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'-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.
Jensen
K G
KG
Department of Toxicology, National Institute for Working Life, S-171 84 Solna, Sweden.
Wiberg
K
K
Klasson-Wehler
E
E
Onfelt
A
A
D000818:Animals; D002460:Cell Line; D002869:Chromosome Aberrations; D006224:Cricetinae; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019362:Cytochrome P-450 CYP2B1 / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D009947:Organotin Compounds / Q000633:toxicity*; D011078:Polychlorinated Biphenyls / Q000633:toxicity*; D051381:Rats
D009947:Organotin Compounds; C067940:2,3,3',4,4'-pentachlorobiphenyl; C030665:triphenyltin; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1