Polyploidy-induction by dihydroxylated monochlorobiphenyls: structure-activity-relationships.

Recently semivolatile lower chlorinated biphenyls have been identified in inner city air, in public buildings like schools, and at many other sites. Inhalation exposure to these compounds, which are readily metabolized to mono- and dihydroxy-biphenyls and further to quinones, is of great concern in light of new studies revealing that at least one such compound, 4-monochlorobiphenyl (PCB3), has tumor initiating and mutagenic activity in rats. In vitro the quinone metabolites of PCB3 induced gene mutations, whereas its mono- and dihydroxylated metabolites increased micronuclei frequency. To gain further insight into the genotoxicity and possible structure-activity-relationships of the dihydroxy-metabolites, we measured the effects of the 2-chloro-, 3-chloro-, and 4-chloro-2',5'-dihydroxybiphenyl (PCB1-HQ, PCB2-HQ, and PCB3-HQ, respectively), and of 4-chloro-3',4'-dihydroxybiphenyl (PCB3-Cat) on cytotoxicity, sister chromatid exchange (SCE), cellular proliferation and chromosome number. Notably only PCB3-Cat caused a significant increase in SCE levels. Cell cycle progression during exposure, which is indicated indirectly in this assay by the occurrence of metaphases with Harlequin-stained chromosomes (cell underwent two S-phases) or uniformly dark-stained chromosomes (underwent less than two S-phases) was inhibited by PCB2-HQ and PCB3-HQ. Most surprising was the finding that up to 96% of metaphases from cells treated with PCB2- or PCB3-HQ were tetraploid, some of which had dark and some Harlequin-stained chromosomes. Neither PCB1-HQ nor PCB3-Cat or the negative (solvent) or positive control (ethylmethane sulfonate, EMS) induced this effect. The mechanism of this polyploidization is unknown. Nearly all cancer cells are hyperdiploid and polyploidization, followed by uneven chromosome loss, is hypothesized as one possible underlying mechanism of carcinogenesis. Thus different PCB metabolites may induce carcinogenesis by different mechanisms, including SCE induction or polyploidization. Understanding the mechanism(s) and structure-activity-relationships of these unexpected effects is needed before we can perform fully data-driven risk assessment of these compounds.