Toxicological Sciences 56, 324-331 (2000)
Copyright © 2000 by the Society of Toxicology
Differential Modulation of Catecholamines by Chlorotriazine Herbicides in Pheochromocytoma (PC12) Cells in Vitro
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* Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599; and
Endocrinology Branch, Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
Epidemiological, wildlife, and laboratory studies have pointed to the possible adverse health effects of chlorotriazine herbicide (i.e., atrazine, simazine, and cyanazine) exposure. However, the cellular mechanism(s) of action of these compounds remains unknown. Recently, it was reported by Cooper et al. (2000, Toxicol. Sci. 53, 297–307) that atrazine disrupts ovarian function by altering hypothalamic catecholamine concentrations and subsequently the regulation of luteinizing hormone (LH) and prolactin (PRL) secretion by the pituitary. In this study, we examined the effect of three chlorotriazines on catecholamine metabolism in vitro using PC12 cells. Intracellular norepinephrine (NE) and dopamine (DA) concentrations and spontaneous NE release were measured following treatment with different concentrations of atrazine, simazine (0, 12.5, 25, 50, 100, and 200 µM) and cyanazine (0, 25, 50, 100, and 400 µM) for 6, 12, 18, 24, and 48 h. Atrazine and simazine significantly decreased intracellular DA concentration in a concentration-dependent manner. Intracellular NE concentration was also significantly decreased by 100 and 200 µM atrazine and 200 µM simazine. Similarly, there was a dose-dependent inhibition of NE release with 100 and 200 µM concentrations of both compounds. Although 100 and 400 µM cyanazine increased intracellular NE concentration, 50, 100, and 400 µM cyanazine significantly increased NE release at 24 and 36 h. In contrast, intracellular DA concentration was decreased by cyanazine, but only at 400 µM. The GABAA-receptor agonist, muscimol (0, 0.01, 0.1, and 1.0 µM) had no effect on either the release or on intracellular catecholamine concentrations from 6 through 24 h of treatment. Cell viability was somewhat lower in the groups exposed to 100 and 200 µM atrazine and simazine. However, the reduction in viability was significant only in the highest dose of atrazine used (200 µM) at 24 h. Cyanazine did not have an effect on the viability at any of the doses tested, and the cells were functional, even up to 48 h of exposure. These data indicate that both atrazine and simazine inhibit the cellular synthesis of DA mediated by the tyrosine hydroxylase (TH), and NE mediated by dopamine ß-hydroxylase (DßH), and, as a result, there is a partial or significant inhibition of NE release. Cyanazine, on the other hand, stimulated the synthesis of intracellular NE, and not DA. Thus, chlorotriazine compounds presumably act at the enzymatic steps or sites of CA biosynthesis to modulate monoaminergic activity in PC12 cells.
Key Words: chlorotriazines; atrazine; simazine; cyanazine; PC12 cell line; dopamine; norepinephrine..
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