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Morsy MM, Hassan HA, Morsi RM, Nafea OE, Farag AI, Ramadan RS. Alogliptin attenuates testicular damage induced by monosodium glutamate in both juvenile and adult male rats by activating autophagy: ROS dependent AMPK/mTOR. Reprod Toxicol 2025; 132:108826. [PMID: 39725177 DOI: 10.1016/j.reprotox.2024.108826] [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: 08/05/2024] [Revised: 12/20/2024] [Accepted: 12/20/2024] [Indexed: 12/28/2024]
Abstract
Monosodium glutamate (MSG) is one of the most commonly used food additives, known for its adverse health effects. Alogliptin (ALO) is a highly selective dipeptidyl peptidase-4 inhibitor, but its role in male reproductive function remains debated. The study was designed to evaluate and compare the potential of ALO in mitigating MSG-induced testicular toxicity in juvenile and adult male rats. Juvenile and adult male rats were treated with either MSG or pretreated with ALO before MSG administration. The rats then received ALO and MSG concurrently for 28 days. Testicular tissues were isolated and subjected to histo-biochemical and molecular assessments. Our results demonstrated that ALO reversed MSG-induced testicular injury, as evidenced by the restoration of reproductive hormone balance (increased serum luteinizing hormone and testosterone concentrations), suppression of oxidative stress injury (decreased testicular malondialdehyde, increased superoxide dismutase activity, and minimal 8-hydroxy-2'-deoxyguanosine immunoreactivity), inflammation (reduced testicular tumor necrosis factor-alpha levels), and fibrosis (decreased testicular collagen fiber deposition). Additionally, ALO impeded apoptosis and activated autophagy by decreasing caspase-3 activity, stimulating the AMPK/mTOR pathway, downregulating Bax and SQSTM-1/p62 expression, upregulating Bcl2 and Beclin 1, promoting testicular proliferation (increased number of proliferating cell nuclear antigen-positive cells in the testis), restoring glycogen content in the testis (mild to moderate periodic acid-Schiff reaction), and preserving testicular architecture. MSG induced more severe adverse testicular effects in juvenile rats, while ALO pretreatment was more protective in adult rats. ALO's anti-inflammatory, antioxidant, antiapoptotic, pro-autophagic, antifibrotic, and proliferative actions in the testis suggest its promising potential for combating male reproductive dysfunction.
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Affiliation(s)
- Manal Mohammad Morsy
- Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
| | - Heba A Hassan
- Clinical Pharmacology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt; Pharmacology Department, Faculty of Medicine, Mutah University, Mutah 61710, Jordan
| | - Reham M Morsi
- Biological Application Department, Nuclear Research Center, Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Ola Elsayed Nafea
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt.
| | - Azza I Farag
- Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt; Department of Physical Therapy, College of Applied Medical Sciences, Qassim University, P.O. Box 6666, Buraydah 51452, Saudi Arabia
| | - Rania Saad Ramadan
- Human Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt; Department of Anatomy, College of Medicine, Al-Baha University, Al-Baha 65525, Saudi Arabia
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Mogus JP, Marin M, Arowolo O, Salemme V, Suvorov A. Developmental exposures to common environmental pollutants result in long-term Reprogramming of hypothalamic-pituitary axis in mice. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 361:124890. [PMID: 39236844 DOI: 10.1016/j.envpol.2024.124890] [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: 04/08/2024] [Revised: 05/22/2024] [Accepted: 09/02/2024] [Indexed: 09/07/2024]
Abstract
Humans are exposed to a range of endocrine disrupting chemicals (EDCs). Many studies demonstrate that exposures to EDCs during critical windows of development can permanently affect endocrine health outcomes. Most experimental studies address changes in secretion of hormones produced by gonads, thyroid gland and adrenals, and little is known about the ability of EDCs to produce long-term changes in the hypothalamic-pituitary (HP) control axes. Here, we examined the long-term effects of three common EDCs on male mouse HP gene expression, following developmental exposures. Pregnant mice were exposed to 0.2 mg/ml solutions of bisphenol S (BPS), 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), or 3,3',5,5'-tetrabromobisphenol A (TBBPA) from pregnancy day 8 through lactation day 21 (weaning day). Male offspring were left untreated until postnatal day 140, where pituitaries and hypothalami were collected. Pituitaries were assed for gene expression via RNA sequencing, while specific genes were assessed for expression in hypothalami via RT-qPCR. Differential expression, as well as gene enrichment and pathway analysis, indicated that all three chemicals induced long-term changes, (mostly suppression) in pituitary genes involved in its endocrine function. BPS and BDE-47 produced effects overlapping significantly at the level of effected genes and pathways. All three chemicals altered pathways of gonad and liver HP axes, while BPS altered HP-adrenal and BDE-47 altered HP-thyroid pathways specifically. All three chemicals reduced expression of immune genes in the pituitaries. Targeted gene expression in the hypothalamus indicates down regulation of hypothalamic endocrine control genes by BPS and BDE-47 groups, concordant with changes in the pituitary, suggesting that these chemicals suppress overall HP endocrine function. Interestingly, all three chemicals altered pituitary genes of GPCR-mediated intracellular signaling molecules, key signalers common to many pituitary responses to hormones. The results of this study show that developmental exposures to common EDCs have long-term impacts on hormonal feedback control at the hypothalamic-pituitary level.
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Affiliation(s)
- Joshua P Mogus
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts - Amherst, USA
| | - Marjorie Marin
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts - Amherst, USA
| | - Olatunbosun Arowolo
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts - Amherst, USA
| | - Victoria Salemme
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts - Amherst, USA; Currently at Department of Pharmacology, Molecular, Cellular and Integrative Physiology Group, University of California - Davis, USA
| | - Alexander Suvorov
- Department of Environmental Health Sciences, School of Public Health and Health Sciences, University of Massachusetts - Amherst, USA.
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Schrenk D, Bignami M, Bodin L, Chipman JK, del Mazo J, Grasl‐Kraupp B, Hogstrand C, (Ron) Hoogenboom L, Leblanc J, Nebbia CS, Nielsen E, Ntzani E, Petersen A, Sand S, Schwerdtle T, Wallace H, Benford D, Fürst P, Hart A, Rose M, Schroeder H, Vrijheid M, Ioannidou S, Nikolič M, Bordajandi LR, Vleminckx C. Update of the risk assessment of polybrominated diphenyl ethers (PBDEs) in food. EFSA J 2024; 22:e8497. [PMID: 38269035 PMCID: PMC10807361 DOI: 10.2903/j.efsa.2024.8497] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2024] Open
Abstract
The European Commission asked EFSA to update its 2011 risk assessment on polybrominated diphenyl ethers (PBDEs) in food, focusing on 10 congeners: BDE-28, -47, -49, -99, -100, -138, -153, -154, -183 and ‑209. The CONTAM Panel concluded that the neurodevelopmental effects on behaviour and reproductive/developmental effects are the critical effects in rodent studies. For four congeners (BDE-47, -99, -153, -209) the Panel derived Reference Points, i.e. benchmark doses and corresponding lower 95% confidence limits (BMDLs), for endpoint-specific benchmark responses. Since repeated exposure to PBDEs results in accumulation of these chemicals in the body, the Panel estimated the body burden at the BMDL in rodents, and the chronic intake that would lead to the same body burden in humans. For the remaining six congeners no studies were available to identify Reference Points. The Panel concluded that there is scientific basis for inclusion of all 10 congeners in a common assessment group and performed a combined risk assessment. The Panel concluded that the combined margin of exposure (MOET) approach was the most appropriate risk metric and applied a tiered approach to the risk characterisation. Over 84,000 analytical results for the 10 congeners in food were used to estimate the exposure across dietary surveys and age groups of the European population. The most important contributors to the chronic dietary Lower Bound exposure to PBDEs were meat and meat products and fish and seafood. Taking into account the uncertainties affecting the assessment, the Panel concluded that it is likely that current dietary exposure to PBDEs in the European population raises a health concern.
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Mechanisms of Male Reproductive Toxicity of Polybrominated Diphenyl Ethers. Int J Mol Sci 2022; 23:ijms232214229. [PMID: 36430706 PMCID: PMC9693139 DOI: 10.3390/ijms232214229] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 11/08/2022] [Accepted: 11/15/2022] [Indexed: 11/19/2022] Open
Abstract
Polybrominated diphenyl ethers (PBDE) are a group of flame retardants used in a variety of artificial materials. Despite being phased out in most industrial countries, they remain in the environment and human tissues due to their persistence, lipophilicity, and bioaccumulation. Populational and experimental studies demonstrate the male reproductive toxicity of PBDEs including increased incidence of genital malformations (hypospadias and cryptorchidism), altered weight of testes and other reproductive tissues, altered testes histology and transcriptome, decreased sperm production and sperm quality, altered epigenetic regulation of developmental genes in spermatozoa, and altered secretion of reproductive hormones. A broad range of mechanistic hypotheses of PBDE reproductive toxicity has been suggested. Among these hypotheses, oxidative stress, the disruption of estrogenic signaling, and mitochondria disruption are affected by PBDE concentrations much higher than concentrations found in human tissues, making them unlikely links between exposures and adverse reproductive outcomes in the general population. Robust evidence suggests that at environmentally relevant doses, PBDEs and their metabolites may affect male reproductive health via mechanisms including AR antagonism and the disruption of a complex network of metabolic signaling.
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Zhang W, Xia S, Zhong X, Gao G, Yang J, Wang S, Cao M, Liang Z, Yang C, Wang J. Characterization of 2,2'4,4'-Tetrabromodiphenyl ether (BDE47)-induced testicular toxicity via single-cell RNA-sequencing. PRECISION CLINICAL MEDICINE 2022; 5:pbac016. [PMID: 35875604 PMCID: PMC9306015 DOI: 10.1093/pcmedi/pbac016] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/12/2022] [Indexed: 11/30/2022] Open
Abstract
Background The growing male reproductive diseases have been linked to higher exposure to certain environmental compounds such as 2,2′,4,4′-tetrabromodiphenyl ether (BDE47) that are widely distributed in the food chain. However, the specific underlying molecular mechanisms for BDE47-induced male reproductive toxicity are not completely understood. Methods Here, for the first time, advanced single-cell RNA sequencing (ScRNA-seq) was employed to dissect BDE47-induced prepubertal testicular toxicity in mice from a pool of 76 859 cells. Results Our ScRNA-seq results revealed shared and heterogeneous information of differentially expressed genes, signaling pathways, transcription factors, and ligands-receptors in major testicular cell types in mice upon BDE47 treatment. Apart from disruption of hormone homeostasis, BDE47 was discovered to downregulate multiple previously unappreciated pathways such as double-strand break repair and cytokinesis pathways, indicative of their potential roles involved in BDE47-induced testicular injury. Interestingly, transcription factors analysis of ScRNA-seq results revealed that Kdm5b (lysine-specific demethylase 5B), a key transcription factor required for spermatogenesis, was downregulated in all germ cells as well as in Sertoli and telocyte cells in BDE47-treated testes of mice, suggesting its contribution to BDE47-induced impairment of spermatogenesis. Conclusions Overall, for the first time, we established the molecular cell atlas of mice testes to define BDE47-induced prepubertal testicular toxicity using the ScRNA-seq approach, providing novel insight into our understanding of the underlying mechanisms and pathways involved in BDE47-associated testicular injury at a single-cell resolution. Our results can serve as an important resource to further dissect the potential roles of BDE47, and other relevant endocrine-disrupting chemicals, in inducing male reproductive toxicity.
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Affiliation(s)
- Wei Zhang
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology) , Shenzhen 518020 , China
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University , Guangzhou 510632 , China
| | - Siyu Xia
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology) , Shenzhen 518020 , China
- Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University , Guangzhou 510632 , China
| | - Xiaoru Zhong
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology) , Shenzhen 518020 , China
| | - Guoyong Gao
- Department of Spine Surgery, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology) , Shenzhen 518020 , China
| | - Jing Yang
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology) , Shenzhen 518020 , China
| | - Shuang Wang
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology) , Shenzhen 518020 , China
| | - Min Cao
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology) , Shenzhen 518020 , China
| | - Zhen Liang
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology) , Shenzhen 518020 , China
| | - Chuanbin Yang
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology) , Shenzhen 518020 , China
| | - Jigang Wang
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology) , Shenzhen 518020 , China
- Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences , Beijing 100700 , China
- Center for Reproductive Medicine, Dongguan Maternal and Child Health Care Hospital, Southern Medical University , Dongguan, 523125, Guangdong , China
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Hu D, Tian L, Li X, Chen Y, Xu Z, Ge RS, Wang Y. Tetramethyl bisphenol a inhibits leydig cell function in late puberty by inducing ferroptosis. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 236:113515. [PMID: 35427877 DOI: 10.1016/j.ecoenv.2022.113515] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 04/06/2022] [Accepted: 04/09/2022] [Indexed: 06/14/2023]
Abstract
Tetramethyl bisphenol A (TMBPA) is a commonly used bisphenol analog, used as a fire retardant. However, whether it inhibits the function of Leydig cells in late puberty remains unclear. In this study, 35-day-old male Sprague-Dawley rats were gavaged with 0, 10, 100, and 200 mg/kg body weight TMBPA for 21 days. TMBPA significantly reduced serum testosterone levels at 10 mg/kg and higher doses without altering serum luteinizing hormone and follicle-stimulating hormone levels. TMBPA significantly increased serum iron concentraion while reducing the ratio of serum glutathione (GSH) and GSH/GSSG (oxidized glutathione disulfide). In addition, TMBPA significantly increased testicular iron amount at 10 mg/kg and higher doses and malondialdehyde level at 200 mg/kg. TMBPA down-regulated the expression of Leydig cell genes, including Nr5a1, Star, Scarb1, Insl3, Cyp11a1, Cyp17a1, Hsd17b3, and Hsd11b1, and their proteins. In addition, TMBPA markedly down-regulated the expression of genes in the ferroptosis pathway (Tp53, Slc7a11, Sod1, Sod2, Cat, Sqstm1, Keap1, and Hmox1). TMBPA significantly reduced the levels of ferroptosis pathway proteins (TP53, SLC7A11, GPX4, SQSTM1, KEAP1, NRF2, and HMOX1) in Leydig cells in vivo. Immature and adult Leydig cell culture in vitro also showed that TMBPA significantly reduced testosterone concentrations in the medium, which can be reversed by a ferroptosis inhibitor. After 24 h of culture in primary Leydig cells at 10 and 50 μM, TMBPA significantly induced reactive oxygen species and lowered the mitochondrial membrane potential. TMBPA also altered protein levels in the ferroptosis pathway in Leydig cells in vitro. In conclusion, TMBPA directly inhibits the activity of rat Leydig cell steroidogenic enzymes and induces the ferroptosis of Leydig cells, thereby inhibiting the testosterone synthesis of Leydig cells in the late puberty.
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Affiliation(s)
- Dichao Hu
- Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Lili Tian
- Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xueyun Li
- Department of pathology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yirui Chen
- Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zheqing Xu
- Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Ren-Shan Ge
- Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
| | - Yiyan Wang
- Department of Anesthesiology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
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Research Progress of PCNA in Reproductive System Diseases. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:2391917. [PMID: 34721621 PMCID: PMC8553460 DOI: 10.1155/2021/2391917] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 09/11/2021] [Accepted: 09/24/2021] [Indexed: 11/26/2022]
Abstract
Reproductive system diseases have become a public health problem that endangers human physical and mental health. The causes of reproductive diseases are complex and diverse. From a biological point of view, abnormal cell proliferation may affect important physiological functions of reproductive organs and cause various gynecological or andrological diseases. Proliferating cell nuclear antigen (PCNA) is the most commonly used indicator for detecting cell proliferation activity. The up- or downregulation of its expression is of great significance in reproductive system diseases. This review summarizes the significance of the latest research on PCNA expression in reproductive system diseases.
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