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Ricker K, Cheng V, Hsieh CJ, Tsai FC, Osborne G, Li K, Yilmazer-Musa M, Sandy MS, Cogliano VJ, Schmitz R, Sun M. Application of the Key Characteristics of Carcinogens to Bisphenol A. Int J Toxicol 2024; 43:253-290. [PMID: 38204208 DOI: 10.1177/10915818231225161] [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] [Indexed: 01/12/2024]
Abstract
The ten key characteristics (KCs) of carcinogens are based on characteristics of known human carcinogens and encompass many types of endpoints. We propose that an objective review of the large amount of cancer mechanistic evidence for the chemical bisphenol A (BPA) can be achieved through use of these KCs. A search on metabolic and mechanistic data relevant to the carcinogenicity of BPA was conducted and web-based software tools were used to screen and organize the results. We applied the KCs to systematically identify, organize, and summarize mechanistic information for BPA, and to bring relevant carcinogenic mechanisms into focus. For some KCs with very large data sets, we utilized reviews focused on specific endpoints. Over 3000 studies for BPA from various data streams (exposed humans, animals, in vitro and cell-free systems) were identified. Mechanistic data relevant to each of the ten KCs were identified, with receptor-mediated effects, epigenetic alterations, oxidative stress, and cell proliferation being especially data rich. Reactive and bioactive metabolites are also associated with a number of KCs. This review demonstrates how the KCs can be applied to evaluate mechanistic data, especially for data-rich chemicals. While individual entities may have different approaches for the incorporation of mechanistic data in cancer hazard identification, the KCs provide a practical framework for conducting an objective examination of the available mechanistic data without a priori assumptions on mode of action. This analysis of the mechanistic data available for BPA suggests multiple and inter-connected mechanisms through which this chemical can act.
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Affiliation(s)
- Karin Ricker
- Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA, USA
| | - Vanessa Cheng
- Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA, USA
| | - Chingyi Jennifer Hsieh
- Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Sacramento, CA, USA
| | - Feng C Tsai
- Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA, USA
| | - Gwendolyn Osborne
- Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA, USA
| | - Kate Li
- Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA, USA
| | - Meltem Yilmazer-Musa
- Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA, USA
| | - Martha S Sandy
- Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA, USA
| | - Vincent J Cogliano
- Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA, USA
| | - Rose Schmitz
- Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA, USA
| | - Meng Sun
- Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Sacramento, CA, USA
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Stanic B, Kokai D, Markovic Filipovic J, Samardzija Nenadov D, Pogrmic-Majkic K, Andric N. Global gene expression analysis reveals novel transcription factors associated with long-term low-level exposure of EA.hy926 human endothelial cells to bisphenol A. Chem Biol Interact 2023:110571. [PMID: 37244401 DOI: 10.1016/j.cbi.2023.110571] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 05/11/2023] [Accepted: 05/25/2023] [Indexed: 05/29/2023]
Abstract
Bisphenol A (BPA) is an endocrine disruptor that binds to estrogen receptors (ER); however, studies have shown that the ER pathway was not always the primary molecular mechanism of BPA's action in cells and that gene transcription could be altered by different exposure times and doses. Here, we sought to understand the correlation between the BPA-responsive genes that have associated biological functions and the transcription factors (TFs) involved in their regulation by repeatedly exposing human endothelial cells EA.hy926 to three nanomolar concentrations of BPA (10-9 M, 10-8 M, and 10-7 M) for 14 weeks, after which changes in global gene expression were determined by RNA sequencing. Cytoscape plug-in iRegulon was used to infer TFs involved in the control of BPA-deregulated genes. The results show a minimal overlap in deregulated genes between three concentrations of BPA, with 10-9 M BPA having the highest number of deregulated genes. TF analysis suggests that all three concentrations of BPA were active in the absence of an ER-mediated pathway. A unique set of TFs (NES≥4) has been identified for each BPA concentration, including the NFκB family and CEBPB for 10-9 M BPA, MEF family, AHR/ARNT, and ZBTB33 for 10-8 M BPA, and IRF1-7 and OVOL1/OVOL2 for 10-7 M BPA, whereas STAT1/STAT2 were common TFs for 10-9 M and 10-7 M BPA. Overall, our data suggest that long-term low-level exposure of EA.hy926 cells to BPA leads to concentration-specific changes in gene expression that are not controlled by the ER-mediated signaling but rather by other mechanisms.
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Affiliation(s)
- Bojana Stanic
- University of Novi Sad, Faculty of Sciences, Department of Biology and Ecology, Serbia.
| | - Dunja Kokai
- University of Novi Sad, Faculty of Sciences, Department of Biology and Ecology, Serbia
| | | | | | | | - Nebojsa Andric
- University of Novi Sad, Faculty of Sciences, Department of Biology and Ecology, Serbia
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Rybczyńska-Tkaczyk K, Skóra B, Szychowski KA. Toxicity of bisphenol A (BPA) and its derivatives in divers biological models with the assessment of molecular mechanisms of toxicity. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023:10.1007/s11356-023-27747-y. [PMID: 37213006 DOI: 10.1007/s11356-023-27747-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 05/15/2023] [Indexed: 05/23/2023]
Abstract
The aim of the study was to determine totoxicity of bisphenol A (BPA) and its derivatives (bisphenol S (BPS), bisphenol F (BPF), and tetrabromobisphenol A (TBBPA)) due to its high accumulation in environment. The performed analysis revealed the toxicity of the BPA, BPF, and BPS against Kurthia gibsoni, Microbacterium sp., and Brevundimonas diminuta as the most sensitive, reaching microbial toxic concentrations in the range of 0.018-0.031 mg ∙ L-1. Moreover, the genotoxicity assay shows the ability of all tested compounds to increase in the β-galactosidase level at the concentration range 7.81-500 µM (in Escherichia coli, PQ37). In turn, the matbolic activation of tested bishpenols has caused the enhacement of the genotoxicity and cytotoxicity effect. Interestingely, the highest phytotoxicity effect was pointed for BPA and TBBPA at the concentrations of 10 mg ∙ L-1 and 50 mg ∙ L-1, which cause the inhibition of root growth by 58% and 45%, respectively (especially for S. alba and S. saccharatum). Furthermore, the cytotoxicity analyses show the ability of BPA, BPS, and TBBPA to significantly decrease the metabolic activity of human keratynoctes in vitro after 24 h of treatment at the micromolar concentrations. Simialry, the impact of the certain bisphenols on proliferation-, apoptosis-, and inflammation-related mRNA expression was shown in tested cell line. Summarizing, the presented results have proved that BPA and its derrivatives are able to show high negative effect on certain living orgnisms such as bacteria, plants, and human cells, which is strict related to pro-apoptotic and genotoxic mechanism of action.
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Affiliation(s)
- Kamila Rybczyńska-Tkaczyk
- Department of Environmental Microbiology, The University of Life Sciences, Leszczyńskiego Street 7, 20-069, Lublin, Poland
| | - Bartosz Skóra
- Department of Biotechnology and Cell Biology, Medical College, University of Information Technology and Management in Rzeszow, Sucharskiego 2, 35-225, Rzeszow, Poland
| | - Konrad A Szychowski
- Department of Biotechnology and Cell Biology, Medical College, University of Information Technology and Management in Rzeszow, Sucharskiego 2, 35-225, Rzeszow, Poland.
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EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP), Lambré C, Barat Baviera JM, Bolognesi C, Chesson A, Cocconcelli PS, Crebelli R, Gott DM, Grob K, Lampi E, Mengelers M, Mortensen A, Rivière G, Silano (until 21 December 2020†) V, Steffensen I, Tlustos C, Vernis L, Zorn H, Batke M, Bignami M, Corsini E, FitzGerald R, Gundert‐Remy U, Halldorsson T, Hart A, Ntzani E, Scanziani E, Schroeder H, Ulbrich B, Waalkens‐Berendsen D, Woelfle D, Al Harraq Z, Baert K, Carfì M, Castoldi AF, Croera C, Van Loveren H. Re-evaluation of the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs. EFSA J 2023; 21:e06857. [PMID: 37089179 PMCID: PMC10113887 DOI: 10.2903/j.efsa.2023.6857] [Citation(s) in RCA: 72] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2023] Open
Abstract
In 2015, EFSA established a temporary tolerable daily intake (t-TDI) for BPA of 4 μg/kg body weight (bw) per day. In 2016, the European Commission mandated EFSA to re-evaluate the risks to public health from the presence of BPA in foodstuffs and to establish a tolerable daily intake (TDI). For this re-evaluation, a pre-established protocol was used that had undergone public consultation. The CEP Panel concluded that it is Unlikely to Very Unlikely that BPA presents a genotoxic hazard through a direct mechanism. Taking into consideration the evidence from animal data and support from human observational studies, the immune system was identified as most sensitive to BPA exposure. An effect on Th17 cells in mice was identified as the critical effect; these cells are pivotal in cellular immune mechanisms and involved in the development of inflammatory conditions, including autoimmunity and lung inflammation. A reference point (RP) of 8.2 ng/kg bw per day, expressed as human equivalent dose, was identified for the critical effect. Uncertainty analysis assessed a probability of 57-73% that the lowest estimated Benchmark Dose (BMD) for other health effects was below the RP based on Th17 cells. In view of this, the CEP Panel judged that an additional uncertainty factor (UF) of 2 was needed for establishing the TDI. Applying an overall UF of 50 to the RP, a TDI of 0.2 ng BPA/kg bw per day was established. Comparison of this TDI with the dietary exposure estimates from the 2015 EFSA opinion showed that both the mean and the 95th percentile dietary exposures in all age groups exceeded the TDI by two to three orders of magnitude. Even considering the uncertainty in the exposure assessment, the exceedance being so large, the CEP Panel concluded that there is a health concern from dietary BPA exposure.
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Yu H, Liu Y. Impact of Extended and Combined Exposure of Bisphenol Compounds on Their Chromosome-Damaging Effect─Increased Potency and Shifted Mode of Action. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2023; 57:498-508. [PMID: 36571243 DOI: 10.1021/acs.est.2c06064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Bisphenol (BP) compounds are important environmental pollutants and endocrine disruptors. BPs are capable of inducing DNA/chromosome breaks (clastogenesis, involved in carcinogenesis), which requires activation by human CYP1A1. We hypothesized that combined BPs and extended (from the standard two-cell cycle) exposure may enhance their genotoxicity via modulating CYP enzymes. In this study, individual and combined BPA/BPF/BPS/BPAF and a human hepatoma (HepG2) cell line were used for testing several genotoxicity end points. Exposing for a two-cell cycle period (48 h), each BP alone (0.625-10 μM) was negative in the micronucleus test, while micronucleus was formed under three- (72 h) and four-cell cycle (96 h) exposure; BP combinations further elevated the potency (with nanomolar thresholds). Immunofluorescence analysis of the centromere with formed micronucleus indicated that 48 h exposure produced centromere-negative micronucleus and phosphorylated histone H2AX (γ-H2AX) (evidencing clastogenesis), while extended (72 and 96 h) exposure formed centromere-positive micronucleus and phosphorylated histone H3 (p-H3) (indicating chromosome loss, i.e., aneugenesis); moreover, 1-aminotriabenzotriazole (CYP inhibitor) selectively blocked the formation of centromere-negative micronucleus and γ-H2AX, without affecting that of centromere-positive micronucleus and p-H3. This study suggests that the genotoxicity of BPs is potentiated by combined and extended exposure, the latter being specific for aneuploidy formation, a CYP activity-independent effect.
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Affiliation(s)
- Hang Yu
- Department of Toxicology, School of Public Health (Guangdong Provincial Key Laboratory of Tropical Disease Research), Southern Medical University, 1023 S. Shatai Road, Guangzhou 510515, China
| | - Yungang Liu
- Department of Toxicology, School of Public Health (Guangdong Provincial Key Laboratory of Tropical Disease Research), Southern Medical University, 1023 S. Shatai Road, Guangzhou 510515, China
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Ďurovcová I, Kyzek S, Fabová J, Makuková J, Gálová E, Ševčovičová A. Genotoxic potential of bisphenol A: A review. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 306:119346. [PMID: 35489531 DOI: 10.1016/j.envpol.2022.119346] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 04/05/2022] [Accepted: 04/20/2022] [Indexed: 05/25/2023]
Abstract
Bisphenol A (BPA), as a major component of some plastic products, is abundant environmental pollutant. Due to its ability to bind to several types of estrogen receptors, it can trigger multiple cellular responses, which can contribute to various manifestations at the organism level. The most studied effect of BPA is endocrine disruption, but recently its prooxidative potential has been confirmed. BPA ability to induce oxidative stress through increased ROS production, altered activity of antioxidant enzymes, or accumulation of oxidation products of biomacromolecules is observed in a wide range of organisms - estrogen receptor-positive and -negative. Subsequently, increased intracellular oxidation can lead to DNA damage induction, represented by oxidative damage, single- and double-strand DNA breaks. Importantly, BPA shows several mechanisms of action and can trigger adverse effects on all organisms inhabiting a wide variety of ecosystem types. Therefore, the main aim of this review is to summarize the genotoxic effects of BPA on organisms across all taxa.
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Affiliation(s)
- Ivana Ďurovcová
- Department of Genetics, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, 842 15, Bratislava, Slovakia.
| | - Stanislav Kyzek
- Department of Genetics, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, 842 15, Bratislava, Slovakia.
| | - Jana Fabová
- Department of Genetics, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, 842 15, Bratislava, Slovakia.
| | - Jana Makuková
- Department of Genetics, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, 842 15, Bratislava, Slovakia.
| | - Eliška Gálová
- Department of Genetics, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, 842 15, Bratislava, Slovakia.
| | - Andrea Ševčovičová
- Department of Genetics, Faculty of Natural Sciences, Comenius University in Bratislava, Ilkovičova 6, 842 15, Bratislava, Slovakia.
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Endocrine-Disrupting Effects of Bisphenol A on the Cardiovascular System: A Review. J Xenobiot 2022; 12:181-213. [PMID: 35893265 PMCID: PMC9326625 DOI: 10.3390/jox12030015] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 06/10/2022] [Accepted: 07/11/2022] [Indexed: 11/21/2022] Open
Abstract
Currently, the plastic monomer and plasticizer bisphenol A (BPA) is one of the most widely used chemicals. BPA is present in polycarbonate plastics and epoxy resins, commonly used in food storage and industrial or medical products. However, the use of this synthetic compound is a growing concern, as BPA is an endocrine-disrupting compound and can bind mainly to estrogen receptors, interfering with different functions at the cardiovascular level. Several studies have investigated the disruptive effects of BPA; however, its cardiotoxicity remains unclear. Therefore, this review’s purpose is to address the most recent studies on the implications of BPA on the cardiovascular system. Our findings suggest that BPA impairs cardiac excitability through intracellular mechanisms, involving the inhibition of the main ion channels, changes in Ca2+ handling, the induction of oxidative stress, and epigenetic modifications. Our data support that BPA exposure increases the risk of developing cardiovascular diseases (CVDs) including atherosclerosis and its risk factors such as hypertension and diabetes. Furthermore, BPA exposure is also particularly harmful in pregnancy, promoting the development of hypertensive disorders during pregnancy. In summary, BPA exposure compromises human health, promoting the development and progression of CVDs and risk factors. Further studies are needed to clarify the human health effects of BPA-induced cardiotoxicity.
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Jun JH, Oh JE, Shim JK, Kwak YL, Cho JS. Effects of bisphenol A on the proliferation, migration, and tumor growth of colon cancer cells: In vitro and in vivo evaluation with mechanistic insights related to ERK and 5-HT3. Food Chem Toxicol 2021; 158:112662. [PMID: 34743013 DOI: 10.1016/j.fct.2021.112662] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/31/2021] [Accepted: 11/03/2021] [Indexed: 01/21/2023]
Abstract
Bisphenol A (BPA) is a well-known endocrine-disrupting chemical related to the carcinogenesis of estrogen-responsive organs. Although human exposure to BPA mainly occurs via the oral route, its association with colon cancer has not been fully elucidated. We investigated the effects of BPA on the proliferation, migration, and tumor growth of colon cancer cells. BPA significantly promoted the proliferation of HT-29 human colon adenocarcinoma cells in a time- and dose-dependent manner. BPA also increased HT-29 cells migration. BPA increased the phosphorylation of extracellular signal-regulated kinase (ERK), and inhibition of the ERK pathway attenuated BPA-induced proliferation and migration. In addition, BPA reduced E-cadherin expression, a key factor impeding epithelial-to-mesenchymal transition, and increased 5-HT3 receptors expression, a major mitogenic factor. In xenograft models, tumor volume of the BPA-treated nude mice was 4.6 times that of the saline-treated group. Our findings provide primary evidence regarding the link between BPA and human colon cancer by demonstrating that BPA promotes the proliferation, migration, and tumor growth of colon cancer cells in both in vitro and in vivo models. In addition, we provided the mechanism of action of BPA, involved in the activation of the ERK pathway, the decrease in E-cadherin, and the increase in 5-HT3 receptors.
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Affiliation(s)
- Ji Hae Jun
- Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ju Eun Oh
- Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae-Kwang Shim
- Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young-Lan Kwak
- Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jin Sun Cho
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Lorigo M, Cairrao E. Fetoplacental vasculature as a model to study human cardiovascular endocrine disruption. Mol Aspects Med 2021; 87:101054. [PMID: 34839931 DOI: 10.1016/j.mam.2021.101054] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 10/15/2021] [Accepted: 11/18/2021] [Indexed: 12/11/2022]
Abstract
Increasing evidence has associated the exposure of endocrine-disrupting chemicals (EDCs) with the cardiovascular (CV) system. This exposure is particularly problematic in a sensitive window of development, pregnancy. Pregnancy exposome can affect the overall health of the pregnancy by dramatic changes in vascular physiology and endocrine activity, increasing maternal susceptibility. Moreover, fetoplacental vascular function is generally altered, increasing the risk of developing pregnancy complications (including cardiovascular diseases, CVD) and predisposing the foetus to adverse health risks later in life. Thus, our review summarizes the existing literature on exposures to EDCs during pregnancy and adverse maternal health outcomes, focusing on the human placenta, vein, and umbilical artery associated with pregnancy complications. The purpose of this review is to highlight the role of fetoplacental vasculature as a model for the study of human cardiovascular endocrine disruption. Therefore, we emphasize that the placenta, together with the umbilical arteries and veins, allows a better characterization of the pregnant woman's exposome. Consequently, it contributes to the protection of the mother and foetus against CV disorders in life.
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Affiliation(s)
- Margarida Lorigo
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, 6200-506, Covilhã, Portugal; FCS - UBI, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal
| | - Elisa Cairrao
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, 6200-506, Covilhã, Portugal; FCS - UBI, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal.
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Jacenik D, Beswick EJ, Krajewska WM, Prossnitz ER. G protein-coupled estrogen receptor in colon function, immune regulation and carcinogenesis. World J Gastroenterol 2019; 25:4092-4104. [PMID: 31435166 PMCID: PMC6700692 DOI: 10.3748/wjg.v25.i30.4092] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 07/03/2019] [Accepted: 07/05/2019] [Indexed: 02/06/2023] Open
Abstract
Estrogens play important roles in the development and progression of multiple tumor types. Accumulating evidence points to the significance of estrogen action not only in tumors of hormonally regulated tissues such as the breast, endometrium and ovary, but also in the development of colorectal cancer (CRC). The effects of estrogens in physiological and pathophysiological conditions are mediated by the nuclear estrogen receptors α and β, as well as the membrane-bound G protein-coupled estrogen receptor (GPER). The roles of GPER in CRC development and progression, however, remain poorly understood. Studies on the functions of GPER in the colon have shown that this estrogen receptor regulates colonic motility as well as immune responses in CRC-associated diseases, such as Crohn’s disease and ulcerative colitis. GPER is also involved in cell cycle regulation, endoplasmic reticulum stress, proliferation, apoptosis, vascularization, cell migration, and the regulation of fatty acid and estrogen metabolism in CRC cells. Thus, multiple lines of evidence suggest that GPER may play an important role in colorectal carcinogenesis. In this review, we present the current state of knowledge regarding the contribution of GPER to colon function and CRC.
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Affiliation(s)
- Damian Jacenik
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz 90-236, Poland
- Department of Internal Medicine, School of Medicine, and UNM Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, United States
| | - Ellen J Beswick
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT 84132, United States
| | - Wanda M Krajewska
- Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz 90-236, Poland
| | - Eric R Prossnitz
- Department of Internal Medicine, School of Medicine, and UNM Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, United States
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Emfietzoglou R, Spyrou N, Mantzoros CS, Dalamaga M. Could the endocrine disruptor bisphenol-A be implicated in the pathogenesis of oral and oropharyngeal cancer? Metabolic considerations and future directions. Metabolism 2019; 91:61-69. [PMID: 30458176 DOI: 10.1016/j.metabol.2018.11.007] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 11/14/2018] [Indexed: 12/20/2022]
Abstract
Bisphenol-A (BPA), a prototype endocrine disrupting molecule, has been associated with many disease entities such as diabetes mellitus, obesity, polycystic ovarian disease, cardiovascular disease, reproductive and neurodevelopmental disorders. BPA has also been associated mainly with not only hormone sensitive cancers such as breast, prostate, endometrial, ovarian, testicular and thyroid cancers but also non-hormonal sensitive cancers such as cervical and lung cancers, osteosarcoma and meningioma. Recent research has investigated the sources of contamination which are responsible for higher BPA concentrations in the oral cavity and oropharyngeal space, representing the first site of BPA exposure after ingestion. Besides growing awareness and case registration, the incidence and prevalence of oral (OC) and oropharyngeal cancer (OPC) have increased during the last decades correlating with the increased production of BPA worldwide. So far, no study in the medical literature has explored the association of BPA with OC and OPC. BPA may be linked to the etiopathogenesis of OC and OPC through a multitude of mechanisms encompassing and interconnecting genetic, epigenetic, inflammatory, immune, metabolic, hormonal and oxidative stress alterations as well as modulation of oral microbiome. Hence, it is not possible to rule out a potential role of BPA exposure in oral and oropharyngeal tissue carcinogenesis, especially knowing its potential to participate in other non-hormonal sensitive malignancies and to deregulate signaling pathways implicated in OC and OPC. This perspective aims at outlining evidence and proposing for the first time a potential link between BPA with OC and OPC, the most frequent subtypes of head and neck malignancies.
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Affiliation(s)
- Rodopi Emfietzoglou
- School of Dentistry, National and Kapodistrian University of Athens, 2 Thivon Str, Goudi, 115 27 Athens, Greece; Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias street, 115 27 Athens, Greece
| | - Nikolaos Spyrou
- 251 Airforce General Hospital, Kanellopoulou 3, 115 25 Athens, Greece
| | - Christos S Mantzoros
- Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
| | - Maria Dalamaga
- Department of Biological Chemistry, School of Medicine, National and Kapodistrian University of Athens, 75 Mikras Asias street, 115 27 Athens, Greece.
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Ramos C, Ladeira C, Zeferino S, Dias A, Faria I, Cristovam E, Gomes M, Ribeiro E. Cytotoxic and genotoxic effects of environmental relevant concentrations of bisphenol A and interactions with doxorubicin. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2019; 838:28-36. [DOI: 10.1016/j.mrgentox.2018.11.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 11/21/2018] [Accepted: 11/26/2018] [Indexed: 02/07/2023]
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13
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Huang ZH, Li N, Rao KF, Liu CT, Huang Y, Ma M, Wang ZJ. Development of a data-processing method based on Bayesian k-means clustering to discriminate aneugens and clastogens in a high-content micronucleus assay. Hum Exp Toxicol 2017; 37:285-294. [PMID: 29233020 DOI: 10.1177/0960327117695635] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Genotoxicants can be identified as aneugens and clastogens through a micronucleus (MN) assay. The current high-content screening-based MN assays usually discriminate an aneugen from a clastogen based on only one parameter, such as the MN size, intensity, or morphology, which yields low accuracies (70-84%) because each of these parameters may contribute to the results. Therefore, the development of an algorithm that can synthesize high-dimensionality data to attain comparative results is important. To improve the automation and accuracy of detection using the current parameter-based mode of action (MoA), the MN MoA signatures of 20 chemicals were systematically recruited in this study to develop an algorithm. The results of the algorithm showed very good agreement (93.58%) between the prediction and reality, indicating that the proposed algorithm is a validated analytical platform for the rapid and objective acquisition of genotoxic MoA messages.
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Affiliation(s)
- Z H Huang
- 1 State Key Laboratory of Environmental Aquatic Chemistry, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
| | - N Li
- 2 Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
| | - K F Rao
- 2 Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
| | - C T Liu
- 3 The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Y Huang
- 4 College of Environmental Science and Engineering, Zhongkai University of Agriculture and Engineering, Guangzhou, China
| | - M Ma
- 5 College of Resources and Environment, University of Chinese Academy of Sciences, Beijing, China.,6 Key Laboratory of Drinking Water Science and Technology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
| | - Z J Wang
- 1 State Key Laboratory of Environmental Aquatic Chemistry, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China
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14
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Cuomo D, Porreca I, Cobellis G, Tarallo R, Nassa G, Falco G, Nardone A, Rizzo F, Mallardo M, Ambrosino C. Carcinogenic risk and Bisphenol A exposure: A focus on molecular aspects in endoderm derived glands. Mol Cell Endocrinol 2017; 457:20-34. [PMID: 28111205 DOI: 10.1016/j.mce.2017.01.027] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 01/16/2017] [Accepted: 01/17/2017] [Indexed: 02/07/2023]
Abstract
Epidemiological and experimental evidence associates the exposure to Bisphenol A with the increase of cancer risk in several organs, including prostate. BPA targets different pathways involved in carcinogenicity including the Nuclear Receptors (i.e. estrogen and androgen receptors), stress regulated proteins and, finally, epigenetic changes. Here, we analyse BPA-dependent carcinogenesis in endoderm-derived glands, thyroid, liver, pancreas and prostate focusing on cell signalling, DNA damage repair pathways and epigenetic modifications. Mainly, we gather molecular data evidencing harmful effects at doses relevant for human risk (low-doses). Since few molecular data are available, above all for the pancreas, we analysed transcriptomic data generated in our laboratory to suggest possible mechanisms of BPA carcinogenicity in endoderm-derived glands, discussing the role of nuclear receptors and stress/NF-kB pathways. We evidence that an in vitro toxicogenomic approach might suggest mechanisms of toxicity applicable to cells having the same developmental origin. Although we cannot draw firm conclusions, published data summarized in this review suggest that exposure to BPA, primarily during the developmental stages, represents a risk for carcinogenesis of endoderm-derived glands.
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Affiliation(s)
- Danila Cuomo
- IRGS, Biogem, Via Camporeale, 83031 Ariano Irpino, Avellino, Italy; Department of Science and Technology, University of Sannio, via Port'Arsa 11, 82100 Benevento, Italy
| | | | - Gilda Cobellis
- Department of Experimental Medicine, Sez. Bozzatti, II University of Naples, 80138 Napoli, Italy
| | - Roberta Tarallo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, 84081 Baronissi, SA, Italy
| | - Giovanni Nassa
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, 84081 Baronissi, SA, Italy; Genomix4Life srl, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, Baronissi, SA, Italy
| | - Geppino Falco
- Department of Biology, University of Naples "Federico II", Napoli, Italy
| | - Antonio Nardone
- Department of Public Health, University of Naples "Federico II", Napoli, Italy
| | - Francesca Rizzo
- Laboratory of Molecular Medicine and Genomics, Department of Medicine, Surgery and Dentistry "Schola Medica Salernitana", University of Salerno, 84081 Baronissi, SA, Italy
| | - Massimo Mallardo
- Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Napoli, Italy
| | - Concetta Ambrosino
- Department of Science and Technology, University of Sannio, via Port'Arsa 11, 82100 Benevento, Italy.
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15
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Schöpel M, Potheraveedu VN, Al-Harthy T, Abdel-Jalil R, Heumann R, Stoll R. The small GTPases Ras and Rheb studied by multidimensional NMR spectroscopy: structure and function. Biol Chem 2017; 398:577-588. [DOI: 10.1515/hsz-2016-0276] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Accepted: 01/23/2017] [Indexed: 12/15/2022]
Abstract
Abstract
Ras GTPases are key players in cellular signalling because they act as binary switches. These states manifest through toggling between an active (GTP-loaded) and an inactive (GDP-loaded) form. The hydrolysis and replenishing of GTP is controlled by two additional protein classes: GAP (GTPase-activating)- and GEF (Guanine nucleotide exchange factors)-proteins. The complex interplay of the proteins is known as the GTPase-cycle. Several point mutations of the Ras protein deregulate this cycle. Mutations in Ras are associated with up to one-third of human cancers. The three isoforms of Ras (H, N, K) exhibit high sequence similarity and mainly differ in a region called HVR (hypervariable region). The HVR governs the differential action and cellular distribution of the three isoforms. Rheb is a Ras-like GTPase that is conserved from yeast to mammals. Rheb is mainly involved in activation of cell growth through stimulation of mTORC1 activity. In this review, we summarise multidimensional NMR studies on Rheb and Ras carried out to characterise their structure-function relationship and explain how the activity of these small GTPases can be modulated by low molecular weight compounds. These might help to design GTPase-selective antagonists for treatment of cancer and brain disease.
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16
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EDCs Mixtures: A Stealthy Hazard for Human Health? TOXICS 2017; 5:toxics5010005. [PMID: 29051438 PMCID: PMC5606671 DOI: 10.3390/toxics5010005] [Citation(s) in RCA: 95] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 01/23/2017] [Accepted: 01/25/2017] [Indexed: 12/27/2022]
Abstract
Endocrine disrupting chemicals (EDCs) are exogenous chemicals that may occur naturally (e.g., phytoestrogens), while others are industrial substances and plasticizers commonly utilized worldwide to which human exposure, particularly at low-doses, is omnipresent, persistent and occurs in complex mixtures. EDCs can interfere with/or mimic estrogenic hormones and, consequently, can simultaneously trigger diverse signaling pathways which result in diverse and divergent biological responses. Additionally, EDCs can also bioaccumulate in lipid compartments of the organism forming a mixed “body burden” of contaminants. Although the independent action of chemicals has been considered the main principle in EDCs mixture toxicity, recent studies have demonstrated that numerous effects cannot be predicted when analyzing single compounds independently. Co-exposure to these agents, particularly in critical windows of exposure, may induce hazardous health effects potentially associated with a complex “body burden” of different origins. Here, we performed an exhaustive review of the available literature regarding EDCs mixtures exposure, toxicity mechanisms and effects, particularly at the most vulnerable human life stages. Although the assessment of potential risks to human health due to exposure to EDCs mixtures is a major topic for consumer safety, information regarding effective mixtures effects is still scarce.
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17
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Wang Z, Liu H, Liu S. Low-Dose Bisphenol A Exposure: A Seemingly Instigating Carcinogenic Effect on Breast Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2017; 4:1600248. [PMID: 28251049 PMCID: PMC5323866 DOI: 10.1002/advs.201600248] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 09/01/2016] [Indexed: 05/21/2023]
Abstract
Breast cancer is the fifth most common cause of cancer death in the world and the second most common fatal cancer in women. Epidemiological studies and clinical data have indicated that hormones, including estrogen, progesterone, and prolactin, play important roles in the initiation and progression of breast cancer. Bisphenol A (BPA) is one of the most commonly used and thoroughly studied endocrine disruptors. It can be released from consumer products and deposited in the environment, thus creating potential for human exposure through oral, inhaled, and dermal routes. Some recent reviews have summarized the known mechanisms of endocrine disruptions by BPA in human diseases, including obesity, reproductive disorders, and birth defects. However, large knowledge gaps still exist on the roles BPA may play in cancer initiation and development. Evidence from animal and in vitro studies has suggested an association between increased incidence of breast cancer and BPA exposure at doses below the safe reference doses that are the most environmentally relevant. Most current studies have paid little attention to the cancer-promoting properties of BPA at low doses. In this review, recent findings on the carcinogenic effects of low-dose BPA on breast cancer and discussed possible biologic mechanisms are summarized.
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Affiliation(s)
- Zhe Wang
- State Key Laboratory of Environmental Chemistry and EcotoxicologyResearch Center for Eco‐Environmental SciencesChinese Academy of SciencesBeijing100085China
- School of Public HealthXinxiang Medical UniversityXinxiangHenan Province453003China
| | - Huiyu Liu
- Beijing Key Laboratory of BioprocessBeijing Advanced Innovation Center for Soft Matter Science and EngineeringBeijing Laboratory of Biomedical MaterialsBeijing University of Chemical TechnologyBeijing100029China
| | - Sijin Liu
- State Key Laboratory of Environmental Chemistry and EcotoxicologyResearch Center for Eco‐Environmental SciencesChinese Academy of SciencesBeijing100085China
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18
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Ribeiro-Varandas E, Pereira HS, Viegas W, Delgado M. Bisphenol A alters transcript levels of biomarker genes for Major Depressive Disorder in vascular endothelial cells and colon cancer cells. CHEMOSPHERE 2016; 153:75-77. [PMID: 27010169 DOI: 10.1016/j.chemosphere.2015.12.085] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 12/01/2015] [Accepted: 12/23/2015] [Indexed: 06/05/2023]
Abstract
Bisphenol A (BPA) is capable of mimicking endogenous hormones with potential consequences for human health and BPA exposure has been associated with several human diseases including neuropsychiatric disorders. Here, quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) results show that BPA at low concentrations (10 ng/mL and 1 μg/mL) induces differential transcript levels of four biomarker genes for Major Depressive Disorder (MDD) in HT29 human colon adenocarcinona cell line and Human Umbilical Vein Endothelial Cells (HUVEC). These results substantiate increasing concerns of BPA exposure in levels currently detected in humans.
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Affiliation(s)
- Edna Ribeiro-Varandas
- Landscape, Environment, Agriculture and Food (LEAF) Centre, Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349-017 Lisboa, Portugal; Lisbon School of Health Technology, Instituto Politécnico de Lisboa, Av. D. João II, Lote 4.69.01, 1990-096 Lisboa, Portugal
| | - H Sofia Pereira
- Landscape, Environment, Agriculture and Food (LEAF) Centre, Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349-017 Lisboa, Portugal
| | - Wanda Viegas
- Landscape, Environment, Agriculture and Food (LEAF) Centre, Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349-017 Lisboa, Portugal
| | - Margarida Delgado
- Landscape, Environment, Agriculture and Food (LEAF) Centre, Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349-017 Lisboa, Portugal; Faculty of Psychology and Life Sciences, Universidade Lusófona de Humanidades e Tecnologias, Campo Grande 376, 1749-024 Lisboa, Portugal.
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19
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Caron-Beaudoin É, Denison MS, Sanderson JT. Effects of Neonicotinoids on Promoter-Specific Expression and Activity of Aromatase (CYP19) in Human Adrenocortical Carcinoma (H295R) and Primary Umbilical Vein Endothelial (HUVEC) Cells. Toxicol Sci 2015; 149:134-44. [PMID: 26464060 DOI: 10.1093/toxsci/kfv220] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The enzyme aromatase (CYP19; cytochrome P450 19) in humans undergoes highly tissue- and promoter-specific regulation. In hormone-dependent breast cancer, aromatase is over-expressed via several normally inactive promoters (PII, I.3, I.7). Aromatase biosynthesizes estrogens, which stimulate breast cancer cell proliferation. The placenta produces estrogens required for healthy pregnancy and the major placental CYP19 promoter is I.1. Exposure to certain pesticides, such as atrazine, is associated with increased CYP19 expression, but little is known about the effects of neonicotinoid insecticides on CYP19. We developed sensitive and robust RT-qPCR methods to detect the promoter-specific expression of CYP19 in human adrenocortical carcinoma (H295R) and primary umbilical vein endothelial (HUVEC) cells, and determined the potential promoter-specific disruption of CYP19 expression by atrazine and the commonly used neonicotinoids imidacloprid, thiacloprid, and thiamethoxam. In H295R cells, atrazine concentration-dependently increased PII- and I.3-mediated CYP19 expression and aromatase catalytic activity. Thiacloprid and thiamethoxam induced PII- and I.3-mediated CYP19 expression and aromatase activity at relatively low concentrations (0.1-1.0 µM), exhibiting non-monotonic concentration-response curves with a decline in gene induction and catalytic activity at higher concentrations. In HUVEC cells, atrazine slightly induced overall (promoter-indistinct) CYP19 expression (30 µM) and aromatase activity (≥ 3 µM), without increasing I.1 promoter activity. None of the neonicotinoids increased CYP19 expression or aromatase activity in HUVEC cells. Considering the importance of promoter-specific (over)expression of CYP19 in disease (breast cancer) or during sensitive developmental periods (pregnancy), our newly developed RT-qPCR methods will be helpful tools in assessing the risk that neonicotinoids and other chemicals may pose to exposed women.
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Affiliation(s)
- Élyse Caron-Beaudoin
- *INRS - Institut Armand-Frappier, Université du Québec, Laval, Quebec, Canada; and
| | - Michael S Denison
- Department of Environmental Toxicology, University of California, Davis, California
| | - J Thomas Sanderson
- *INRS - Institut Armand-Frappier, Université du Québec, Laval, Quebec, Canada; and
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20
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Xin L, Lin Y, Wang A, Zhu W, Liang Y, Su X, Hong C, Wan J, Wang Y, Tian H. Cytogenetic evaluation for the genotoxicity of bisphenol-A in Chinese hamster ovary cells. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2015; 40:524-529. [PMID: 26318564 DOI: 10.1016/j.etap.2015.08.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 08/04/2015] [Accepted: 08/05/2015] [Indexed: 06/04/2023]
Abstract
Bisphenol A (BPA), identified as an endocrine disruptor, is an important man-made compound used in a wide range of consumer products. The MTT assay, comet assay, micronucleus test, chromosome aberration test, and Ames assay were conducted to assess the cytotoxic, genotoxic, cytogenetic effects, and mutagenic activity of BPA. After BPA exposure, we showed significant increases in cytotoxicity and level of DNA damage indicated by Olive tail moment, tail length, and % tail DNA in a similar dose- and time-dependent manner. Significant increases in micronucleus frequency and conventional chromosome aberrations were also observed after BPA treatment. The major types of structural aberrations were breaks, gaps, and fragments. However, no positive mutagenic activity of BPA was observed in any of the tester strains. Taken together, the data obtained in this study clearly demonstrated that BPA is not mutagenic but could exhibit significant genotoxic and cytogenetic effects in Chinese hamster ovary cells.
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Affiliation(s)
- Lili Xin
- School of Public Health, Medical College of Soochow University, 199 Renai Road, Suzhou 215123, Jiangsu, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou 215123, China
| | - Yao Lin
- Experimental Center of Medical College, Soochow University, 199 Renai Road, Suzhou 215123, Jiangsu, China
| | - Aiqing Wang
- Experimental Center of Medical College, Soochow University, 199 Renai Road, Suzhou 215123, Jiangsu, China
| | - Wei Zhu
- School of Radiation Medicine and Protection, Medical College of Soochow University, 199 Renai Road, Suzhou 215123, Jiangsu, China
| | - Yu Liang
- Sanitation & Environment Technology Institute, Soochow University, 199 Renai Road, Suzhou 215123, Jiangsu, China
| | - Xiaojun Su
- Sanitation & Environment Technology Institute, Soochow University, 199 Renai Road, Suzhou 215123, Jiangsu, China
| | - Chengjiao Hong
- Experimental Center of Medical College, Soochow University, 199 Renai Road, Suzhou 215123, Jiangsu, China
| | - Jianmei Wan
- Experimental Center of Medical College, Soochow University, 199 Renai Road, Suzhou 215123, Jiangsu, China
| | - Yarong Wang
- Experimental Center of Medical College, Soochow University, 199 Renai Road, Suzhou 215123, Jiangsu, China
| | - Hailin Tian
- School of Public Health, Medical College of Soochow University, 199 Renai Road, Suzhou 215123, Jiangsu, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou 215123, China.
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21
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Bisphenol A at the reference level counteracts doxorubicin transcriptional effects on cancer related genes in HT29 cells. Toxicol In Vitro 2015; 29:2009-14. [PMID: 26320837 DOI: 10.1016/j.tiv.2015.08.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2015] [Revised: 08/25/2015] [Accepted: 08/26/2015] [Indexed: 11/21/2022]
Abstract
Human exposure to Bisphenol A (BPA) results mainly from ingestion of food and beverages. Information regarding BPA effects on colon cancer, one of the major causes of death in developed countries, is still scarce. Likewise, little is known about BPA drug interactions although its potential role in doxorubicin (DOX) chemoresistance has been suggested. This study aims to assess potential interactions between BPA and DOX on HT29 colon cancer cells. HT29 cell response was evaluated after exposure to BPA, DOX, or co-exposure to both chemicals. Transcriptional analysis of several cancer-associated genes (c-fos, AURKA, p21, bcl-xl and CLU) shows that BPA exposure induces slight up-regulation exclusively of bcl-xl without affecting cell viability. On the other hand, a sub-therapeutic DOX concentration (40 nM) results in highly altered c-fos, bcl-xl, and CLU transcript levels, and this is not affected by co-exposure with BPA. Conversely, DOX at a therapeutic concentration (4 μM) results in distinct and very severe transcriptional alterations of c-fos, AURKA, p21 and CLU that are counteracted by co-exposure with BPA resulting in transcript levels similar to those of control. Co-exposure with BPA slightly decreases apoptosis in relation to DOX 4 μM alone without affecting DOX-induced loss of cell viability. These results suggest that BPA exposure can influence chemotherapy outcomes and therefore emphasize the necessity of a better understanding of BPA interactions with chemotherapeutic agents in the context of risk assessment.
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22
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Goodson WH, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A, Lasfar A, Carnero A, Azqueta A, Amedei A, Charles AK, Collins AR, Ward A, Salzberg AC, Colacci AM, Olsen AK, Berg A, Barclay BJ, Zhou BP, Blanco-Aparicio C, Baglole CJ, Dong C, Mondello C, Hsu CW, Naus CC, Yedjou C, Curran CS, Laird DW, Koch DC, Carlin DJ, Felsher DW, Roy D, Brown DG, Ratovitski E, Ryan EP, Corsini E, Rojas E, Moon EY, Laconi E, Marongiu F, Al-Mulla F, Chiaradonna F, Darroudi F, Martin FL, Van Schooten FJ, Goldberg GS, Wagemaker G, Nangami GN, Calaf GM, Williams GP, Wolf GT, Koppen G, Brunborg G, Lyerly HK, Krishnan H, Ab Hamid H, Yasaei H, Sone H, Kondoh H, Salem HK, Hsu HY, Park HH, Koturbash I, Miousse IR, Scovassi A, Klaunig JE, Vondráček J, Raju J, Roman J, Wise JP, Whitfield JR, Woodrick J, Christopher JA, Ochieng J, Martinez-Leal JF, Weisz J, Kravchenko J, Sun J, Prudhomme KR, Narayanan KB, Cohen-Solal KA, Moorwood K, Gonzalez L, Soucek L, Jian L, D’Abronzo LS, Lin LT, Li L, Gulliver L, McCawley LJ, Memeo L, Vermeulen L, Leyns L, Zhang L, Valverde M, Khatami M, Romano MF, Chapellier M, Williams MA, Wade M, et alGoodson WH, Lowe L, Carpenter DO, Gilbertson M, Manaf Ali A, Lopez de Cerain Salsamendi A, Lasfar A, Carnero A, Azqueta A, Amedei A, Charles AK, Collins AR, Ward A, Salzberg AC, Colacci AM, Olsen AK, Berg A, Barclay BJ, Zhou BP, Blanco-Aparicio C, Baglole CJ, Dong C, Mondello C, Hsu CW, Naus CC, Yedjou C, Curran CS, Laird DW, Koch DC, Carlin DJ, Felsher DW, Roy D, Brown DG, Ratovitski E, Ryan EP, Corsini E, Rojas E, Moon EY, Laconi E, Marongiu F, Al-Mulla F, Chiaradonna F, Darroudi F, Martin FL, Van Schooten FJ, Goldberg GS, Wagemaker G, Nangami GN, Calaf GM, Williams GP, Wolf GT, Koppen G, Brunborg G, Lyerly HK, Krishnan H, Ab Hamid H, Yasaei H, Sone H, Kondoh H, Salem HK, Hsu HY, Park HH, Koturbash I, Miousse IR, Scovassi A, Klaunig JE, Vondráček J, Raju J, Roman J, Wise JP, Whitfield JR, Woodrick J, Christopher JA, Ochieng J, Martinez-Leal JF, Weisz J, Kravchenko J, Sun J, Prudhomme KR, Narayanan KB, Cohen-Solal KA, Moorwood K, Gonzalez L, Soucek L, Jian L, D’Abronzo LS, Lin LT, Li L, Gulliver L, McCawley LJ, Memeo L, Vermeulen L, Leyns L, Zhang L, Valverde M, Khatami M, Romano MF, Chapellier M, Williams MA, Wade M, Manjili MH, Lleonart ME, Xia M, Gonzalez Guzman MJ, Karamouzis MV, Kirsch-Volders M, Vaccari M, Kuemmerle NB, Singh N, Cruickshanks N, Kleinstreuer N, van Larebeke N, Ahmed N, Ogunkua O, Krishnakumar P, Vadgama P, Marignani PA, Ghosh PM, Ostrosky-Wegman P, Thompson PA, Dent P, Heneberg P, Darbre P, Leung PS, Nangia-Makker P, Cheng Q(S, Robey R, Al-Temaimi R, Roy R, Andrade-Vieira R, Sinha RK, Mehta R, Vento R, Di Fiore R, Ponce-Cusi R, Dornetshuber-Fleiss R, Nahta R, Castellino RC, Palorini R, Hamid RA, Langie SA, Eltom SE, Brooks SA, Ryeom S, Wise SS, Bay SN, Harris SA, Papagerakis S, Romano S, Pavanello S, Eriksson S, Forte S, Casey SC, Luanpitpong S, Lee TJ, Otsuki T, Chen T, Massfelder T, Sanderson T, Guarnieri T, Hultman T, Dormoy V, Odero-Marah V, Sabbisetti V, Maguer-Satta V, Rathmell W, Engström W, Decker WK, Bisson WH, Rojanasakul Y, Luqmani Y, Chen Z, Hu Z. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis 2015; 36 Suppl 1:S254-S296. [PMID: 26106142 PMCID: PMC4480130 DOI: 10.1093/carcin/bgv039] [Show More Authors] [Citation(s) in RCA: 186] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 01/23/2015] [Accepted: 01/31/2015] [Indexed: 02/07/2023] Open
Abstract
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
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Affiliation(s)
- William H. Goodson
- *To whom correspondence should be addressed. William H.Goodson III, California Pacific Medical Center Research Institute, 2100 Webster Street #401, San Francisco, CA 94115, USA. Tel: +41 59 233925; Fax: +41 57 761977;
| | - Leroy Lowe
- Getting to Know Cancer, Room 229A, 36 Arthur Street, Truro, Nova Scotia B2N 1X5, Canada
- Lancaster Environment Centre, Lancaster University, Bailrigg, Lancaster LA1 4AP, UK
| | - David O. Carpenter
- Institute for Health and the Environment, University at Albany, 5 University Pl., Rensselaer, NY 12144, USA
| | | | - Abdul Manaf Ali
- School of Biotechnology, Faculty of Agriculture Biotechnology and Food Sciences, Sultan Zainal Abidin University, Tembila Campus, 22200 Besut, Terengganu, Malaysia
| | | | - Ahmed Lasfar
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, State University of New Jersey, Piscataway, NJ 08854, USA
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla, Consejo Superior de Investigaciones Cientificas. Hospital Universitario Virgen del Rocio, Univ. de Sevilla., Avda Manuel Siurot sn. 41013 Sevilla, Spain
| | - Amaya Azqueta
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Navarra, Pamplona 31008, Spain
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Firenze, Florence 50134, Italy
| | - Amelia K. Charles
- School of Biological Sciences, University of Reading, Hopkins Building, Reading, Berkshire RG6 6UB, UK
| | | | - Andrew Ward
- Department of Biochemistry and Biology, University of Bath, Claverton Down, Bath BA2 7AY, UK
| | - Anna C. Salzberg
- Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
| | - Anna Maria Colacci
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy
| | - Ann-Karin Olsen
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo N-0403, Norway
| | - Arthur Berg
- Department of Public Health Sciences, College of Medicine, Pennsylvania State University, Hershey, PA 17033, USA
| | | | - Binhua P. Zhou
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40508, USA
| | - Carmen Blanco-Aparicio
- Spanish National Cancer Research Centre, CNIO, Melchor Fernandez Almagro, 3, 28029 Madrid, Spain
| | - Carolyn J. Baglole
- Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada
| | - Chenfang Dong
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40508, USA
| | - Chiara Mondello
- Istituto di Genetica Molecolare, CNR, Via Abbiategrasso 207, 27100 Pavia, Italy
| | - Chia-Wen Hsu
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892–3375, USA
| | - Christian C. Naus
- Department of Cellular and Physiological Sciences, Life Sciences Institute, Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada
| | - Clement Yedjou
- Department of Biology, Jackson State University, Jackson, MS 39217, USA
| | - Colleen S. Curran
- Department of Molecular and Environmental Toxicology, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Dale W. Laird
- Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 3K7, Canada
| | - Daniel C. Koch
- Stanford University Department of Medicine, Division of Oncology, Stanford, CA 94305, USA
| | - Danielle J. Carlin
- Superfund Research Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27560, USA
| | - Dean W. Felsher
- Department of Medicine, Oncology and Pathology, Stanford University,Stanford, CA 94305, USA
| | - Debasish Roy
- Department of Natural Science, The City University of New York at Hostos Campus, Bronx, NY 10451, USA
| | - Dustin G. Brown
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523–1680, USA
| | - Edward Ratovitski
- Department of Head and Neck Surgery/Head and Neck Cancer Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Elizabeth P. Ryan
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523–1680, USA
| | - Emanuela Corsini
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy
| | - Emilio Rojas
- Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, México
| | - Eun-Yi Moon
- Department of Bioscience and Biotechnology, Sejong University, Seoul 143–747, Korea
| | - Ezio Laconi
- Department of Biomedical Sciences, University of Cagliari, 09124 Cagliari, Italy
| | - Fabio Marongiu
- Department of Biomedical Sciences, University of Cagliari, 09124 Cagliari, Italy
| | - Fahd Al-Mulla
- Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | - Ferdinando Chiaradonna
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
- SYSBIO Centre of Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
| | - Firouz Darroudi
- Human Safety and Environmental Research, Department of Health Sciences, College of North Atlantic, Doha 24449, State of Qatar
| | - Francis L. Martin
- Lancaster Environment Centre, Lancaster University, Bailrigg, Lancaster LA1 4AP, UK
| | - Frederik J. Van Schooten
- Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, Maastricht 6200, The Netherlands
| | - Gary S. Goldberg
- Department of Molecular Biology, School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA
| | - Gerard Wagemaker
- Hacettepe University, Center for Stem Cell Research and Development, Ankara 06640, Turkey
| | - Gladys N. Nangami
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - Gloria M. Calaf
- Center for Radiological Research, Columbia University Medical Center, New York, NY 10032, USA
- Instituto de Alta Investigacion, Universidad de Tarapaca, Arica, Chile
| | - Graeme P. Williams
- School of Biological Sciences, University of Reading, Reading, RG6 6UB, UK
| | - Gregory T. Wolf
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Gudrun Koppen
- Environmental Risk and Health Unit, Flemish Institute for Technological Research, 2400 Mol, Belgium
| | - Gunnar Brunborg
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo N-0403, Norway
| | - H. Kim Lyerly
- Department of Surgery, Pathology, Immunology, Duke University Medical Center, Durham, NC 27710, USA
| | - Harini Krishnan
- Department of Molecular Biology, School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA
| | - Hasiah Ab Hamid
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, 43400 Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Hemad Yasaei
- Department of Life Sciences, College of Health and Life Sciences and the Health and Environment Theme, Institute of Environment, Health and Societies, Brunel University Kingston Lane, Uxbridge, Middlesex UB8 3PH, UK
| | - Hideko Sone
- National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibraki 3058506, Japan
| | - Hiroshi Kondoh
- Department of Geriatric Medicine, Kyoto University Hospital 54 Kawaharacho, Shogoin, Sakyo-ku Kyoto, 606–8507, Japan
| | - Hosni K. Salem
- Department of Urology, Kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 11559, Egypt
| | - Hsue-Yin Hsu
- Department of Life Sciences, Tzu-Chi University, Hualien 970, Taiwan
| | - Hyun Ho Park
- School of Biotechnology, Yeungnam University, Gyeongbuk 712-749, South Korea
| | - Igor Koturbash
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - Isabelle R. Miousse
- Department of Environmental and Occupational Health, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
| | - A.Ivana Scovassi
- Istituto di Genetica Molecolare, CNR, Via Abbiategrasso 207, 27100 Pavia, Italy
| | - James E. Klaunig
- Department of Environmental Health, Indiana University, School of Public Health, Bloomington, IN 47405, USA
| | - Jan Vondráček
- Department of Cytokinetics, Institute of Biophysics Academy of Sciences of the Czech Republic, Brno, CZ-61265, Czech Republic
| | - Jayadev Raju
- Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada
| | - Jesse Roman
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
- Robley Rex VA Medical Center, Louisville, KY 40202, USA
| | - John Pierce Wise
- Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth St., Portland, ME 04104, USA
| | - Jonathan R. Whitfield
- Mouse Models of Cancer Therapies Group, Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain
| | - Jordan Woodrick
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA
| | - Joseph A. Christopher
- Cancer Research UK. Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK
| | - Josiah Ochieng
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | | | - Judith Weisz
- Departments of Obstetrics and Gynecology and Pathology, Pennsylvania State University College of Medicine, Hershey PA 17033, USA
| | - Julia Kravchenko
- Department of Surgery, Pathology, Immunology, Duke University Medical Center, Durham, NC 27710, USA
| | - Jun Sun
- Department of Biochemistry, Rush University, Chicago, IL 60612, USA
| | - Kalan R. Prudhomme
- Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University, Corvallis, OR 97331, USA
| | | | - Karine A. Cohen-Solal
- Department of Medicine/Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA
| | - Kim Moorwood
- Department of Biochemistry and Biology, University of Bath, Claverton Down, Bath BA2 7AY, UK
| | - Laetitia Gonzalez
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Laura Soucek
- Mouse Models of Cancer Therapies Group, Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona 08010, Spain
| | - Le Jian
- School of Public Health, Curtin University, Bentley, WA 6102, Australia
- Department of Urology, University of California Davis, Sacramento, CA 95817, USA
| | - Leandro S. D’Abronzo
- Department of Urology, University of California Davis, Sacramento, CA 95817, USA
| | - Liang-Tzung Lin
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Lin Li
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, The People’s Republic of China
| | - Linda Gulliver
- Faculty of Medicine, University of Otago, Dunedin 9054, New Zealand
| | - Lisa J. McCawley
- Department of Biomedical Engineering and Cancer Biology, Vanderbilt University, Nashville, TN 37235, USA
| | - Lorenzo Memeo
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Via Penninazzo 7, Viagrande (CT) 95029, Italy
| | - Louis Vermeulen
- Center for Experimental Molecular Medicine, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands
| | - Luc Leyns
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, 1050 Brussels, Belgium
| | - Luoping Zhang
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720-7360, USA
| | - Mahara Valverde
- Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, México
| | - Mahin Khatami
- Inflammation and Cancer Research, National Cancer Institute (NCI) (Retired), National Institutes of Health, Bethesda, MD 20892, USA
| | - Maria Fiammetta Romano
- Department of Molecular Medicine and Medical Biotechnology, Federico II University of Naples, 80131 Naples, Italy
| | - Marion Chapellier
- Centre De Recherche En Cancerologie,De Lyon, Lyon, U1052-UMR5286, France
| | - Marc A. Williams
- United States Army Institute of Public Health, Toxicology Portfolio-Health Effects Research Program, Aberdeen Proving Ground, Edgewood, MD 21010-5403, USA
| | - Mark Wade
- Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Via Adamello 16, 20139 Milano, Italy
| | - Masoud H. Manjili
- Department of Microbiology and Immunology, Virginia Commonwealth University, Massey Cancer Center, Richmond, VA 23298, USA
| | - Matilde E. Lleonart
- Institut De Recerca Hospital Vall D’Hebron, Passeig Vall d’Hebron, 119–129, 08035 Barcelona, Spain
| | - Menghang Xia
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892–3375, USA
| | - Michael J. Gonzalez Guzman
- University of Puerto Rico, Medical Sciences Campus, School of Public Health, Nutrition Program, San Juan 00921, Puerto Rico
| | - Michalis V. Karamouzis
- Department of Biological Chemistry, Medical School, University of Athens, Institute of Molecular Medicine and Biomedical Research, 10676 Athens, Greece
| | | | - Monica Vaccari
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, 40126 Bologna, Italy
| | | | - Neetu Singh
- Advanced Molecular Science Research Centre (Centre for Advanced Research), King George’s Medical University, Lucknow, Uttar Pradesh 226 003, India
| | - Nichola Cruickshanks
- Departments of Neurosurgery and Biochemistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Nicole Kleinstreuer
- Integrated Laboratory Systems Inc., in support of the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods, RTP, NC 27709, USA
| | - Nik van Larebeke
- Analytische, Milieu en Geochemie, Vrije Universiteit Brussel, Brussel B1050, Belgium
| | - Nuzhat Ahmed
- Department of Obstetrics and Gynecology, University of Melbourne, Victoria 3052, Australia
| | - Olugbemiga Ogunkua
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - P.K. Krishnakumar
- Center for Environment and Water, Research Institute, King Fahd University of Petroleum and Minerals, Dhahran 3126, Saudi Arabia
| | - Pankaj Vadgama
- School of Engineering and Materials Science, Queen Mary University of London, Mile End Road, London, E1 4NS, UK
| | - Paola A. Marignani
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada
| | - Paramita M. Ghosh
- Department of Urology, University of California Davis, Sacramento, CA 95817, USA
| | - Patricia Ostrosky-Wegman
- Department of Genomic Medicine and Environmental Toxicology, Institute for Biomedical Research, National Autonomous University of Mexico, Mexico City 04510, México
| | - Patricia A. Thompson
- Department of Pathology, Stony Brook School of Medicine, Stony Brook University, The State University of New York, Stony Brook, NY 11794-8691, USA
| | - Paul Dent
- Departments of Neurosurgery and Biochemistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Petr Heneberg
- Charles University in Prague, Third Faculty of Medicine, CZ-100 00 Prague 10, Czech Republic
| | - Philippa Darbre
- School of Biological Sciences, The University of Reading, Whiteknights, Reading RG6 6UB, England
| | - Po Sing Leung
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong SAR, The People’s Republic of China
| | | | - Qiang (Shawn) Cheng
- Computer Science Department, Southern Illinois University, Carbondale, IL 62901, USA
| | - R.Brooks Robey
- White River Junction Veterans Affairs Medical Center, White River Junction, VT 05009, USA
- Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Rabeah Al-Temaimi
- Human Genetics Unit, Department of Pathology, Faculty of Medicine, Kuwait University, Jabriya 13110, Kuwait
| | - Rabindra Roy
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington DC 20057, USA
| | - Rafaela Andrade-Vieira
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada
| | - Ranjeet K. Sinha
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Rekha Mehta
- Regulatory Toxicology Research Division, Bureau of Chemical Safety, Food Directorate, Health Canada, Ottawa, Ontario K1A 0K9, Canada
| | - Renza Vento
- Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies, Polyclinic Plexus, University of Palermo, Palermo 90127, Italy
- Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA 19122, USA
| | - Riccardo Di Fiore
- Department of Biological, Chemical, and Pharmaceutical Sciences and Technologies, Polyclinic Plexus, University of Palermo, Palermo 90127, Italy
| | | | - Rita Dornetshuber-Fleiss
- Department of Pharmacology and Toxicology, University of Vienna, Vienna A-1090, Austria
- Institute of Cancer Research, Department of Medicine, Medical University of Vienna, Wien 1090, Austria
| | - Rita Nahta
- Departments of Pharmacology and Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA 30322, USA
| | - Robert C. Castellino
- Division of Hematology and Oncology, Department of Pediatrics, Children’s Healthcare of Atlanta, GA 30322, USA
- Department of Pediatrics, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA
| | - Roberta Palorini
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
- SYSBIO Centre of Systems Biology, Department of Biotechnology and Biosciences, University of Milano-Bicocca, 20126 Milan, Italy
| | - Roslida A. Hamid
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, 43400 Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Sabine A.S. Langie
- Environmental Risk and Health Unit, Flemish Institute for Technological Research, 2400 Mol, Belgium
| | - Sakina E. Eltom
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - Samira A. Brooks
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Sandra Ryeom
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Sandra S. Wise
- Department of Applied Medical Sciences, University of Southern Maine, 96 Falmouth St., Portland, ME 04104, USA
| | - Sarah N. Bay
- Program in Genetics and Molecular Biology, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA 30322, USA
| | - Shelley A. Harris
- Population Health and Prevention, Research, Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, M5G 2L7, Canada
- Departments of Epidemiology and Occupational and Environmental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, M5T 3M7, Canada
| | - Silvana Papagerakis
- Department of Otolaryngology - Head and Neck Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Simona Romano
- Department of Molecular Medicine and Medical Biotechnology, Federico II University of Naples, 80131 Naples, Italy
| | - Sofia Pavanello
- Department of Cardiac, Thoracic and Vascular Sciences, Unit of Occupational Medicine, University of Padova, Padova 35128, Italy
| | - Staffan Eriksson
- Department of Anatomy, Physiology and Biochemistry, The Swedish University of Agricultural Sciences, PO Box 7011, VHC, Almas Allé 4, SE-756 51, Uppsala, Sweden
| | - Stefano Forte
- Department of Experimental Oncology, Mediterranean Institute of Oncology, Via Penninazzo 7, Viagrande (CT) 95029, Italy
| | - Stephanie C. Casey
- Stanford University Department of Medicine, Division of Oncology, Stanford, CA 94305, USA
| | - Sudjit Luanpitpong
- Siriraj Center of Excellence for Stem Cell Research, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Tae-Jin Lee
- Department of Anatomy, College of Medicine, Yeungnam University, Daegu 705–717, South Korea,
| | - Takemi Otsuki
- Department of Hygiene, Kawasaki Medical School, Matsushima Kurashiki, Okayama 701-0192, Japan,
| | - Tao Chen
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, United States Food and Drug Administration, Jefferson, AR 72079, USA
| | - Thierry Massfelder
- INSERM U1113, team 3 ‘Cell Signalling and Communication in Kidney and Prostate Cancer’, University of Strasbourg, Faculté de Médecine, 67085 Strasbourg, France
| | - Thomas Sanderson
- INRS-Institut Armand-Frappier, 531 Boulevard des Prairies, Laval, QC H7V 1B7, Canada,
| | - Tiziana Guarnieri
- Department of Biology, Geology and Environmental Sciences, Alma Mater Studiorum Università di Bologna, Via Francesco Selmi, 3, 40126 Bologna, Italy
- Center for Applied Biomedical Research, S. Orsola-Malpighi University Hospital, Via Massarenti, 9, 40126 Bologna, Italy
- National Institute of Biostructures and Biosystems, Viale Medaglie d’ Oro, 305, 00136 Roma, Italy
| | - Tove Hultman
- Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, PO Box 7028, 75007 Uppsala, Sweden
| | - Valérian Dormoy
- INSERM U1113, team 3 ‘Cell Signalling and Communication in Kidney and Prostate Cancer’, University of Strasbourg, Faculté de Médecine, 67085 Strasbourg, France
- Department of Cell and Developmental Biology, University of California, Irvine, CA 92697, USA
| | - Valerie Odero-Marah
- Department of Biology/Center for Cancer Research and Therapeutic Development, Clark Atlanta University, Atlanta, GA 30314, USA
| | - Venkata Sabbisetti
- Harvard Medical School/Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Veronique Maguer-Satta
- United States Army Institute of Public Health, Toxicology Portfolio-Health Effects Research Program, Aberdeen Proving Ground, Edgewood, MD 21010-5403, USA
| | - W.Kimryn Rathmell
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC 27599, USA
| | - Wilhelm Engström
- Department of Biosciences and Veterinary Public Health, Faculty of Veterinary Medicine, Swedish University of Agricultural Sciences, PO Box 7028, 75007 Uppsala, Sweden
| | | | - William H. Bisson
- Environmental and Molecular Toxicology, Environmental Health Science Center, Oregon State University, Corvallis, OR 97331, USA
| | - Yon Rojanasakul
- Department of Pharmaceutical Sciences, West Virginia University, Morgantown,WV, 26506,USA
| | - Yunus Luqmani
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, PO Box 24923, Safat 13110, Kuwait and
| | - Zhenbang Chen
- Department of Biochemistry and Cancer Biology, Meharry Medical College, Nashville, TN 37208, USA
| | - Zhiwei Hu
- Department of Surgery, The Ohio State University College of Medicine, The James Comprehensive Cancer Center, Columbus, OH 43210, USA
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23
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Langie SA, Koppen G, Desaulniers D, Al-Mulla F, Al-Temaimi R, Amedei A, Azqueta A, Bisson WH, Brown D, Brunborg G, Charles AK, Chen T, Colacci A, Darroudi F, Forte S, Gonzalez L, Hamid RA, Knudsen LE, Leyns L, Lopez de Cerain Salsamendi A, Memeo L, Mondello C, Mothersill C, Olsen AK, Pavanello S, Raju J, Rojas E, Roy R, Ryan E, Ostrosky-Wegman P, Salem HK, Scovassi I, Singh N, Vaccari M, Van Schooten FJ, Valverde M, Woodrick J, Zhang L, van Larebeke N, Kirsch-Volders M, Collins AR. Causes of genome instability: the effect of low dose chemical exposures in modern society. Carcinogenesis 2015; 36 Suppl 1:S61-S88. [PMID: 26106144 PMCID: PMC4565613 DOI: 10.1093/carcin/bgv031] [Citation(s) in RCA: 143] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 12/08/2014] [Accepted: 12/11/2014] [Indexed: 12/17/2022] Open
Abstract
Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis.
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Affiliation(s)
- Sabine A.S. Langie
- Environmental Risk and Health Unit, Flemish Institute for Technological Research (VITO), Boeretang 200, 2400 Mol, Belgium
- Health Canada, Environmental Health Sciences and Research Bureau, Environmental Health Centre, Ottawa, Ontario K1A0K9, Canada
- Department of Pathology, Kuwait University, Safat 13110, Kuwait
- Department of Experimental and Clinical Medicine, University of Firenze, Florence 50134, Italy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Navarra, Pamplona 31009, Spain
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, PO Box 4404, N-0403 Oslo, Norway
- Hopkins Building, School of Biological Sciences, University of Reading, Reading, Berkshire RG6 6UB, UK
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
- Human and Environmental Safety Research, Department of Health Sciences, College of North Atlantic, Doha, State of Qatar
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, Brussels 1050, Belgium
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra, Serdang 43400, Selangor, Malaysia
- University of Copenhagen, Department of Public Health, Copenhagen 1353, Denmark
- Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy
- Medical Physics & Applied Radiation Sciences, McMaster University, Hamilton, Ontario L8S4L8, Canada
- Department of Cardiac, Thoracic and Vascular Sciences, Unit of Occupational Medicine, University of Padova, Padova 35128, Italy
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
- Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de México, México CP 04510, México
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow 226003, Uttar Pradesh, India
- Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, 6200MD, PO Box 61, Maastricht, The Netherlands
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720-7360, USA
- Laboratory for Analytical and Environmental Chemistry, Vrije Universiteit Brussel, Brussels 1050, Belgium
- Study Centre for Carcinogenesis and Primary Prevention of Cancer, Ghent University, Ghent 9000, Belgium
- Department of Nutrition, University of Oslo, Oslo 0316, Norway
| | - Gudrun Koppen
- *To whom correspondence should be addressed. Tel: +32 14335165; Fax: +32 14580523
| | - Daniel Desaulniers
- Health Canada, Environmental Health Sciences and Research Bureau, Environmental Health Centre, Ottawa, Ontario K1A0K9, Canada
| | - Fahd Al-Mulla
- Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | | | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Firenze, Florence 50134, Italy
| | - Amaya Azqueta
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Navarra, Pamplona 31009, Spain
| | - William H. Bisson
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
| | - Dustin Brown
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Gunnar Brunborg
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, PO Box 4404, N-0403 Oslo, Norway
| | - Amelia K. Charles
- Hopkins Building, School of Biological Sciences, University of Reading, Reading, Berkshire RG6 6UB, UK
| | - Tao Chen
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA
| | - Annamaria Colacci
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Firouz Darroudi
- Human and Environmental Safety Research, Department of Health Sciences, College of North Atlantic, Doha, State of Qatar
| | - Stefano Forte
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy
| | - Laetitia Gonzalez
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, Brussels 1050, Belgium
| | - Roslida A. Hamid
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra, Serdang 43400, Selangor, Malaysia
| | - Lisbeth E. Knudsen
- University of Copenhagen, Department of Public Health, Copenhagen 1353, Denmark
| | - Luc Leyns
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, Brussels 1050, Belgium
| | | | - Lorenzo Memeo
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy
| | - Chiara Mondello
- Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy
| | - Carmel Mothersill
- Medical Physics & Applied Radiation Sciences, McMaster University, Hamilton, Ontario L8S4L8, Canada
| | - Ann-Karin Olsen
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, PO Box 4404, N-0403 Oslo, Norway
| | - Sofia Pavanello
- Department of Cardiac, Thoracic and Vascular Sciences, Unit of Occupational Medicine, University of Padova, Padova 35128, Italy
| | - Jayadev Raju
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
| | - Emilio Rojas
- Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de México, México CP 04510, México
| | - Rabindra Roy
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Elizabeth Ryan
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Patricia Ostrosky-Wegman
- Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de México, México CP 04510, México
| | - Hosni K. Salem
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
| | - Ivana Scovassi
- Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy
| | - Neetu Singh
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow 226003, Uttar Pradesh, India
| | - Monica Vaccari
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Frederik J. Van Schooten
- Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, 6200MD, PO Box 61, Maastricht, The Netherlands
| | - Mahara Valverde
- Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de México, México CP 04510, México
| | - Jordan Woodrick
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Luoping Zhang
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720-7360, USA
| | - Nik van Larebeke
- Laboratory for Analytical and Environmental Chemistry, Vrije Universiteit Brussel, Brussels 1050, Belgium
- Study Centre for Carcinogenesis and Primary Prevention of Cancer, Ghent University, Ghent 9000, Belgium
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Ribeiro-Varandas E, Pereira HS, Monteiro S, Neves E, Brito L, Boavida Ferreira R, Viegas W, Delgado M. Bisphenol A disrupts transcription and decreases viability in aging vascular endothelial cells. Int J Mol Sci 2014; 15:15791-805. [PMID: 25207595 PMCID: PMC4200871 DOI: 10.3390/ijms150915791] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 05/04/2014] [Accepted: 06/13/2014] [Indexed: 12/16/2022] Open
Abstract
Bisphenol A (BPA) is a widely utilized endocrine disruptor capable of mimicking endogenous hormones, employed in the manufacture of numerous consumer products, thereby interfering with physiological cellular functions. Recent research has shown that BPA alters epigenetic cellular mechanisms in mammals and may be correlated to enhanced cellular senescence. Here, the effects of BPA at 10 ng/mL and 1 µg/mL, concentrations found in human samples, were analyzed on HT29 human colon adenocarcinona cell line and Human Umbilical Vein Endothelial Cells (HUVEC). Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) transcriptional analysis of the Long Interspersed Element-1 (LINE-1) retroelement showed that BPA induces global transcription deregulation in both cell lines, although with more pronounced effects in HUVEC cells. Whereas there was an increase in global transcription in HT29 exclusively after 24 h of exposure, this chemical had prolonged effects on HUVEC. Immunoblotting revealed that this was not accompanied by alterations in the overall content of H3K9me2 and H3K4me3 epigenetic marks. Importantly, cell viability assays and transcriptional analysis indicated that prolonged BPA exposure affects aging processes in senescent HUVEC. To our knowledge this is the first report that BPA interferes with senescence in primary vascular endothelial cells, therefore, suggesting its association to the etiology of age-related human pathologies, such as atherosclerosis.
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Affiliation(s)
- Edna Ribeiro-Varandas
- Centro de Botânica Aplicada à Agricultura (CBAA), Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349-017 Lisboa, Portugal; E-Mails: (E.R.-V.); (H.S.P.); (S.M.); (E.N.); (L.B.); (R.B.F.); (W.V.)
| | - H. Sofia Pereira
- Centro de Botânica Aplicada à Agricultura (CBAA), Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349-017 Lisboa, Portugal; E-Mails: (E.R.-V.); (H.S.P.); (S.M.); (E.N.); (L.B.); (R.B.F.); (W.V.)
| | - Sara Monteiro
- Centro de Botânica Aplicada à Agricultura (CBAA), Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349-017 Lisboa, Portugal; E-Mails: (E.R.-V.); (H.S.P.); (S.M.); (E.N.); (L.B.); (R.B.F.); (W.V.)
| | - Elsa Neves
- Centro de Botânica Aplicada à Agricultura (CBAA), Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349-017 Lisboa, Portugal; E-Mails: (E.R.-V.); (H.S.P.); (S.M.); (E.N.); (L.B.); (R.B.F.); (W.V.)
- Escola Superior de Tecnologia e Gestão Jean Piaget do Litoral Alentejano (ESTGJPLA), Instituto Piaget, Campus Académico de Santo André, Ap. 38, 7500-999 Vila Nova de Santo André, Portugal
| | - Luísa Brito
- Centro de Botânica Aplicada à Agricultura (CBAA), Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349-017 Lisboa, Portugal; E-Mails: (E.R.-V.); (H.S.P.); (S.M.); (E.N.); (L.B.); (R.B.F.); (W.V.)
| | - Ricardo Boavida Ferreira
- Centro de Botânica Aplicada à Agricultura (CBAA), Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349-017 Lisboa, Portugal; E-Mails: (E.R.-V.); (H.S.P.); (S.M.); (E.N.); (L.B.); (R.B.F.); (W.V.)
- Instituto de Tecnologia Química e Biológica (ITQB), Universidade Nova de Lisboa (UNL), Av. da República, 2780-157 Oeiras, Portugal
| | - Wanda Viegas
- Centro de Botânica Aplicada à Agricultura (CBAA), Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349-017 Lisboa, Portugal; E-Mails: (E.R.-V.); (H.S.P.); (S.M.); (E.N.); (L.B.); (R.B.F.); (W.V.)
| | - Margarida Delgado
- Centro de Botânica Aplicada à Agricultura (CBAA), Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349-017 Lisboa, Portugal; E-Mails: (E.R.-V.); (H.S.P.); (S.M.); (E.N.); (L.B.); (R.B.F.); (W.V.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +351-213-653-100 (ext. 3281); Fax: +351-213-653-195
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Ribeiro-Varandas E, Ressurreição F, Viegas W, Delgado M. Cytotoxicity of Eupatorium cannabinum L. ethanolic extract against colon cancer cells and interactions with Bisphenol A and Doxorubicin. Altern Ther Health Med 2014; 14:264. [PMID: 25056133 PMCID: PMC4117973 DOI: 10.1186/1472-6882-14-264] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 07/10/2014] [Indexed: 12/18/2022]
Abstract
Background Eupatorium cannabinum L. has long been utilized in traditional medicine, however no information is available regarding cellular effects of full extracts. Here we assessed the effects of E. cannabinum ethanolic extract (EcEE) on the colon cancer line HT29. Potential interactions with bisphenol A (BPA) a synthetic phenolic compound to which humans are generally exposed and a commonly used chemotherapeutic agent, doxorubicin (DOX) were also evaluated. Methods HT29 cells were exposed to different concentrations (0.5 to 50 μg/ml) of EcEE alone or in combination with BPA or DOX. Cell viability was analyzed through resazurin assay. Gene transcription levels for NCL, FOS, p21, AURKA and bcl-xl were determined through qRT-PCR. Cytological analysis included evaluation of nuclear and mitotic anomalies after DAPI staining, immunodetection of histone H3 lysine 9 acetylation (H3K9ac) and assessment of DNA damage by TUNEL assay. Results Severe loss of HT29 cell viability was detected for 50 μg/ml EcEE immediately after 24 h exposure whereas the lower concentrations assayed (0.5, 5 and 25 μg/ml) resulted in significant viability decreases after 96 h. Exposure to 25 μg/ml EcEE for 48 h resulted in irreversible cell damage leading to a drastic decrease in cell viability after 72 h recovery in EcEE-free medium. 48 h 25 μg/ml EcEE treatment also induced alteration of colony morphology, H3K9 hyperacetylation, transcriptional up regulation of p21 and down regulation of NCL, FOS and AURKA, indicating reduced proliferation capacity. This treatment also resulted in drastic mitotic and nuclear disruption accompanied by up-regulation of bcl-xl, limited TUNEL labeling and nuclear size increase, suggestive of a non-apoptocic cell death pathway. EcEE/BPA co-exposure increased mitotic anomalies particularly for the lowest EcEE concentration, although without major effects on viability. Conversely, EcEE/DOX co-exposure decreased cell viability in relation to DOX for all EcEE concentrations, without affecting the DOX-induced cell cycle arrest. Conclusions EcEE has cytotoxic activity on HT29 cancer cells leading to mitotic disruption and non-apoptotic cell death without severe induction of DNA damage. Interaction experiments showed that EcEE can increase BPA aneugenic effects and EcEE synergistic effects with DOX supporting a potential use as adjuvant in chemotherapeutic approaches.
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Abstract
Rates of metabolic diseases have increased at an astounding rate in recent decades. Even though poor diet and physical inactivity are central drivers, these lifestyle changes alone fail to fully account for the magnitude and rapidity of the epidemic. Thus, attention has turned to identifying novel risk factors, including the contribution of environmental endocrine disrupting chemicals. Epidemiologic and preclinical data support a role for various contaminants in the pathogenesis of diabetes. In addition to the vascular risk associated with dysglycemia, emerging evidence implicates multiple pollutants in the pathogenesis of atherosclerosis and cardiovascular disease. Reviewed herein are studies linking endocrine disruptors to these key diseases that drive significant individual and societal morbidity and mortality. Identifying chemicals associated with metabolic and cardiovascular disease as well as their mechanisms of action is critical for developing novel treatment strategies and public policy to mitigate the impact of these diseases on human health.
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Affiliation(s)
- Andrew G. Kirkley
- Committee on Molecular Pathogenesis and Molecular Medicine
- University of Chicago, Chicago, IL
| | - Robert M. Sargis
- Committee on Molecular Metabolism and Nutrition
- Kovler Diabetes Center
- Section of Endocrinology, Diabetes and Metabolism
- University of Chicago, Chicago, IL
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Helmestam M, Davey E, Stavreus-Evers A, Olovsson M. Bisphenol A affects human endometrial endothelial cell angiogenic activity in vitro. Reprod Toxicol 2014; 46:69-76. [PMID: 24632125 DOI: 10.1016/j.reprotox.2014.03.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Revised: 02/25/2014] [Accepted: 03/03/2014] [Indexed: 12/21/2022]
Abstract
The widespread Bisphenol A (BPA) is classified as an endocrine-disrupting chemical (EDC) with estrogenic properties. Human endometrial endothelial cells (HEECs) play a key role in the endometrial angiogenesis that is under the control of estradiol. The hypothesis was that BPA may affect endometrial angiogenesis by disturbing some functional properties of the HEEC. To study this, primary HEECs were exposed to environmentally relevant doses of BPA. The HEECs were co-cultured with primary endometrial stromal cells to create conditions as similar to the in vivo situation as possible. The effects of BPA were evaluated by proliferation and viability assays, tube-formation assays, quantitative PCRs, Western blots and ELISAs. BPA slightly increased HEEC tube formation and VEGF-D protein expression compared with vehicle, without affecting HEEC viability or proliferation. Bisphenol A thus caused changes in HEEC activities in vitro, and may therefore have disturbing effects on endometrial angiogenesis.
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Affiliation(s)
- Malin Helmestam
- Department of Women's and Children's Health, Uppsala University, Uppsala SE-751 85, Sweden.
| | - Eva Davey
- Department of Women's and Children's Health, Uppsala University, Uppsala SE-751 85, Sweden
| | - Anneli Stavreus-Evers
- Department of Women's and Children's Health, Uppsala University, Uppsala SE-751 85, Sweden
| | - Matts Olovsson
- Department of Women's and Children's Health, Uppsala University, Uppsala SE-751 85, Sweden
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