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Effects of atrazine (ATR), deisopropylatrazine (DIA), Diaminochlorotriazine (DACT) on the hypothalamic-pituitary-adrenal (HPA) axis in female rats
Citation:
FRAITES, M. P., S. C. LAWS, J. M. FERRELL, A. R. BUCKALEW, L. J. MILLS, S. JAYARAMAN, AND R. L. COOPER. Effects of atrazine (ATR), deisopropylatrazine (DIA), Diaminochlorotriazine (DACT) on the hypothalamic-pituitary-adrenal (HPA) axis in female rats. Presented at Triangle Consortium for Reproductive Biology, Durham, NC, February 23, 2008.
Impact/Purpose:
Presentation @ TCRB Conference
Description:
We previously reported that a single dose of the herbicide ATR stimulated the HPA axis in the male rat while equimolar doses of its primary metabolite, DACT, had a minimal effect. In this study, we evaluated the effects of one or four daily doses of ATR, DACT, and an intermediate metabolite, DIA, on adrenocorticotropin (ACTH), corticosterone (CORT) and progesterone (P4) release in the intact female Long-Evans Hooded rat. Plasma ATR and metabolite concentrations were also measured to confirm circulating levels following equimolar dosing and correlate metabolite loads with hormonal responses. Females displaying 4-day estrous cycles were acclimated to oral gavage by predosing with 1% methyl cellulose vehicle. Animals then received 4 consecutive doses of vehicle, ATR (12.5 or 75 mg/kg/day), or equimolar doses of DACT or DIA beginning on the day of estrus at 0900 hours (14/10 light cycle, lights on at 0500 hours). Another group of regularly cycling females was gavaged once with vehicle, 75 mg/kg ATR, or an equimolar dose of DACT or DIA at 0900 hours on proestrus. All rats were decapitated 15 minutes after the last dose. Plasma ACTH and serum CORT and P4 were measured by radioimmunoassay. Gas chromatography-mass spectrometry was used to measure plasma concentrations of ATR and metabolites following the fourth dose in select samples. Single or multiple doses of 75 mg/kg/day ATR or equimolar doses of DIA significantly elevated circulating ACTH, CORT, and P4 compared to vehicle controls. However, ACTH release following the fourth dose was significantly less than that seen after a single dose suggesting habituation of the response. Treatment with 12.5 mg/kg/day ATR or equimolar DIA had minimal effect on HPA activation. DACT exposure did not alter any measured endpoint. Plasma concentrations of metabolites were three to eight times greater in animals dosed with metabolite compared to those dosed with equimolar ATR. No significant correlation was observed between circulating levels of any hormone and metabolite. We conclude that ATR and DIA activate the HPA axis in the female rat although this response is attenuated with multiple exposures to ATR perhaps due to an acclimation of the axis. This study confirms our earlier finding in male rats that the primary metabolite, DACT, has a negligible effect on the HPA axis. Preliminary data indicate that doses of DIA or DACT equimolar to ATR dose do not lead to comparable plasma concentrations of metabolites. There is no clear correlation between plasma levels of metabolite and stress hormones; therefore, it may be necessary to determine metabolite concentrations within the hypothalamus, the proposed target site of action.