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POTENTIAL MECHANISMS RESPONSIBLE FOR CHLOROTRIAZINE-INDUCED ALTERATIONS IN CATECHOLAMINES IN PHEOCHROMOCYTOMA (PC12) CELLS
Das, P. C., W. K. McElroy, AND R L. Cooper. POTENTIAL MECHANISMS RESPONSIBLE FOR CHLOROTRIAZINE-INDUCED ALTERATIONS IN CATECHOLAMINES IN PHEOCHROMOCYTOMA (PC12) CELLS. LIFE SCIENCES 73(24):3123-3138, (2003).
Potential Mechanisms Responsible for Chlorotriazine-induced Changes in Catecholamine Metabolism in Pheochromocytoma (PC12) Cells*
PARIKSHIT C. DAS1, WILLIAM K. McELROY2 , AND RALPH L. COOPER2+
1Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599; 2Endocrinology Branch, Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA
Chlorotriazines interact with undifferentiated PC12 cells in vitro to modulate the catecholamines, but the mechanism(s) responsible for this effect had not been determined. In this study we evaluated (1) the distribution of 14C-Atrazine in PC12 cells, (2) the effect of atrazine, simazine and cyanazine on the enzymes responsible for the synthesis of dopamine (DA) and norepinephrine (NE), and (3) the possible intracellular pathway of associated with the chlorotriazine-induced changes in catecholamine synthesis and release. Incubating PC12 cells in the presence of 100 M 14C-Atrazine for 0.5-36 h revealed that approximately 12% of the labeled compound was located within the intact cells between 6-36 h with almost uniform subcellular localization. Atrazine and simazine inhibited the protein expression of TH (~25%), D H (~50 and 25%), intracellular DA and NE, and released NE after 12-24 h exposure. In contrast cyanazine stimulated the protein expression of TH (15-20%), D H (~225%), intracellular and released NE at 12-36 h. Combined, these changes indicate that D H is affected more by the chlorotriazines than TH. This observation was supported by experiments in which it was shown that simultaneous exposure to agents known to enhance D H concentration (e.g., 8 bromo-cyclic AMP, Dexamethazone or forskolin) would reverse the effect of the atrazine and simazine. On the other hand cyanazine lessened the catecholamine-depleting effect of -Methyl-p-tyrosine on the intracellular concentration of NE and NE release, but not the concentration of DA. These observations imply that the disruption of norepinephrine synthesis and release following exposure to the chlorotriazine herbicides is the result of altered D H expression. Whether this is a direct effect on D H or through cellular second messenger mechanisms regulating D H remains to be evaluated.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
REPRODUCTIVE TOXICOLOGY DIVISION