Human CYP2E1-activated mutagenicity of dioxin-like PCBs 105 and 118—Experimental data consistent with molecular docking results

Hu, Keqi; Yu, Hang; Li, Zihuan; Jin, Guifang; Jia, Hansi; Song, Meiqi; Liu, Yungang

doi:10.1016/j.tox.2020.152438

Cited by 14 publications

(16 citation statements)

References 44 publications

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“…The computational structural setup for proteins and organic compounds was as recently described . In brief, the structures of the ligand binding domains (LBD) of PXR and CAR were modeled based on the crystal structure from the RCSB Protein Data Bank (1XVP for CAR, and 3CTB for PXR) by using a Swiss-model server.…”

Section: Methodsmentioning

confidence: 99%

“…The computational structural setup for proteins and organic compounds was as recently described. 41 In brief, the structures of the ligand binding domains (LBD) of PXR and CAR were modeled based on the crystal structure from the RCSB Protein Data Bank (1XVP for CAR, and 3CTB for PXR) by using a Swiss-model server. As there is no proper crystal structure of human AhR in the database, the LBD of AhR was analogously modeled according to the template of HIF-2α (PDB: 3H7W), as validated in a recent report.…”

Section: ■ Introductionmentioning

confidence: 99%

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

Song

et al. 2021

Environ. Sci. Technol.

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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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Section: Methodsmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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

Song

et al. 2021

Environ. Sci. Technol.

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“…A low-pass, whole-genome bisulfite sequencing (WGBS) approach analyzing human placenta samples from the prospective high-risk MARBLES ASD cohort demonstrated that DNA methylation profiles distinguished ASD from control placenta and the top differentially methylated region (DMR) mapped to CYP2E1 ( Zhu et al, 2019 ). Notably, CYP2E1 plays a key role in the metabolism of PCBs ( Chen et al, 2018 ; Hu et al, 2020 ; Liu et al, 2017 ; Uwimana et al, 2019 ). Furthermore, in the MARBLES cohort, PCBs were detected in the serum of the pregnant mothers at levels that were experimentally shown to impact neurodevelopmental processes in model systems ( Sethi et al, 2017a , 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Placenta and fetal brain share a neurodevelopmental disorder DNA methylation profile in a mouse model of prenatal PCB exposure

et al. 2022

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“…Dioxin-like PCBs such as PCB 77 and 81 were shown to have direct genotoxic effects on Chinese hamster V79-derived cell line by inducing micronuclei formation, and induced expression of CYP1A1, CYP2E1 and γ-H2AX protein (a marker of DNA double-strand breaks) [65,66].…”

Section: Possible Hepatocarcinogenic Mechanisms Of Pcbsmentioning

confidence: 99%

Impact of PCBs, Furan and Dioxin on Hepatocarcinogenesis

Helal¹,

Ghanem²,

El-Sikaily³

2022

Environmental Sciences

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Stockholm Convention defined polychlorinated biphenyls (PCBs) as a group of persistent organic pollutants (POPs) such as dioxin/furan, dichlorodiphenyltrichloroethane, polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, aldrin, polychlorinated dibenzofurans and organometallic compounds (such as organotin and organomercury) which share the same characteristics of being persistent, bioaccumulative and toxic and can travel long distance through various media. They have diverse health impacts with different underlined molecular mechanisms. Recently, PCBs were referred as potent carcinogens with persistent existence in the environment. As the liver is the organ of detoxification, it is the major target organ for toxic effects induced by environmental contaminants, including PCBs. PCBs, furan and dioxin exert their hepatocarcinogenic effect through different mechanisms such as induction of oxidative stress, an increase of reactive oxygen species (ROS), mutagenic induction to oncogenes and epigenetic alteration to hepatic cells. In this chapter, we will provide an updated overview about PCBs, furan and dioxins, their impact on liver cancer initiation and progression on various in vivo and in vitro systems and its underlined molecular mechanisms. Also, a special emphasis will be directed to highlight zebrafish as in vivo model system to analyse the hepatocarcinogenic effect of these pollutants.

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Human CYP2E1-activated mutagenicity of dioxin-like PCBs 105 and 118—Experimental data consistent with molecular docking results

Cited by 14 publications

References 44 publications

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

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

Placenta and fetal brain share a neurodevelopmental disorder DNA methylation profile in a mouse model of prenatal PCB exposure

Impact of PCBs, Furan and Dioxin on Hepatocarcinogenesis

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