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APOPTOSIS DURING DEVELOPMENT AND AGING AND IN RESPONSE TO MERCURY EXPOSURE.
Citation:
White, L. D., D. K. Parran, AND S Barone. APOPTOSIS DURING DEVELOPMENT AND AGING AND IN RESPONSE TO MERCURY EXPOSURE. Presented at Society of Toxicology, San Francisco, CA, 3/25-29/2000.
Description:
In the central nervous system from embryogenesis through senescence, cell number is regulated, in part, by apoptosis. Each region of the nervous system has a characteristic temporal pattern of programmed cell death, which includes far greater numbers of cells undergoing apoptosis during early postnatal development. This early apoptosis is found in proliferative zones whereas few apoptotic cells are found in adult animals. A number of environmental contaminants, including methylmercury (CH3Hg), have been shown to alter this normal pattern of cell death. CH3Hg, an ubiquitous environmental toxicant, has a profound effect on the developing central nervous system. Gestational exposure to CH3Hg leads to neurological abnormalities resulting in both death of neurons and altered cytoarchitecture in the developing CNS. To ascertain the mechanisms leading to this increased apoptosis, we examined the effects CH3Hg and mercuric chloride (HgCl2) on cell death in rat pheochromocytoma (PC12) cells. Doses of 0, 0.01, 0.03, 0.1, 0.3, 1, 3 and 10 ?M of either CH3Hg or HgCl2 in the presence or absence of 50 ng/ml NGF for 24 hours were followed by analysis of DNA fragmentation, cell size, and morphology. In the presence of NGF, CH3Hg caused increased levels of fragmented DNA at concentrations of 1, 3 and 10 ?M, while HgCl2 had no significant effect on fragmented DNA at any of the tested concentrations. A significant decrease in cell size was observed at 0.3-10 ?M of CH3Hg, while no significant change in cell body size was seen following exposure to HgCl2. In the absence of NGF, control levels of fragmented DNA were approximately 8-12 times higher than in the presence of NGF. Morphological and fragmented DNA assay data indicate that at doses above 3 ?M necrosis is induced in these cells by. These data suggest that, in the presence of NGF, CH3Hg but not HgCl2, induces apoptotic cell death. Further, these data support the hypothesis that NGF modulates apoptosis and history of exposure to trophic factors like NGF can alter a neurotoxicant's mechanism of action. (This abstract does not reflect USEPA policy).