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ACUTE EXPOSURE TO MOLINATE ALTERS NEUROENDOCRINE CONTROL OF OVULATION IN THE RAT
Citation:
Stoker, T E., S D. PERREAULT, K Bremser, R S. Marshall, A S. Murr, AND R L. Cooper. ACUTE EXPOSURE TO MOLINATE ALTERS NEUROENDOCRINE CONTROL OF OVULATION IN THE RAT. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 84(1):38-48, (2005).
Impact/Purpose:
To evaluate whether Molinate, a thiocarbamate herbicide, alters ovulation
Description:
Molinate, a thiocarbamate herbicide, has been shown previously to impair reproductive capability in the male rat. In a two-generation study, molinate exposure to female rats resulted in altered pregnancy outcome. However, published data is lacking on the effects of acute exposure to molinate in the female. Based on this earlier work and our previous observations with related dithiocarbamate compounds, we hypothesized that molinate may alter the ovulatory surge of luteinizing hormone (LH). Specifically, we hypothesized that a single exposure to molinate during the critical window for the neural trigger of ovulation, on the day of vaginal proestrus, would block the LH surge and delay ovulation. To examine the effect of molinate on the LH surge, ovariectomized (OVX) rats were implanted with silastic capsules containing estradiol benzoate (EB) to mimic physiological levels on the day of proestrus. The LH surge was then examined by taking serial tail bleeds at 0, 2, 4 or 6 h after a single oral exposure at 1300 h. 25 mg/kg molinate caused a significant suppression of the LH surge in 67% of the rats, while 50 mg/kg molinate suppressed the LH surge in 83.3 % of the females. These doses also suppressed the estradiol-induced rise in prolactin. In a second group of OVX/EB females, we examined pituitaries and brains by killing females at 0, 1, 3 or 6 hours post dose. In this study, both the 25 and 50 mg/kg dose of molinate significantly suppressed LH and prolactin (PRL) secretion at 1600 and 1900 hour. Both pituitary PRL and LH concentrations were increased at 1600 in the 25 and 50 mg/kg groups. Intact regularly cycling females gavaged with 0, 25 or 50 mg/kg molinate in corn oil at 1300h on vaginal proestrus were examined on estrus or estrus +1 day for the presence of oocytes in the oviduct. All control females had oocytes in the oviduct on estrus. Molinate at 3.125 mg/kg did not delay ovulation, while 6.25 to 50 mg/kg delayed ovulation for 24 hours. The effect of molinate on estrous cyclicity was also examined following a daily dose of 50 mg/kg (21 days). Estrous cyclicity was irregular in the 50 mg/kg molinate group, showing extended days in estrus. At the end of the exposure, these females were OVX and implanted with EB, as described above, to examine LH and PRL. A suppression of both serum LH and PRL surges at 1600 h was still observed in these females following the dose of 50 mg/kg. Two experiments were then conducted to determine whether or not molinate blocked the LH surge via a CNS mode of action or via an alteration in pituitary response. In the first experiment, we examined the release of LH from the pituitary by giving a bolus of GnRH to the catheterized female following acute molinate exposure. No difference was seen in the response of the serum LH release between the control and molinate dosed females, which suggested that the effect of molinate is centrally mediated. To further examine the potential role of the CNS, we analyzed LH pulses in catheterized long-term OVX females, which can be directly correlated with stimulation of the pituitary by GnRH. Molinate exposure resulted in a significant decrease in the LH pulse frequency. These results indicate that molinate is able to delay ovulation by suppressing the LH surge on the day of proestrus and that the brain is the target site for this pesticide. These effects could explain in part the effects on pregnancy outcome seen in earlier reproductive studies.