Induction of aberrant mitosis with PCBs: particular efficiency of 2,3,3 ',4,4 '-pentachlorobiphenyl and synergism with triphenyltin

The polychlorinated biphenyls 2,2',5,5'- and 3,3',4,4'-tetrachlorobiphenyl, 2,3,3',4,4'- and 3,3',4,4',5-pentachlorobiphenyl and 2,2',4,4',5,5'-hexach lorobiphenyl were tested for spindle-disturbing activity in V79 Chinese ham ster cells, Clones lacking endogenous cytochrome P450 activity or expressin g rat CYP1A1 or CYP2B1 were used. Induction of abnormal chromosomal arrange ments in mitosis were found to be favoured by o-chlorine substitutions, but not by co-planarity giving affinity, for example, for the Ah receptor and CYP1A isoenzymes. Only 2,2',5,5'-tetrachloro- and 2,3,3',4,4'-pentachlorobi phenyl gave dose-response curves similar to many other compounds tested in vitro, showing an increase from the background level of 10 to 100% disturbe d mitoses with nominal concentrations >10(-6) M, i.e, concentrations far ab ove the total PCB concentrations found in human blood. Cells transfected wi th rat CYP2B1 were more sensitive to the most active congener, 2,3',4,4'-pe ntachlorobiphenyl, than cells lacking P450 activity or expressing CYP1A1, I nduction of abnormal mitosis by PCB metabolites formed by P450 enzymes cann ot be excluded, but does not seem likely because of the short treatment tim e and the reportedly slow metabolism of PCBs, 2,3,3',4,4'-Pentachlorobiphen yl showed synergistic activity with the potent spindle poison triphenyltin. Inactive concentrations of both agents (10 and 50 nM, respectively) caused abnormal configurations when combined. This is an important finding since exposure to mixtures of compounds is common and it motivates further studie s of subthreshold activities of highly lipophilic environmental contaminant s.