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DISTRIBUTION OF ATRAZINE IN PC12 CELLS AND MODULATION OF CATECHOLAMINE SYNTHESIS
Citation:
Das, P. C., W. K. McElroy, AND R L. Cooper. DISTRIBUTION OF ATRAZINE IN PC12 CELLS AND MODULATION OF CATECHOLAMINE SYNTHESIS. Presented at Society of Toxicology, San Francisco, CA, March 25 - 29, 2001.
Description:
Previously, we reported that atrazine disrupts ovarian function by altering hypothalamic catecholamine (CA) concentrations and the consequent regulation of pituitary LH release and prolactin secretion in the young female rat. We also showed that atrazine directly interacts with the undifferentiated PC12 cells to reduce CA concentration and release in vitro, which corroborates the in vivo findings. This study was designed to identify whether atrazine i) binds to the PC12 cell membrane or other organelles, and ii) mediates a direct effect on the synthetic enzymes through the second messenger systems in altering intracellular catecholamine and NE release. PC12 cells were incubated with 100 ?M 14C-atrazine alone, and cold-atrazine in combination with 100 ?M Dimethytetrahydropterine, 100 ?M FeCl3, 1 mM 8-Br-cAMP, 1 ?M Dexamethasone, 4% DMSO, and 100 ?M Forskolin for 1 through 36 h. Atrazine preferentially binds to the nucleus, mitochondria-vesicles, microsome, and membrane within 3-12 h of exposure. In the process, atrazine decreased the immunoreactive tyrosine hydroxylase (TH) protein by ~25%, and significantly decreased the intracellular DA levels, which could not be reversed by any of the cofactors/activators of CA synthesis. However, the decrease in intracellular concentration and release of NE was reversed by FeCl3 at early time points, by DMSO at 24 h, and by Forskolin at 6-24 h. Cell viability was not altered by any treatment. These data suggest that atrazine suppresses CA synthesis by inhibiting the synthetic enzymes TH and/or dopamine- -hydroxylase in PC12 cells, probably through transcriptional and/or via translational regulatory pathways. (UNC TA No. CT827206. This abstract does not reflect U.S. EPA policy.)