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

Birth Defects Res. 2018 Feb 15;110(3):246-258. doi: 10.1002/bdr2.1130. Epub 2017 Nov 14.


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. © 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.

Keywords: LH surge; adaptation; atrazine; gavage; phase I metabolism; phase II metabolism; sensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrazine / toxicity*
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Hypothalamo-Hypophyseal System / metabolism
  • Hypothalamo-Hypophyseal System / pathology
  • Liver / enzymology*
  • Liver / pathology
  • Luteinizing Hormone / metabolism*
  • Pituitary-Adrenal System / metabolism
  • Pituitary-Adrenal System / pathology
  • Rats
  • Rats, Sprague-Dawley


  • Luteinizing Hormone
  • Atrazine