Neurochemical Effects of Environmental Chemicals: In Vitro and In Vivo Correlations on Second Messenger Pathwaysa
| Autor: | Hugh A. Tilson, Prasada Rao S. Kodavanti |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Inositol Phosphates Neurotoxins Biology Second Messenger Systems General Biochemistry Genetics and Molecular Biology chemistry.chemical_compound Neurochemical History and Philosophy of Science In vivo Toxicity Tests Animals Humans Rats Long-Evans Inositol Protein Kinase C Protein kinase C Arachidonic Acid General Neuroscience Brain Polychlorinated Biphenyls In vitro Rats chemistry Biochemistry Second messenger system Calcium Environmental Pollutants Nitric Oxide Synthase Signal transduction Intracellular |
| Zdroj: | Annals of the New York Academy of Sciences. 919:97-105 |
| ISSN: | 1749-6632 0077-8923 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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