THE NEUROTOXICITY OF POLYCHLORINATED-BIPHENYLS

Like dioxin, some polychlorinated biphenyl (PCB) congeners produce tox icity by binding to an aryl hydrocarbon (Ah) receptor. Other PCB conge ners that have little or no activity at the Ah receptor have been show n to accumulate in the brain following in vivo exposure and decrease d opamine content. Subsequent research has found that non-dioxin-like PC Bs also interfere with calcium homeostatic mechanisms and intracellula r second messenger systems in vitro in neuronal cultures and brain sub cellular fractions. The biological significance of these effects of PC Bs in nervous system preparations is not known, although a number of c alcium-dependent processes are important for nervous system function a nd development. Structure-activity relationship (SAR) studies based on measures of PCB-induced alterations in protein kinase C (PKC) translo cation and Ca2+-buffering indicate that congeners with chlorine substi tutions at the ortho-position are active in vitro, while non-ortho con geners are relatively inactive. Subsequent research has found that chl oride substitution patterns that favor non-co-planarity are associated with activity in nervous system preparations. Recent in vivo studies in adults have shown that repeated exposure to a PCB mixture Aroclor 1 254 increases translocation of PKC and decreases Ca (2+)-buffering in the brain. Increased levels of ortho-substituted non-coplanar PCB cong eners were observed in the brains of Aroclor 1254-treated animals rela tive to vehicle controls. Current research is focusing on the possibil ity that PCB-induced alterations in calcium homeostasis and intracellu lar second messengers may be related to the developmental neurotoxicit y of PCBs. (C) 1998 Inter Press, Inc.