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ALTERATION OF CATECHOLAMINES IN PHOECHROMOCYTOMA (PC12) CELLS IN VITRO BY THE METABOLITES OF CHLOROTRIAZINE HERBICIDE
Das, P. C., W. K. McElroy, AND R L. Cooper. ALTERATION OF CATECHOLAMINES IN PHOECHROMOCYTOMA (PC12) CELLS IN VITRO BY THE METABOLITES OF CHLOROTRIAZINE HERBICIDE. TOXICOLOGICAL SCIENCES 59(1):127-137, (2001).
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 following treatment with different concentrations of the metabolites hydroxyatrazine (HA), 2-amino-4-chloro-6-isopropyl amino-s-triazine (deethylatrazine), 2-amino-4-chloro-6-ethylamino-s-triazine (deisopropylatrazine) and diaminochlorotriazine (DACT) at concentrations ranging from 0-400 ?M for up to 24 h after the initiation of treatment. Hydroxyatrazine significantly decreased intracellular DA and NE concentration in a dose and time-dependent manner. This metabolite also caused a significant inhibition of NE release from the cells. In contrast, deethylatrazine and deisopropylatrazine significantly increased intracellular DA concentration following exposure to 50 - 200 ? from 12 to 24 h. Intracellular NE was significantly reduced at these same concentrations of deethylatrazine at 24 h while the concentration of NE in PC12 cells exposed to deisopropylatrazine was not altered at any dose or time-point measured. NE release was decreased at 18 (200 ?M) and 24 h (100 and 200 ?M) following exposure to deethylatrazine and at 24h (100 and 200 ?M) following deisopropylatrazine. DACT, at the highest concentration (160 ? ), significantly increased intracellular DA and NE concentrations at 18 and 24 h. NE release was also increased at 40-160 ?M at 24h. The viability of the PC12 cells was tested using the trypan blue exclusion method. Following 18-24 h treatment, with HA, cell viability was reduced 10-12% at the two higher concentrations (200 and 400 ? ), but with other metabolites the viability was reduced by only 2-5% at highest concentrations. These data indicate that HA effects catecholamines synthesis and release in PC12 cells in a manner that is similar to atrazine and simazine. On the other hand, deethylatrazine, deisopropylatrazine and DACT (at higher doses) altered catecholamine synthesis in a manner which is similar to that observed in the rat brain following in vivo exposure (i.e., increased DA and decreased NE concentration) suggesting that the catecholamine neurons may be a target for the chlorotriazines and/or their metabolites.
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