] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 02/28/2021] [Accepted: 03/06/2021] [Indexed: 06/12/2023]
Abstract
Bisphenol A (BPA), an endocrine-disrupting chemical that is largely produced and used in the plastics industry, causes environmental pollution and is absorbed by humans through consumption of food and liquids in polycarbonate containers. BPA exerts developmental and genetic toxicities to embryos and offsprings, but the embryotoxicity mechanism of this chemical is unclear. This study aimed to explore the toxic effect of BPA on embryonic development and elucidate its toxicity mechanism. Embryos of Xenopus laevis as a model were treated with different concentrations (0.1, 1, 10, and 20 μM) of BPA at the two-cell stage to investigate the developmental toxicity of BPA. Embryonic development and behaviors were monitored 24 h-96 h of BPA exposure. BPA concentrations greater than 1 μM exerted significant teratogenic effects on the Xenopus embryos, which showed short tail axis, miscoiled guts, and bent notochord as the main malformations. The 20 μM BPA-treated embryos were seriously damaged in all aspects and exhibited deformity, impaired behavioral ability, and tissue damage. The DNA integrity and apoptosis of the Xenopus embryos were also investigated. Exposure to BPA concentrations higher than 0.1 μM significantly induced DNA damage (p < 0.05). The 10 and 20 μM BPA-treated embryos exhibited higher levels of cleaved caspase-3 protein than the control. The ratios of bax/bcl-2 mRNA were significantly higher in the 10 μM and 20 μM-treated embryos than the ratio in the control group. Overall, data indicated that BPA can delay the early development, induce DNA damage and apoptosis, and eventually cause multiple malformations in Xenopus embryos.
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Affiliation(s)
- Yaming Ge
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, 453003, China
| | - Fei Ren
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, 453003, China; College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Lingli Chen
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, 453003, China
| | - Dongfang Hu
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, 453003, China
| | - Xinrui Wang
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, 453003, China
| | - Yunli Cui
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, 453003, China
| | - Yu Suo
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, 453003, China
| | - Hongli Zhang
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, 453003, China
| | - Junping He
- College of Animal Science and Veterinary Medicine, Shanxi Agricultural University, Taigu, Shanxi, 030801, China
| | - Zhihong Yin
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, 453003, China
| | - Hongmei Ning
- College of Animal Science and Veterinary Medicine, Henan Institute of Science and Technology, Xinxiang, Henan, 453003, China.
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Schulz MC, Sargis RM. Inappropriately sweet: Environmental endocrine-disrupting chemicals and the diabetes pandemic. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2021; 92:419-456. [PMID: 34452693 DOI: 10.1016/bs.apha.2021.04.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Afflicting hundreds of millions of individuals globally, diabetes mellitus is a chronic disorder of energy metabolism characterized by hyperglycemia and other metabolic derangements that result in significant individual morbidity and mortality as well as substantial healthcare costs. Importantly, the impact of diabetes in the United States is not uniform across the population; rather, communities of color and those with low income are disproportionately affected. While excessive caloric intake, physical inactivity, and genetic susceptibility are undoubted contributors to diabetes risk, these factors alone fail to fully explain the rapid global rise in diabetes rates. Recently, environmental contaminants acting as endocrine-disrupting chemicals (EDCs) have been implicated in the pathogenesis of diabetes. Indeed, burgeoning data from cell-based, animal, population, and even clinical studies now indicate that a variety of structurally distinct EDCs of both natural and synthetic origin have the capacity to alter insulin secretion and action as well as global glucose homeostasis. This chapter reviews the evidence linking EDCs to diabetes risk across this spectrum of evidence. It is hoped that improving our understanding of the environmental drivers of diabetes development will illuminate novel individual-level and policy interventions to mitigate the impact of this devastating condition on vulnerable communities and the population at large.
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Affiliation(s)
- Margaret C Schulz
- School of Public Health, University of Illinois at Chicago, Chicago, IL, United States; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL, United States
| | - Robert M Sargis
- School of Public Health, University of Illinois at Chicago, Chicago, IL, United States; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL, United States; Jesse Brown Veterans Affairs Medical Center, Chicago, IL, United States.
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Baralić K, Živančević K, Jorgovanović D, Javorac D, Radovanović J, Gojković T, Buha Djordjevic A, Ćurčić M, Mandinić Z, Bulat Z, Antonijević B, Đukić-Ćosić D. Probiotic reduced the impact of phthalates and bisphenol A mixture on type 2 diabetes mellitus development: Merging bioinformatics with in vivo analysis. Food Chem Toxicol 2021; 154:112325. [PMID: 34097988 DOI: 10.1016/j.fct.2021.112325] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/28/2021] [Accepted: 06/03/2021] [Indexed: 12/18/2022]
Abstract
Linkage between bis(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and bisphenol A (BPA) co-exposure and type 2 diabetes mellitus (T2DM), as well as ability of multi-strained probiotic to reduce DEHP, DBP and BPA mixture-induced oxidative damage in rat pancreas were investigated. The Comparative Toxicogenomics Database, Cytoscape software and ToppGene Suite were used for data-mining. Animals were sorted into seven groups (n = 6): (1) Control group: corn oil, (2) P: probiotic: Saccharomyces boulardii + Lactobacillus rhamnosus + Lactobacillus plantarum LP 6595 + Lactobacillus plantarum HEAL9; (3) DEHP: 50 mg/kg b.w./day, (4) DBP: 50 mg/kg b.w./day, (5) BPA: 25 mg/kg b.w./day, and (6) MIX: 50 mg/kg b.w./day DEHP + 50 mg/kg b.w/day DBP + 25 mg/kg b.w./day BPA; (7) MIX + P. Rats were sacrificed after 28 days of oral exposure. In silico investigation highlighted 44 DEHP, DBP and BPA mutual genes linked to the T2DM, while apoptosis and oxidative stress were highlighted as the main mechanisms of DEHP, DBP and BPA mixture-linked T2DM. In vivo experiment confirmed the presence of significant changes in redox status parameters (TOS, SOD and SH groups) only in the MIX group, indicating possible additive effects, while probiotic ameliorated mixture-induced redox status changes in rat pancreatic tissue.
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Affiliation(s)
- Katarina Baralić
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221, Belgrade, Serbia.
| | - Katarina Živančević
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221, Belgrade, Serbia
| | - Dragica Jorgovanović
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221, Belgrade, Serbia
| | - Dragana Javorac
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221, Belgrade, Serbia
| | - Jelena Radovanović
- Clinic for Paediatric and Preventive Dentistry, School of Dental Medicine, University of Belgrade, 11000, Belgrade, Serbia; Department of Radiobiology and Molecular Genetics, "Vinča" Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, 11000, Belgrade, Serbia
| | - Tamara Gojković
- Department of Medical Biochemistry, University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221, Belgrade, Serbia
| | - Aleksandra Buha Djordjevic
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221, Belgrade, Serbia
| | - Marijana Ćurčić
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221, Belgrade, Serbia
| | - Zoran Mandinić
- Clinic for Paediatric and Preventive Dentistry, School of Dental Medicine, University of Belgrade, 11000, Belgrade, Serbia
| | - Zorica Bulat
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221, Belgrade, Serbia
| | - Biljana Antonijević
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221, Belgrade, Serbia
| | - Danijela Đukić-Ćosić
- Department of Toxicology "Akademik Danilo Soldatović", University of Belgrade - Faculty of Pharmacy, Vojvode Stepe 450, 11221, Belgrade, Serbia
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Bjørklund G, Tippairote T, Dadar M, Lizcano F, Aaseth J, Borisova O. The Roles of Dietary, Nutritional and Lifestyle Interventions in Adipose Tissue Adaptation and Obesity. Curr Med Chem 2021; 28:1683-1702. [PMID: 32368968 DOI: 10.2174/0929867327666200505090449] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 03/03/2020] [Accepted: 03/28/2020] [Indexed: 11/22/2022]
Abstract
The obesity and the associated non-communicable diseases (NCDs) are globally increasing in their prevalence. While the modern-day lifestyle required less ventilation of metabolic energy through muscular activities, this lifestyle transition also provided the unlimited accession to foods around the clock, which prolong the daily eating period of foods that contained high calorie and high glycemic load. These situations promote the high continuous flux of carbon substrate availability in mitochondria and induce the indecisive bioenergetic switches. The disrupted bioenergetic milieu increases the uncoupling respiration due to the excess flow of the substrate-derived reducing equivalents and reduces ubiquinones into the respiratory chain. The diversion of the uncoupling proton gradient through adipocyte thermogenesis will then alleviate the damaging effects of free radicals to mitochondria and other organelles. The adaptive induction of white adipose tissues (WAT) to beige adipose tissues (beAT) has shown beneficial effects on glucose oxidation, ROS protection and mitochondrial function preservation through the uncoupling protein 1 (UCP1)-independent thermogenesis of beAT. However, the maladaptive stage can eventually initiate with the persistent unhealthy lifestyles. Under this metabolic gridlock, the low oxygen and pro-inflammatory environments promote the adipose breakdown with sequential metabolic dysregulation, including insulin resistance, systemic inflammation and clinical NCDs progression. It is unlikely that a single intervention can reverse all these complex interactions. A comprehensive protocol that includes dietary, nutritional and all modifiable lifestyle interventions, can be the preferable choice to decelerate, stop, or reverse the NCDs pathophysiologic processes.
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Affiliation(s)
- Geir Bjørklund
- Council for Nutritional and Environmental Medicine (CONEM), Mo i Rana, Norway
| | - Torsak Tippairote
- Doctor of Philosophy Program in Nutrition, Faculty of Medicine Ramathibodi Hospital and Institute of Nutrition, Mahidol University, Bangkok, Thailand
| | - Maryam Dadar
- Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj, Iran
| | | | - Jan Aaseth
- Research Department, Innlandet Hospital Trust, Brumunddal, Norway
| | - Olga Borisova
- Odesa I. I. Mechnikov National University, Odessa, Ukraine
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Ahmed Zaki MS, Haidara MA, Abdallaa AM, Mohammed H, Sideeg AM, Eid RA. Role of dietary selenium in alleviating bisphenol A toxicity of liver albino rats: Histological, ultrastructural, and biomarker assessments. J Food Biochem 2021; 45:e13725. [PMID: 33847390 DOI: 10.1111/jfbc.13725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/22/2021] [Accepted: 03/26/2021] [Indexed: 02/05/2023]
Abstract
Bisphenol A (BPA) is used as a plasticizer in polycarbonate plastics. It has been used in consumer products and epoxy resins for decades as protective coatings and linings for food and beverage bottles. This can trigger human reactions to BPA which interferes with estrogen receptors. Our study explored the ameliorative effects of selenium (Se) in male rats on liver damage caused by BPA. Rats were divided into four groups at random: The first one obtained olive oil and acted as a control. Se (0.5 mg/kg diet) was given for the second group. The third one was treated with BPA (10 mg/kg body weight/day) orally. Concomitantly Se (0.5 mg/kg diet) and BPA (10 mg/kg body weight/day) were given orally in the fourth one. Liver specimens were prepared for light, electron microscopes and the serum samples were screened for biochemical markers. In the BPA received group, histological findings indicated apoptotic hepatic histological changes such as sinusoidal congestion, cytoplasmic vacuolation and leukocyte infiltration. Ultrastructurally, the same group had mitochondrial degeneration, rough endoplasmic reticulum swelling, and nuclear pyknosis, as well as fat droplet deposition and lysosome enhancement. Liver enzymes: In the BPA group, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been substantially increased. Moreover, histological and ultrastructural improvements were seen in the rat population treated with BPA and Se, whereas ALT and AST levels were lowered and malondialdehyde (MDA), glutathione peroxidase (GPx), human C reactive protein (hCRP), and the serum levels of interleukin-6 (IL-6) were significantly modulated. PRACTICAL APPLICATIONS: Bisphenol A (BPA) is used in the manufacturing of polycarbonate plastic (e.g., water bottles, baby bottles) and epoxy resins (e.g., inner coating in metallic food cans). It is a non-polymer preservative for other plastics, one of the contaminants of the atmosphere and a common endocrine estrogenic disruptor. Our study explored the ameliorative effects of selenium (Se) in male rats on liver damage caused by BPA. Rats were divided into four groups at random: The first one obtained olive oil and acted as a control. Se (0.5 mg/kg diet) was given for the second group. The third one was treated with BPA (10 mg/kg body weight/day) orally. Concomitant Se (0.5 mg/kg diet) and BPA (10 mg/kg body weight/day) were given in the fourth one. Liver specimens were prepared for light, electron microscopes and the serum samples were screened for biochemical markers.
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Affiliation(s)
- Mohamed Samir Ahmed Zaki
- Anatomy Department, College of Medicine, King Khalid University, Abha, Saudi Arabia
- Histology Department, College of Medicine, Zagazig University, Zagazig, Egypt
| | - Mohamed A Haidara
- Physiology Department, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Asim M Abdallaa
- Anatomy Department, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Heitham Mohammed
- Anatomy Department, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Abulqasim M Sideeg
- Anatomy Department, College of Medicine, King Khalid University, Abha, Saudi Arabia
| | - Refaat A Eid
- Pathology Department, College of Medicine, King Khalid University, Abha, Saudi Arabia
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Huang CC, Yang CY, Su CC, Fang KM, Yen CC, Lin CT, Liu JM, Lee KI, Chen YW, Liu SH, Huang CF. 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene, a Major Active Metabolite of Bisphenol A, Triggers Pancreatic β-Cell Death via a JNK/AMPKα Activation-Regulated Endoplasmic Reticulum Stress-Mediated Apoptotic Pathway. Int J Mol Sci 2021; 22:ijms22094379. [PMID: 33922211 PMCID: PMC8122752 DOI: 10.3390/ijms22094379] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/18/2021] [Accepted: 04/20/2021] [Indexed: 11/16/2022] Open
Abstract
4-methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene (MBP), a major active metabolite of bisphenol A (BPA), is generated in the mammalian liver. Some studies have suggested that MBP exerts greater toxicity than BPA. However, the mechanism underlying MBP-induced pancreatic β-cell cytotoxicity remains largely unclear. This study demonstrated the cytotoxicity of MBP in pancreatic β-cells and elucidated the cellular mechanism involved in MBP-induced β-cell death. Our results showed that MBP exposure significantly reduced cell viability, caused insulin secretion dysfunction, and induced apoptotic events including increased caspase-3 activity and the expression of active forms of caspase-3/-7/-9 and PARP protein. In addition, MBP triggered endoplasmic reticulum (ER) stress, as indicated by the upregulation of GRP 78, CHOP, and cleaved caspase-12 proteins. Pretreatment with 4-phenylbutyric acid (4-PBA; a pharmacological inhibitor of ER stress) markedly reversed MBP-induced ER stress and apoptosis-related signals. Furthermore, exposure to MBP significantly induced the protein phosphorylation of JNK and AMP-activated protein kinase (AMPK)α. Pretreatment of β-cells with pharmacological inhibitors for JNK (SP600125) and AMPK (compound C), respectively, effectively abrogated the MBP-induced apoptosis-related signals. Both JNK and AMPK inhibitors also suppressed the MBP-induced activation of JNK and AMPKα and of each other. In conclusion, these findings suggest that MBP exposure exerts cytotoxicity on β-cells via the interdependent activation of JNK and AMPKα, which regulates the downstream apoptotic signaling pathway.
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Affiliation(s)
- Cheng-Chin Huang
- Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan; (C.-C.H.); (J.-M.L.); (K.-IL.)
| | - Ching-Yao Yang
- Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan;
| | - Chin-Chuan Su
- Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua County 500, Taiwan;
- School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Kai-Min Fang
- Department of Otolaryngology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan;
| | - Cheng-Chieh Yen
- Department of Occupational Safety and Health, College of Health Care and Management, Chung Shan Medical University, Taichung 402, Taiwan;
| | - Ching-Ting Lin
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan;
| | - Jui-Min Liu
- Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan; (C.-C.H.); (J.-M.L.); (K.-IL.)
| | - Kuan-I Lee
- Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan; (C.-C.H.); (J.-M.L.); (K.-IL.)
| | - Ya-Wen Chen
- Department of Physiology and Graduate Institute of Basic Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung 404, Taiwan;
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
- Correspondence: (S.-H.L.); (C.-F.H.)
| | - Chun-Fa Huang
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan;
- Department of Nursing, College of Medical and Health Science, Asia University, Taichung 413, Taiwan
- Correspondence: (S.-H.L.); (C.-F.H.)
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Bisphenols and the Development of Type 2 Diabetes: The Role of the Skeletal Muscle and Adipose Tissue. ENVIRONMENTS 2021. [DOI: 10.3390/environments8040035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Bisphenol A (BPA) and bisphenol S (BPS) are environmental contaminants that have been associated with the development of insulin resistance and type 2 diabetes (T2D). Two organs that are often implicated in the development of insulin resistance are the skeletal muscle and the adipose tissue, however, seldom studies have investigated the effects of bisphenols on their metabolism. In this review we discuss metabolic perturbations that occur in both the skeletal muscle and adipose tissue affected with insulin resistance, and how exposure to BPA or BPS has been linked to these changes. Furthermore, we highlight the possible effects of BPA on the cross-talk between the skeletal muscle and adipose tissue.
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Callaghan MA, Alatorre-Hinojosa S, Connors LT, Singh RD, Thompson JA. Plasticizers and Cardiovascular Health: Role of Adipose Tissue Dysfunction. Front Pharmacol 2021; 11:626448. [PMID: 33716730 PMCID: PMC7947604 DOI: 10.3389/fphar.2020.626448] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 12/22/2020] [Indexed: 12/12/2022] Open
Abstract
Since the 1950s, the production of plastics has increased 200-fold, reaching 360 million tonnes in 2019. Plasticizers, additives that modify the flexibility and rigidity of the product, are ingested as they migrate into food and beverages. Human exposure is continuous and widespread; between 75 and 97% of urine samples contain detectable levels of bisphenols and phthalates, the most common plasticizers. Concern over the toxicity of plasticizers arose in the late 1990s, largely focused around adverse developmental and reproductive effects. More recently, many studies have demonstrated that exposure to plasticizers increases the risk for obesity, type 2 diabetes, and cardiovascular disease (CVD). In the 2000s, many governments including Canada, the United States and European countries restricted the use of certain plasticizers in products targeted towards infants and children. Resultant consumer pressure motivated manufacturers to substitute plasticizers with analogues, which have been marketed as safe. However, data on the effects of these new substitutes are limited and data available to-date suggest that many exhibit similar properties to the chemicals they replaced. The adverse effects of plasticizers have largely been attributed to their endocrine disrupting properties, which modulate hormone signaling. Adipose tissue has been well-documented to be a target of the disrupting effects of both bisphenols and phthalates. Since adipose tissue function is a key determinant of cardiovascular health, adverse effects of plasticizers on adipocyte signaling and function may underlie their link to cardiovascular disease. Herein, we discuss the current evidence linking bisphenols and phthalates to obesity and CVD and consider how documented impacts of these plasticizers on adipocyte function may contribute to the development of CVD.
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Affiliation(s)
- Mikyla A Callaghan
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Libin Cardiovascular Institute, Calgary, AB, Canada
| | | | - Liam T Connors
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Libin Cardiovascular Institute, Calgary, AB, Canada
| | - Radha D Singh
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Libin Cardiovascular Institute, Calgary, AB, Canada
| | - Jennifer A Thompson
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Libin Cardiovascular Institute, Calgary, AB, Canada.,Alberta Children's Health Research Institute, Calgary, AB, Canada
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Jones J, Reneau P, Dos Santos JM. Metabolically healthy obese vs. Metabolic syndrome - The crosslink between nutritional exposure to bisphenols and physical exercise. Med Hypotheses 2021; 149:110542. [PMID: 33662862 DOI: 10.1016/j.mehy.2021.110542] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 02/14/2021] [Indexed: 12/24/2022]
Abstract
Obesity has become a worldwide pandemic as well as a major contributing factor to the increasing rate of type 2 diabetes (T2D). However, there is an intriguing variance demonstrated by a subset of obesity defined as metabolically healthy obesity (MHO). MHO individuals are less prone to develop obesity-related metabolic complications, such as metabolic syndrome (MetS) and further T2D. The exact reason why an MHO person does not present the cluster of risk factors associated with insulin resistance is unknown due to the challenge to mimic MHO in experimental settings. However, MHO individuals present lower sedentary behaviors in comparison to individuals with MetS, which might indicate that an adaptation to skeletal muscle, such as increased insulin sensitivity and glucose transporter (GLUT4), could play a major role in their healthy characteristics. The hypothesis invoked in this paper is that lower exposure to bisphenol together with increased levels of physical exercise underlie the physiological aspects behind MHO characteristics. Evidence suggests that exposure to "obseogens," such as bisphenol A (BPA), appears to impair insulin secretion and insulin response in cells containing GLUT4. Epidemiological studies have associated higher levels of BPA, as well as bisphenol S and F, in children with a risk for MetS development. Therefore, the combination between low bisphenol exposure and increased physical exercise may not necessarily affect body weight, but it could modify several metabolic pathways inhibiting insulin resistance, which characterize the heathy status of the MHO. If confirmed, this hypothesis could lead to therapeutic approaches to reverse MetS and inhibit T2D onset.
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Affiliation(s)
- Jessica Jones
- School of Education Health and Human Performance, Fairmont State University, United States
| | - Paul Reneau
- School of Education Health and Human Performance, Fairmont State University, United States
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Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel) 2021; 12:genes12020264. [PMID: 33670352 PMCID: PMC7918513 DOI: 10.3390/genes12020264] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 02/05/2021] [Accepted: 02/06/2021] [Indexed: 12/14/2022] Open
Abstract
Bisphenol A (BPA) is a xenoestrogen chemical commonly used to manufacture polycarbonate plastics and epoxy resin and might affect various human organs. However, the cellular effects of BPA on the eyes have not been widely investigated. This study aimed to investigate the cellular cytotoxicity by BPA exposure on human retinoblastoma cells. BPA did not show cytotoxic effects, such as apoptosis, alterations to cell viability and cell cycle regulation. Comparative analysis of the transcriptome and proteome profiles were investigated after long-term exposure of Y79 cells to low doses of BPA. Transcriptome analysis using RNA-seq revealed that mRNA expression of the post-transcriptional regulation-associated gene sets was significantly upregulated in the BPA-treated group. Cell cycle regulation-associated gene sets were significantly downregulated by exposure to BPA. Interestingly, RNA-seq analysis at the transcript level indicated that alternative splicing events, particularly retained introns, were noticeably altered by low-dose BPA treatment. Additionally, proteome profiling using MALDI-TOF-MS identified a total of nine differentially expressed proteins. These results suggest that alternative splicing events and altered gene/protein expression patterns are critical phenomena affected by long-term low-dose BPA exposure. This represents a novel marker for the detection of various diseases associated with environmental pollutants such as BPA.
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48
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Farrugia F, Aquilina A, Vassallo J, Pace NP. Bisphenol A and Type 2 Diabetes Mellitus: A Review of Epidemiologic, Functional, and Early Life Factors. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:E716. [PMID: 33467592 PMCID: PMC7830729 DOI: 10.3390/ijerph18020716] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/10/2021] [Accepted: 01/13/2021] [Indexed: 12/12/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance and eventual pancreatic β-cell dysfunction, resulting in persistent high blood glucose levels. Endocrine disrupting chemicals (EDCs) such as bisphenol A (BPA) are currently under scrutiny as they are implicated in the development of metabolic diseases, including T2DM. BPA is a pervasive EDC, being the main constituent of polycarbonate plastics. It can enter the human body by ingestion, through the skin, and cross from mother to offspring via the placenta or breast milk. BPA is a xenoestrogen that alters various aspects of beta cell metabolism via the modulation of oestrogen receptor signalling. In vivo and in vitro models reveal that varying concentrations of BPA disrupt glucose homeostasis and pancreatic β-cell function by altering gene expression and mitochondrial morphology. BPA also plays a role in the development of insulin resistance and has been linked to long-term adverse metabolic effects following foetal and perinatal exposure. Several epidemiological studies reveal a significant association between BPA and the development of insulin resistance and impaired glucose homeostasis, although conflicting findings driven by multiple confounding factors have been reported. In this review, the main findings of epidemiological and functional studies are summarised and compared, and their respective strengths and limitations are discussed. Further research is essential for understanding the exact mechanism of BPA action in various tissues and the extent of its effects on humans at environmentally relevant doses.
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Affiliation(s)
- Francesca Farrugia
- Department of Physiology and Biochemistry, University of Malta, MSD 2080 Msida, Malta; (F.F.); (A.A.); (J.V.)
| | - Alexia Aquilina
- Department of Physiology and Biochemistry, University of Malta, MSD 2080 Msida, Malta; (F.F.); (A.A.); (J.V.)
| | - Josanne Vassallo
- Department of Physiology and Biochemistry, University of Malta, MSD 2080 Msida, Malta; (F.F.); (A.A.); (J.V.)
- Centre for Molecular Medicine and Biobanking, University of Malta, MSD 2080 Msida, Malt
| | - Nikolai Paul Pace
- Department of Physiology and Biochemistry, University of Malta, MSD 2080 Msida, Malta; (F.F.); (A.A.); (J.V.)
- Centre for Molecular Medicine and Biobanking, University of Malta, MSD 2080 Msida, Malt
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Yao Y, Lawrence DA. Susceptibility to COVID-19 in populations with health disparities: Posited involvement of mitochondrial disorder, socioeconomic stress, and pollutants. J Biochem Mol Toxicol 2021; 35:e22626. [PMID: 32905655 PMCID: PMC9340490 DOI: 10.1002/jbt.22626] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/30/2020] [Accepted: 08/25/2020] [Indexed: 12/18/2022]
Abstract
SARS-CoV-2 is a novel betacoronavirus that has caused the global health crisis known as COVID-19. The implications of mitochondrial dysfunction with COVID-19 are discussed as well as deregulated mitochondria and inter-organelle functions as a posited comorbidity enhancing detrimental outcomes. Many environmental chemicals (ECs) and endocrine-disrupting chemicals can do damage to mitochondria and cause mitochondrial dysfunction. During infection, SARS-CoV-2 via its binding target ACE2 and TMPRSS2 can disrupt mitochondrial function. Viral genomic RNA and structural proteins may also affect the normal function of the mitochondria-endoplasmic reticulum-Golgi apparatus. Drugs considered for treatment of COVID-19 should consider effects on organelles including mitochondria functions. Mitochondrial self-balance and clearance via mitophagy are important in SARS-CoV-2 infection, which indicate monitoring and protection of mitochondria against SARS-CoV-2 are important. Mitochondrial metabolomic analysis may provide new indicators of COVID-19 prognosis. A better understanding of the role of mitochondria during SARS-CoV-2 infection may help to improve intervention therapies and better protect mitochondrial disease patients from pathogens as well as people living with poor nutrition and elevated levels of socioeconomic stress and ECs.
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Affiliation(s)
- Yunyi Yao
- Wadsworth Center, New York State Department of Health, Center for Medical Science, Albany, New York
| | - David A Lawrence
- Wadsworth Center, New York State Department of Health, Center for Medical Science, Albany, New York
- Department of Environmental Health Sciences, University at Albany School of Public Health, Rensselaer, New York
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Rezaee-Tazangi F, Zeidooni L, Rafiee Z, Fakhredini F, Kalantari H, Alidadi H, Khorsandi L. Taurine effects on Bisphenol A-induced oxidative stress in the mouse testicular mitochondria and sperm motility. JBRA Assist Reprod 2020; 24:428-435. [PMID: 32550655 PMCID: PMC7558901 DOI: 10.5935/1518-0557.20200017] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Objectives: This study was performed to investigate the protective effects of taurine (2-aminoethanesulfonic acid, TAU) on oxidative stress in the isolated mouse testicular mitochondria, mitochondrial membrane potential (MMP), viability and motility of the exposed sperms to the BPA. Methods: We treated epididymal spermatozoa obtained from mice and isolated mouse testicular mitochondria with BPA (0.8 mmol/mL) and various doses of TAU (5, 10, 30 and 50 µmol/L). We used the MTT assay and Rhodamine 123 uptake to assess sperm viability and MMP. We assessed the oxidative stress through measuring ROS (reactive oxygen species), MDA (malondialdehyde), GSH (glutathione), and SOD (super-oxide dismutase) levels in the testicular mitochondrial tissue. Results: BPA significantly elevated ROS, MDA and MMP levels, and markedly reduced SOD and GSH levels in the isolated mitochondria. BPA also considerably impaired spermatozoa viability and motility. Pretreatment with 30 and 50 µmol/L of TAU could considerably suppressed mitochondrial oxidative stress, enhanced MMP, and improved sperm motility and viability. Conclusion: TAU may attenuate the BPA-induced mitochondrial toxicity and impaired sperm motility via decreasing oxidative stress.
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Affiliation(s)
- Fatemeh Rezaee-Tazangi
- Student Research committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Leila Zeidooni
- Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Zeinab Rafiee
- Department of Anatomical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Fereshtesadat Fakhredini
- Department of Anatomical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Heybatollah Kalantari
- Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hadis Alidadi
- Toxicology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Layasadat Khorsandi
- Department of Anatomical Sciences, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.,Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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