title: Neurochemical effects of environmental chemicals: in vitro and in vivo correlations on second messenger pathways.
abstract: Polychlorinated biphenyls (PCBs) are persistent, bioaccumulative, toxic, and widely distributed environmental chemicals. There is now both epidemiological and experimental evidence that PCBs cause cognitive deficits; however, the underlying cellular or molecular mechanism(s) is not known. We have hypothesized that altered signal transduction/second messenger homeostasis by PCBs may be associated with these effects since second messengers in signal transduction pathways, such as calcium, inositol phosphates (IP), and protein kinase C (PKC), play key roles in neuronal development and their function. In vitro studies using cerebellar granule neurons and isolated organelle preparations indicate that ortho-PCBs increase intracellular free Ca2+ levels by inhibiting microsomal and mitochondrial Ca2+ buffering and the Ca2+ extrusion process. Ortho-PCBs also increase agonist-stimulated IP accumulation and cause PKC translocation at low micromolar concentrations where no cytotoxicity is observed. On the other hand, non-ortho-PCBs are not effective in altering these events. Further SAR studies indicate that congeners with chlorine substitutions favoring non-coplanarity are active in vitro, while congeners favoring coplanarity are relatively inactive. Subsequent in vivo studies have shown that repeated exposure to a PCB mixture, Aroclor 1254, increases PKC translocation and decreases Ca2+ buffering in the brain, similar to in vitro studies. These changes in vivo are associated with elevated levels of non-coplanar ortho-PCB congeners at levels equivalent to 40-50 microM in brain, the concentrations that significantly inhibited second messenger systems in neuronal cultures in vitro. Current research is focusing on PCB-induced alterations in second messenger systems following developmental exposure.
authors.affiliation: Cellular and Molecular Toxicology Branch, Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. k.
authors.forename: P R
authors.initials: PR
authors.lastname: Kodavanti
authors.forename: H A
authors.initials: HA
authors.lastname: Tilson
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004785:Environmental Pollutants / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D009498:Neurotoxins / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D015290:Second Messenger Systems / Q000187:drug effects*; D018675:Toxicity Tests
chemical_list: D004785:Environmental Pollutants; D007295:Inositol Phosphates; D009498:Neurotoxins; D016718:Arachidonic Acid; D011078:Polychlorinated Biphenyls; D019001:Nitric Oxide Synthase; D011493:Protein Kinase C; D002118:Calcium