Characterization of activation of the hypothalamic-pituitary-adrenal axis by the herbicide atrazine in the female rat

Chad D. Foradori, Jessica E. Healy, Arthur D. Zimmerman, Robert J. Kemppainen, Melaney A. Jones, Casey C. Read, B. Douglas White, Kun Don Yi, Laura R. Hinds, Anthony F. Lacagnina, Alicia M. Quihuis, Charles B. Breckenridge, Robert J. Handa

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Abstract

Atrazine (ATR) is a commonly used pre-emergence and early postemergence herbicide. Rats gavaged with ATR and its chlorometabolites desethylatrazine (DEA) and deisopropylatrazine (DIA) respond with a rapid and dose-dependent rise in plasma corticosterone, whereas the major chlorometabolite, diaminochlorotriazine (DACT), has little or no effect on corticosterone levels. In this study, we investigated the possible sites of ATR activation of the hypothalamic-pituitary-adrenal (HPA) axis. ATR treatment had no effect on adrenal weights but altered adrenal morphology. Hypophysectomized rats or rats under dexamethasone suppression did not respond to ATR treatment, suggesting that ATR does not directly stimulate the adrenal gland to induce corticosterone synthesis. Immortalized mouse corticotrophs (AtT-20) and primary rat pituitary cultures were treated with ATR, DEA, DIA, or DACT. None of the compounds induced an increase in ACTH secretion or potentiated ACTH release in conjunction with CRH on ACTH release. In female rats gavaged with ATR, pretreatment with the CRH receptor antagonist astressin completely blocked the ATR-induced rise in corticosterone concentrations, implicating CRH release in ATR-induced HPA activation. Intracerebroventricular infusion of ATR, DEA, and DIA but not DACT at concentrations equivalent to peak plasma concentrations after gavage dosing resulted in an elevation of plasma corticosterone concentrations. However, ATR did not induce c-Fos immunoreactivity in the paraventricular nucleus of the hypothalamus. These results indicate that ATR activates the HPA axis centrally and requires CRH receptor activation, but it does not stimulate cellular pathways associated with CRH neuronal excitation.

Original languageEnglish (US)
Pages (from-to)3378-3388
Number of pages11
JournalEndocrinology
Volume159
Issue number9
DOIs
StatePublished - Jan 1 2018

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ASJC Scopus subject areas

  • Endocrinology

Cite this

Foradori, C. D., Healy, J. E., Zimmerman, A. D., Kemppainen, R. J., Jones, M. A., Read, C. C., White, B. D., Yi, K. D., Hinds, L. R., Lacagnina, A. F., Quihuis, A. M., Breckenridge, C. B., & Handa, R. J. (2018). Characterization of activation of the hypothalamic-pituitary-adrenal axis by the herbicide atrazine in the female rat. Endocrinology, 159(9), 3378-3388. https://doi.org/10.1210/en.2018-00474