Hydroxyl metabolite of PCB 180 induces DNA damage signaling and enhances the DNA damaging effect of benzo[a]pyrene

•Levels of a PCB180 metabolite in rat liver correlated to DNA damage signaling in vivo.•This metabolite, 3′-OH-PCB180, induced CYP1A1 mRNA, pChk1and γH2AX in HepG2 cells.•Estradiol amplified, and the antioxidant NAC prevented, DNA damage signaling in vitro.•3′-OH-PCB180 amplified DNA damage signaling induced by benzo[a]pyrene.•It is concluded that PCB180 induce genotoxic stress via CYP1A1 induction and ROS.

Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) and their hydroxyl metabolites (OH-PCBs) are ubiquitous environmental contaminants in human tissues and blood. The toxicological impact of these metabolites is poorly understood. In this study rats were exposed to ultrapure PCB180 (10-1000 mg/kg bw) for 28 days and induction of genotoxic stress in liver was investigated. DNA damage signaling proteins (pChk1Ser317 and γH2AXSer319) were increased dose dependently in female rats. This increase was paralleled by increasing levels of the metabolite 3′-OH-PCB180. pChk1 was the most sensitive marker. In in vitro studies HepG2 cells were exposed to 1 μM of PCB180 and 3′-OH-PCB180 or the positive control benzo[a]pyrene (BaP, 5 μM). 3′-OH-PCB180, but not PCB180, induced CYP1A1 mRNA and γH2AX. CYP1A1 mRNA induction was seen at 1 h, and γH2AX at 3 h. The anti-oxidant N-Acetyl-l-Cysteine (NAC) completely prevented, and 17β-estradiol amplified the γH2AX induction by 3′-OH-PCB180. As 3′-OH-PCB180 induced CYP1A1, a major BaP-metabolizing and activating enzyme, interactions between 3′-OH-PCB180 and BaP was also studied. The metabolite amplified the DNA damage signaling response to BaP. In conclusion, metabolism of PCB180 to its hydroxyl metabolite and the subsequent induction of CYP1A1 seem important for DNA damage induced by PCB180 in vivo. Amplification of the response with estradiol may explain why DNA damage was only seen in female rats.