Featured structure-activity relationships for some tri- and tetrachlorobiphenyls in human CYP2E1-activated mutagenicity — Impact of the extent of ortho-chlorination

Chen, Yuting; Zhu, Na; Luo, Yuyi; Hu, Keqi; Liu, Yungang

doi:10.1016/j.chemosphere.2018.06.169

Cited by 16 publications

(9 citation statements)

References 33 publications

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“…Goat antimouse IgG antibodies (DyLight 800) (AMJ-AB2015) were from Amyjet Scientific (Wuhan, China). These antibodies (from the same sources as above) worked well in our relevant studies …”

Section: Methodsmentioning

confidence: 64%

“…These antibodies (from the same sources as above) worked well in our relevant studies. 25 Cell Lines. V79-Mz was completely deficient in the expression of CYPs, SULTs, and UDP-glucuronosyltransferases (UGTs); 26 therefore, it had been used as the parental line for the construction of human CYP-expressing cell lines 27 and was used in the present study as a metabolismincompetent control.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

“…The micronuclei formed in C3A cells by each BP compound were further analyzed for the presence or absence of a centromere, by immunofluorescence staining of CENP-B, a method established to distinguish between clastogenic and aneugenic action. 25 The immunofluorescence staining of the micronuclei formed by test compounds and positive controls is shown in Figure S6 (Supporting Information). As indicated in Table 2, BPA, BPF, and BPS elevated CENP-B negative micronuclei formation from 10 to 80 μM in a concentration-dependent manner; however, none of them induced CENP-B positive micronuclei in that range of concentration, which suggests that these BP compounds may be pure clastogens.…”

Section: Environmentalmentioning

confidence: 99%

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Potent Clastogenicity of Bisphenol Compounds in Mammalian Cells—Human CYP1A1 Being a Major Activating Enzyme

Chen

et al. 2020

Environ. Sci. Technol.

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Bisphenols (BPs) are environmental pollutants with relevant DNA damage in human population; however, they are generally inactive in standard mutagenicity assays, possibly due to insufficient metabolic activation. In this study, induction of micronuclei and double-strand DNA breaks by BPA, BPF, and BPS in Chinese hamster V79-derived cell lines expressing various human CYP enzymes and a human hepatoma (C3A) (metabolism-proficient) cell line were investigated. Molecular docking of BPs to human CYPs indicated some substrate–enzyme potentials, including CYP1A1 for each compound, which did not induce micronuclei in V79-derived cell lines expressing human CYP1A2, 2E1, or 3A4 but became positive in human CYP1A1-expressing (V79-hCYP1A1) cells. In V79-hCYP1A1 and C3A cells, all compounds induced double-strand DNA breaks and micronuclei formation, which were blocked/significantly attenuated by 1-aminobenzotriazole (CYP inhibitor) or 7-hydroxyflavone (selective CYP1A1 inhibitor). Coexposure of C3A cells to pentachlorophenol (sulfotransferase 1 inhibitor) or ketoconazole (UDP-glucuronosyltransferase 1A inhibitor) potentiated micronuclei induction by each compound, with thresholds lowered from 2.5–5.0 to 0.6–1.2 μM. Immunofluorescence staining of centromere protein B with micronuclei formed in C3A cells by each compound indicated pure clastogenic effects. In conclusion, BPs are potently clastogenic in mammalian cells, which require activation primarily by human CYP1A1 and are negatively modulated by phase II metabolism.

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“…Goat antimouse IgG antibodies (DyLight 800) (AMJ-AB2015) were from Amyjet Scientific (Wuhan, China). These antibodies (from the same sources as above) worked well in our relevant studies …”

Section: Methodsmentioning

confidence: 64%

Section: ■ Materials and Methodsmentioning

confidence: 99%

Section: Environmentalmentioning

confidence: 99%

See 1 more Smart Citation

Potent Clastogenicity of Bisphenol Compounds in Mammalian Cells—Human CYP1A1 Being a Major Activating Enzyme

Chen

et al. 2020

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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“…A low-pass whole genome bisulfite sequencing (WGBS) approach analyzing human placenta samples from a prospective high-risk 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%

Genome-Wide DNA Methylation Profiles of Neurodevelopmental Disorder Genes in Mouse Placenta and Fetal Brain Following Prenatal Exposure to Polychlorinated Biphenyls

Laufer

et al. 2021

Preprint

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Background: Polychlorinated biphenyls (PCBs) are developmental neurotoxicants implicated as environmental risk factors for neurodevelopmental disorders (NDD), including autism spectrum disorders (ASD). Objective: We examined the effects of prenatal exposure to a human-relevant mixture of PCBs on the DNA methylome of fetal mouse brain and placenta to determine if there was a shared subset of differentially methylated regions (DMRs). Methods: A PCB mixture formulated to model the 12 most abundant congeners detected in the serum of pregnant women from a prospective high-risk ASD cohort was administered to female mice prior to and during pregnancy. Whole-genome bisulfite sequencing (WGBS) was performed to assess genome-wide DNA methylation profiles of placenta and brain on gestational day 18. Results: We found thousands of significant (empirical p < 0.05) DMRs distinguishing placentas and brains from PCB-exposed embryos from sex-matched vehicle controls. In both placenta and brain, PCB-associated DMRs were significantly (p < 0.005) enriched for functions related to neurodevelopment, cellular adhesion, and cellular signaling, and significantly (Odds Ratio > 2.4, q < 0.003) enriched for bivalent chromatin marks. The placenta and brain PCB DMRs overlapped significantly (Z-score = 4.5, p = 0.0001) by genomic coordinate and mapped to a shared subset of genes significantly (q < 0.05) enriched for Wnt signaling, Slit/Robo signaling, and genes differentially expressed in multiple NDD/ASD models. The placenta and brain DMRs also significantly (q < 0.05) overlapped by genomic coordinate with brain samples from humans with Rett syndrome and Dup15q syndrome. Discussion: These results demonstrate that placenta can be used as a surrogate for embryonic brain DNA methylation changes over genes relevant to NDD/ASD in a mouse model of prenatal PCB exposure.

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Featured structure-activity relationships for some tri- and tetrachlorobiphenyls in human CYP2E1-activated mutagenicity — Impact of the extent of ortho-chlorination

Cited by 16 publications

References 33 publications

Potent Clastogenicity of Bisphenol Compounds in Mammalian Cells—Human CYP1A1 Being a Major Activating Enzyme

Potent Clastogenicity of Bisphenol Compounds in Mammalian Cells—Human CYP1A1 Being a Major Activating Enzyme

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

Genome-Wide DNA Methylation Profiles of Neurodevelopmental Disorder Genes in Mouse Placenta and Fetal Brain Following Prenatal Exposure to Polychlorinated Biphenyls

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