Induction of micronuclei and cell cycle arrest by some tri- and tetrachlorobiphenyls in mammalian cells deficient in xenobiotic-metabolizing enzymes.

Abstract

Polychlorinated biphenyls (PCBs) are persistent organic pollutants with continued public health concerns. The lower chlorinated biphenyls are supposed to be mutagenic following metabolic activation. However, in a preliminary study, we recently observed induction of micronuclei by several PCBs in a subclone of Chinese hamster V79 cell line, V79-Mz, which is deficient in xenobiotic-metabolizing enzyme activities. In this study, metabolism-free genotoxicity of PCBs was investigated, using 10 tri- and tetrachlorobiphenyls, in V79, V79-Mz, and human hepatoma (HepG2) cell lines. Among the four tetrachlorobiphenyls, 2,4,4',5- and 2,3'4,4'-tetrachlorobiphenyl-both having a noncoplanar configuration-induced micronuclei in V79-Mz cells, while their coplanar analogs 3,4,4',5- and 3,3',4,4'-tetrachlorobiphenyl were inactive. Furthermore, 2,3,3'- (PCB 20) and 2,3,4'-trichlorobiphenyl (PCB 22) started to induce micronuclei in V79-Mz cells at 10 μM and higher concentrations, demonstrating more potent effects than observed with 2,2',3-, 2,2',4-, 2,2',5, and 2,4,4'-trichlorobiphenyl. As representative compounds, PCB 20 and 22 induced micronuclei in relatively high concentrations in HepG2 cells (p53-proficient), though they did not induce Hprt gene mutations in V79-Mz cells. PCB 20 and 22 increased mitotic index and induced cell cycle arrest at the G2/M phase, with effects more potent in V79-Mz than in V79 cells. This study suggests that 2,3,4'- and 2,3,3'-substituted PCBs are micronuclei inducers and G2/M arresters among a number of trichlorobiphenyls in mammalian cell lines, though with potency lower than that observed recently in V79-derived cells expressing human CYP2E1. Similarly, some noncoplanar tetrachlorobiphenyls possess metabolism-independent chromosome-damaging potentials. Environ. Mol. Mutagen. 58:199-208, 2017. © 2017 Wiley Periodicals, Inc.