Neurotoxicity of environmental chemicals and their mechanism of action

Despite a ban on their manufacture in 1977, polychlorinated biphenyls (PCBs ) are still found in significant quantities in the environment. Development al exposure to PCBs and related compounds has been reported to be neurotoxi c in human and animals. Research in our laboratory has focused on the possi ble site(s) and mechanism(s) of PCB-induced developmental neurotoxicity. Re cent experiments with rats found that developmental exposure to Aroclor-125 4 (ARC) affects the acquisition of a lever press response and produces long -term changes in calcium buffering and protein kinase C (PKC) activity in t he brain. In vitro studies in our laboratory have found that ARC increases [H-3]phorbol ester binding, an indirect measure of PKC translocation, and i nhibits calcium buffering in microsomes and mitochondria. Other experiments indicate that PCB congeners with chlorine substitutions at ortho- or low l ateral substitutions are active in vitro, while non-ortho-substituted conge ners are less active or inactive. Other research suggests that the lack of coplanarity of the PCB molecule is related to in vitro activity of PCB cong eners. These studies indicate that in vivo developmental exposure to PCBs a lters behavior and second messenger systems during adulthood, while in vitr o experiments indicate that nervous system activity is related to ortho-sub stituted congeners that tend to be non-coplanar in configuration. Our resul ts are consistent with the hypothesis that developmental neurotoxicity of A RC is due, in part, to the presence of ortho-substituted PCB congeners. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.