Toxicological Sciences 59, 127-137 (2001)
Copyright © 2001 by the Society of Toxicology
Neurotoxicology |
Alteration of Catecholamines in Pheochromocytoma (PC12) Cells in Vitro by the Metabolites of Chlorotriazine Herbicide
,1
* Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599; and
Endocrinology Branch, MD-72, Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
The effects of four major chlorotriazine metabolites on the constitutive synthesis of the catecholamines dopamine (DA) and norepinephrine (NE) were examined, using undifferentiated PC12 cells. NE release and intracellular DA and NE concentrations were quantified, for up to 24 h after initiation of treatment with different concentrations, ranging from 0 to 400 µM, of the metabolites hydroxyatrazine (HA), 2-amino-4-chloro-6-isopropylamino-s-triazine (deethylchlorotriazine), 2-amino-4-chloro-6-ethylamino-s-triazine (deisopropylchlorotriazine), and diaminochlorotriazine (DACT). Hydroxyatrazine significantly decreased intracellular DA and NE concentrations in a dose- and time-dependent manner. This metabolite also caused a significant inhibition of NE release from the cells. In contrast, deethylchlorotriazine and deisopropylchlorotriazine significantly increased intracellular DA concentration following exposure to 50–200 µM from 12 to 24 h. Intracellular NE was significantly reduced at these same concentrations of deethylchlorotriazine at 24 h while the concentration of NE in PC12 cells exposed to deisopropylchlorotriazine was not altered at any dosage or time point measured. NE release was decreased at 18 (200 µM) and 24 h (100 and 200 µM) following exposure to deethylchlorotriazine and at 24 h (100 and 200 µM) following deisopropylchlorotriazine. DACT, at the highest concentration (160 µM), significantly increased intracellular DA and NE concentrations at 18 and 24 h. NE release was also increased at 40–160 µM at 24 h. The viability of the PC12 cells was tested using the trypan blue exclusion method. Following 18 to 24 h of treatments with HA, cell viability was reduced 10–12% at the two higher concentrations (200 and 400 µM), but, with other metabolites, the viability was reduced by only 2 to 5% at the highest concentrations. These data indicate that HA affects catecholamine synthesis and release in PC12 cells in a manner that is similar to synthesis of atrazine and simazine. On the other hand, deethylchlorotriazine and deisopropylchlorotriazine altered catecholamine synthesis in a manner similar to that observed in the rat brain following in vivo exposure (i.e., increased DA and decreased NE concentration), whereas DACT appeared to produce an increase in NE release as well as in the intracellular DA and NE concentrations. Overall, these findings suggest that the catecholamine neurons may be a target for the chlorotriazines and/or their metabolites, that the metabolites produce a unique pattern of catecholamine response, and that all of the changes were seen within the same range of doses.
Key Words: chlorotriazine metabolites; hydroxyatrazine; deethylchlorotriazine; deisopropylchlorotriazine; diaminochlorotriazine; PC12 cells; dopamine; norepinephrine.
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