Changes in Sensitivity to the Effects of Atrazine on the Luteinizing Hormone Surge in Female Sprague-Dawley Rats after Repeated Daily Doses: Correlation with Liver Enzyme Expression

Background: Atrazine suppression of the LH surge slowly develops over time and peaks after 4 days; sensitivity to atrazine decreases after 8 or 14 days of dosing. Adaptation of the LH response was correlated with increased phase I and phase II liver enzyme activity/expression. Methods: The effect of atrazine on the LH surge was evaluated in female Sprague-Dawley rats administered 100 mg/kg/day atrazine by gavage for 1, 2, 3, or 4 consecutive days or 6.5, 50, or 100 mg/kg/day atrazine for 4, 8, or 14 days. Results: No statistically significant effects of atrazine were seen on peak plasma LH or LH area under the curve (AUC) after one, two, or three doses of 100 mg/kg/day. Four daily doses of 50 or 100 mg/kg atrazine significantly reduced peak LH and LH AUCs, whereas 6.5 mg/kg/day had no effect. After 8 or 14 days of treatment, statistically significantly reduced peak LH and LH AUC were observed in the 100 mg/kg/day dose group, but not in the 6.5 or 50 mg/kg/day dose groups, although significantly reduced LH was observed in one sample 9 hr after lights-on in the 50 mg/kg/day dose group on day 14. The number of days of treatment required to achieve a significant suppression of the LH surge is consistent with the repeat-dose pharmacokinetics of the chlorotriazines. Conclusion: The apparent adaptation to the effect of atrazine on the LH surge after 8 or 14 days may be related to the induction of phase I or, more likely, phase II metabolism observed in this study after 8 days, or to a decreased sensitivity of the hypothalamic-pituitary-adrenal axis or an homeostatic adaption of the effect of atrazine on the LH surge mechanism. Birth Defects Research 110:246–258, 2018.