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Influence of Bisphenol Compounds at Nanomolar Concentrations on Chromosome Damage Induced by Metabolically Activated Carcinogens in HepG2 Cells

  • Hang Yu
    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
    More by Hang Yu
  • Meiqi Song
    Meiqi Song
    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
    More by Meiqi Song
  • Keqi Hu
    Keqi Hu
    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
    More by Keqi Hu
  • Yujian Wang
    Yujian Wang
    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
    More by Yujian Wang
  • Ruifang Fan
    Ruifang Fan
    School of Life Science, South China Normal University, Guangzhou 510631, China
    More by Ruifang Fan
  • Zongying Yang
    Zongying Yang
    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
  • Hansruedi Glatt
    Hansruedi Glatt
    Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE), Arthur-Scheunert-Allee 114-116, Nuthetal D-14558, Germany
    Department of Food Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Straße 8-10, Berlin D-10589, Germany
  • Albert Braeuning
    Albert Braeuning
    Department of Food Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Straße 8-10, Berlin D-10589, Germany
  • , and 
  • Yungang Liu*
    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
    *Email: [email protected]. Phone: +86-20-61648554.
    More by Yungang Liu
Cite this: Environ. Sci. Technol. 2021, 55, 14, 10001–10011
Publication Date (Web):July 9, 2021
https://doi.org/10.1021/acs.est.1c02189
Copyright © 2021 American Chemical Society

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    Abstract

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    Bisphenol (BP) compounds are endocrine-disrupting organic pollutants. BPs may increase the messenger RNA (mRNA) transcripts of nuclear receptors (NRs) regulating the expression of xenobiotic-metabolizing cytochrome P450 (CYP) enzymes. Their impact on the genotoxicity of metabolically activated carcinogens, however, remains unknown. In this study, effects of the bisphenols A, F, S, and AF on the expression of the aryl hydrocarbon receptor (AhR), the pregnane X receptor (PXR), the constitutive androstane receptor, and individual xenobiotic-metabolizing CYP enzymes in a human hepatoma (HepG2) cell line were investigated, along with in silico binding studies of BPs to each receptor. The results indicated that each BP at 1 to 100 nM concentrations increased the mRNA transcripts and protein levels of AhR, PXR, CYP1A1, 1A2, 1B1, 2E1, and 3A4. The predicted affinities of the BPs for binding AhR were comparable to those of potent agonists. Pretreatment of HepG2 cells with each BP potentiated the induction of micronuclei by benzo[a]pyrene, aflatoxin B1, benzene, and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; this effect was abolished/reduced by inhibitors of NRs and/or CYPs. Our study suggests that BPs at human exposure levels may aggravate chromosome damage by several impactful carcinogens in human cells by inducing relevant CYP enzymes, mostly via NR modulation.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.est.1c02189.

    • V79-derived cell lines and materials for RT-PCR of NRs/CYPs; validation of primary antibodies against CYPs and the complete data of BP impact on NR/CYP protein levels; molecular docking and dynamics analysis of the binding of BPs to each NR; complete data of the impact of each BP on each carcinogen-induced micronucleus formation; and the influence of NR/CYP modulators on BPA-potentiated, each carcinogen-induced micronucleus formation (PDF)

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    Cited By

    This article is cited by 13 publications.

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    2. Hang Yu, Yungang Liu. 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 (1) , 498-508. https://doi.org/10.1021/acs.est.2c06064
    3. Elize A. Santos Musachio, Marcia Rósula Poetini, Dieniffer Espinosa Janner, Eliana Jardim Fernandes, Luana Barreto Meichtry, Mustafa Munir Mustafa Dahleh, Gustavo Petri Guerra, Marina Prigol. Safer alternatives? Bisphenol F and Bisphenol S induce oxidative stress in Drosophila melanogaster larvae and trigger developmental damage. Food and Chemical Toxicology 2023, 175 , 113701. https://doi.org/10.1016/j.fct.2023.113701
    4. Huang Chenchen, Hu Keqi, Zeng Yanhong, Jiang Yiye, Tian Yankuan, Luo Xiaojun, Mai Bixian. In vitro hepatic metabolism of polychlorinated biphenyls with different chlorine-substituted structures in rats and humans: Kinetics, metabolism, and potential nuclear receptor affinities. Science of The Total Environment 2023, 864 , 161043. https://doi.org/10.1016/j.scitotenv.2022.161043
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    10. Zongying Yang, Hang Yu, Hongwei Tu, Zhihong Chen, Keqi Hu, Hansi Jia, Yungang Liu. Influence of aryl hydrocarbon receptor and sulfotransferase 1A1 on bisphenol AF-induced clastogenesis in human hepatoma cells. Toxicology 2022, 471 , 153175. https://doi.org/10.1016/j.tox.2022.153175
    11. Meiqi Song, Yujian Wang, Zhihong Chen, Hongbin Gao, Zongying Yang, Hang Yu, Yungang Liu. Human CYP enzyme-activated genotoxicity of 2,2′,4,4′-tetrabromobiphenyl ether in mammalian cells. Chemosphere 2022, 291 , 132784. https://doi.org/10.1016/j.chemosphere.2021.132784
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    13. Jia-Yue Wang, Jing-Xin Li, Jing Ning, Zhenlong Yu, Yan Tian, Baojing Zhang, Yan Wang, Sa Deng, Ya-Chen Li, Xia Lv, Xiaochi Ma. Human Cytochrome P450 3a-Mediated Two-Step Oxidation Metabolism of Dimethomorph: Implicated in Mechanism-Based Enzyme Inactivation. SSRN Electronic Journal 2021, 46 https://doi.org/10.2139/ssrn.3989499

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