Characterization of the Hypothalamic-Pituitary-Adrenal Axis Response to Atrazine and Metabolites in the Female Rat

Abstract

Atrazine (ATR) has recently been shown to activate the hypothalamic-pituitary-adrenal (HPA) axis in rodents. The current study investigated the effect of ATR and two of its chlorinated metabolites, desisopropylatrazine (DIA) and diamino-s-chlorotriazine (DACT), on the HPA axis in the Long-Evans female rat. A single oral gavage administration of 75 mg/kg ATR or 60.2 mg/kg DIA (a dose equimolar to the applied ATR dose) during the morning of proestrus resulted in significant, acute increases in circulating adrenocorticotropic hormone (ACTH), corticosterone, and progesterone. Oral doses of ATR or DIA were given daily over the course of the 4-day ovarian cycle starting on the day of vaginal estrus, resulted in a similar, dose-responsive activation of the HPA axis. The increase in ACTH, corticosterone, and progesterone by these compounds was of a similar magnitude to that produced by 5-min restraint stress. Single or multiple oral exposures to DACT, on the other hand, did not significantly alter pituitary-adrenal hormone release. These results were observed despite plasma levels of DACT being higher than any other metabolite at the time of hormone measurement. Overall, circulating metabolite concentrations following equimolar dosing were much higher than those observed after ATR administration. Additional studies indicated that the activation of the HPA axis by oral exposure to ATR and DIA was not due simply to the stimulation of gastrointestinal afferents. Similar responses were observed in rats which received an oral dose of ATR following bilateral subdiaphramatic vagotomy and following intravenous administration of DIA in jugular vein catheterized animals. We conclude that ATR and the metabolite DIA significantly activate the HPA axis following oral exposure in the female rat. Activation of this endocrine axis by these chlorotriazines could contribute to the induced changes of female reproductive function reported previously.

Atrazine-induced elevation or attenuation of the LH surge in the ovariectomized, estrogen-primed female rat: role of adrenal progesterone

“…In contrast, luteal phase Pd3G was reduced, suggesting that long-term ATRZ exposures resulted in insufficient P 4 secretion during this portion of the cycle. Such a decrease, at least outwardly, seems consistent with the previously indicated attenuation in P 4 following multiple days of ATRZ treatment reported by Fraites et al (2009) and with the current differences in P 4 at 1 h (in all of the present Experiments) between single and four daily exposures in response to the 100 mg/kg treatment.…”

“…The results reported by Fraites et al (2009) showed that just 15 min after a single oral 75 mg/kg exposure in intact rats, ATRZ was able to induce a rapid spike in P 4 to w19 ng/ml, a concentration that was greater than fourfold over controls. At 15 min after the last of four daily ATRZ doses, Fraites et al found that the mean P 4 concentration was 7 ng/ml, markedly lower than the 1-day value, suggesting a decline in the P 4 response with multiple exposures.…”

Effect of Age, Duration of Exposure, and Dose of Atrazine on Sexual Maturation and the Luteinizing Hormone Surge in the Female Sprague–Dawley Rat

“…The possibility exists that the acute effect of ATZ on the HPA axis could mediate the effect of ATZ on the HPG axis, resulting in a suppression of the LH surge. ATZ and deisopropylatrazine induced a rapid increase in plasma progesterone and corticosterone secretion within minutes following gavage dosing (Fraites et al., 2009) and corticosterone levels remained elevated for up to 24 hr following large bolus doses of ATZ (Foradori et al., 2011). Elevated plasma corticosterone is known to suppress the LH surge (Kamel and Kubajak, 1987; Gore et al., 2006).…”

“…Elevated plasma corticosterone is known to suppress the LH surge (Kamel and Kubajak, 1987; Gore et al., 2006). However, the administration of diaminochlorotriazine (DACT), a metabolite of ATZ, did not increase plasma progesterone and corticosterone levels (Fraites et al., 2009), whereas DACT suppressed the LH surge in female SD rats when administered by gavage daily for 4 days (Cooper et al., 2000), 1 month (Minnema, 2001), or 6 months in diet (Minnema, 2002). Thus, the absence of an effect of DACT on plasma progesterone and corticosterone levels is inconsistent with the hypothesis that these adrenal hormones mediate the effect of DACT on the LH surge.…”

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“…Recent studies in male rats indicated that hypothalamopituitary-adrenal axis could be turned on by atrazine and its metabolites. This results in a rise in adrenocorticotropic hormone release, and it is responsible for elevated adrenal steroidogenesis (Fraites et al, 2009;Laws et al, 2009;Pogrmic-Majkic et al, 2010). There are various reports on atrazine toxicity which concludes that at higher concentrations it affects, but some cases it does not follow.…”