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.

Sources and toxicities of phenolic polychlorinated biphenyls (OH-PCBs)

“…It is noteworthy that non-genotoxic concentrations of PCB 77 combined with PCB 52, which alone did not produce chromosome damage in human lymphocytes in vitro , caused a vastly enhanced cytogenetic effect if combined, and this synergistic effect was also observed in rat bone marrow cells in vivo (Meisner et al 1992, Sargent et al 1991, Sargent et al 1989). Also, several mono- and di-chlorinated PCBs were shown to very efficiently induce micronuclei formation and hprt mutations in hamster V79 cells that express CYP 2E1 and surprisingly the most active congeners were some non-planar tri- and tetra-chlorinated congeners (Liu et al 2016, Wang et al 2017, Zhang et al 2016). V79 cells without CYP or other forms of P-450 were protected from PCB genotoxicity demonstrating that CYP 2E1 may be a predominant enzyme bioactivating PCBs with 1 to 4 chlorines to genotoxins.…”