Mutagenesis, Vol. 15, No. 1, 9-15,
January 2000
© 2000 UK Environmental Mutagen Society/Oxford University Press
Induction of aberrant mitosis with PCBs: particular efficiency of 2,3,3',4,4'-pentachlorobiphenyl and synergism with triphenyltin
Department of Toxicology, National Institute for Working Life, S-171 84 Solna and 1 Environmental Chemistry and 2 Genetic and Cellular Toxicology, Wallenberg Laboratory, S-106 91 Stockholm, Sweden
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'-hexachlorobiphenyl were tested for spindle-disturbing activity in V79 Chinese hamster cells. Clones lacking endogenous cytochrome P450 activity or expressing rat CYP1A1 or CYP2B1 were used. Induction of abnormal chromosomal arrangements 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'-pentachlorobiphenyl gave dose–response curves similar to many other compounds tested in vitro, showing an increase from the background level of 10 to 100% disturbed mitoses with nominal concentrations >10–6 M, i.e. concentrations far above the total PCB concentrations found in human blood. Cells transfected with rat CYP2B1 were more sensitive to the most active congener, 2,3,3',4,4'-pentachlorobiphenyl, than cells lacking P450 activity or expressing CYP1A1. Induction of abnormal mitosis by PCB metabolites formed by P450 enzymes cannot be excluded, but does not seem likely because of the short treatment time and the reportedly slow metabolism of PCBs. 2,3,3',4,4'-Pentachlorobiphenyl 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 studies of subthreshold activities of highly lipophilic environmental contaminants.
3 To whom correspondence should be addressed. Tel: +46 8 162 914; Fax: +46 8 612 4004; Email: onfelt{at}genetics.su.se
4 Present address: Department of Drug Metabolism, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark
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