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Bisphenol compounds (BPs) are ubiquitously existing pollutants. Recent evidence shows that they may be activated by human CYP1A1 for clastogenic effects; however, factors that influence/mediate CYP1A1-activated 4,4′-(hexafluoroisopropylidene)diphenol (BPAF) toxicity, particularly the aryl hydrocarbon receptor (AhR), sulfotransferase (SULT) 1A1 [known to conjugate 2,2-bis(4-hydroxyphenol)-propane (BPA)] and reactive oxygen species (ROS), remain unclear. In this study, a human hepatoma (HepG2) cell line was genetically engineered for the expression of human CYP1A1 and SULT1A1, producing HepG2-hCYP1A1 and HepG2-hSULT1A1, respectively. They were used in the micronucleus test and γ-H2AX analysis (Western blot) (indicating double-strand DNA breaks) with BPAF; the role of AhR in mediating BPAF toxicity was investigated by coexposure of AhR modulators in HepG2 and its derivative C3A (with no genetic modifications but enhanced CYP expression). The results indicated induction of micronuclei by BPAF (≥ 2.5 µM, for 2-cell cycle) in HepG2-hCYP1A1 and C3A, while inactive in HepG2 and HepG2-hSULT1A1; however, BPAF induced micronuclei in HepG2 pretreated with 3,3′,4,4′,5-pentachlorobiphenyl (PCB126, AhR activator), and BAY-218 (AhR inhibitor) blocked the effect of BPAF in C3A. In HepG2-hCYP1A1 BPAF selectively induced centromere-free micronuclei (immunofluorescent assay) and double-strand DNA breaks. In HepG2 cells receiving conditional medium from BPAF-HepG2-hCYP1A1 incubation micronuclei were formed, while negative in HepG2-hSULT1A1. Finally, the intracellular levels of ROS, superoxide dismutase and reduced glutathione in C3A and HepG2-hCYP1A1 exposed to BPAF were all moderately increased, while unchanged in HepG2 cells. In conclusion, like other BPs BPAF is activated by human CYP1A1 for potent clastogenicity, and this effect is enhanced by AhR while alleviated by SULT1A1. [Display omitted] • Bisphenol AF (BPAF) induces chromosome/DNA breaks in human cells. • BPAF is activated by human CYP1A1 while detoxified by SULT1A1. • Activation of aromatic hydrocarbon receptor enhances genotoxicity of BPAF. • Reactive oxygen species seems insignificant in CYP1A1-activated BPAF genotoxicity. [ABSTRACT FROM AUTHOR]

Polychlorinated biphenyls (PCBs) are persistent organic pollutants and human carcinogens. It was reported that rat CYP1A1 and catfish CYP1A can hydroxylate 3,3',4,4',5-pentachlorobiphenyl (PCB 126) and 3,3',4,4'-tetrachlorobiphenyl (PCB 77), while potential roles of other CYP1 enzymes in the metabolism of dioxin-like (DL) PCBs remain unconfirmed. In this study, three representative DL-PCBs, i.e., PCB 77, PCB 126, and 3,4,4',5-tetrachlorobiphenyl (PCB 81), were investigated on their genotoxicity in Chinese hamster V79-derived cell lines genetically engineered for the expression of human CYP1A1, 1A2 and 1B1, and in the human hepatoma C3A cell line, which endogenously expresses various CYPs. Under both 6 h/18 h and 18 h/6 h (exposure/recovery) regimes, PCB 77 and 81 induced micronuclei in V79-hCYP1B1 cells at micromolar levels, with slightly higher potency in the latter regime, while they were inactive in the parental V79-Mz cells and the V79-derived cell lines expressing human CYP1A1 and 1A2. However, PCB 126 was negative in each cell line. Likewise, PCB 77 and 81 induced micronuclei formation in C3A cells, which expressed CYP1B1. This effect was blocked by co-exposure to tetramethoxystilbene (30 nM), a selective CYP1B1 inhibitor. Immuno-fluorescent staining of centromere protein B in the micronuclei in PCB-treated cultures showed a predominance of centromere-negative micronuclei, which indicated a clastogenic effect. Moreover, all three PCBs elevated the level of γ-H2AX protein (indicating DNA double-strand breaks) in C3A cells, and these effects were blocked by tetramethoxystilbene (10 nM). This study demonstrates that some DL-PCBs are clastogenic in mammalian cells following metabolic activation by human CYP1B1. [ABSTRACT FROM AUTHOR]