title: Acute exposure to molinate alters neuroendocrine control of ovulation in the rat.
abstract: Molinate, a thiocarbamate herbicide, has been reported to impair reproductive capability in the male rat and alter pregnancy outcome in a two-generation study. Published data are lacking on the effects of acute exposure to molinate in the female. Based on this work and our previous observations with related dithiocarbamate compounds, we hypothesized that a single exposure to molinate during the critical window for the neural trigger of ovulation on the day of proestrus (PRO) would block the luteinizing hormone (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 to mimic physiological levels on proestrus. Doses of 25 and 50 mg/kg molinate significantly suppressed LH and prolactin secretion. Intact regularly cycling females gavaged with 0, 25, or 50 mg/kg molinate at 1300 h on PRO 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 doses of 6.25 to 50 mg/kg delayed ovulation for 24 h. Estrous cyclicity was examined after daily exposure to 50 mg/kg (21 days). Estrous cyclicity was irregular in the molinate group, showing extended days in estrus. Two experiments were conducted to determine whether molinate blocked the LH surge via a central nervous system (CNS) mode of action or via an alteration in pituitary response. In the first experiment, we evaluated the release of LH in control and molinate-treated rats after a bolus dose of exogenous GnRH. Luteinizing hormone release was comparable in the two groups, suggesting that the effect of molinate is centrally mediated. To further examine the potential role of the CNS, we examined the pulsatile release of LH present in the long-term OVX females. In this model, the pulsatile pattern of LH secretion is directly correlated with GnRH release from the hypothalamus. A significant decrease in the LH pulse frequency was observed in molinate-treated females. 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 primary target site for the effects on pituitary hormone secretion.
authors.affiliation: National Health and Environmental Effects Research Laboratory, Office of Research and Development, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. stoker.tammy@epa.gov
authors.forename: Tammy E
authors.initials: TE
authors.lastname: Stoker
authors.forename: Sally D
authors.initials: SD
authors.lastname: Perreault
authors.forename: Katrine
authors.initials: K
authors.lastname: Bremser
authors.forename: Renee S
authors.initials: RS
authors.lastname: Marshall
authors.forename: Ashley
authors.initials: A
authors.lastname: Murr
authors.forename: Ralph L
authors.initials: RL
authors.lastname: Cooper
mesh_terms: D000818:Animals; D001381:Azepines / Q000633:toxicity*; D001921:Brain / Q000201:enzymology; D002802:Cholinesterases / Q000097:blood / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004967:Estrogens / Q000008:administration & dosage / Q000494:pharmacology; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D007031:Hypothalamus / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood; D009490:Neurosecretory Systems / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism; D010052:Ovariectomy; D010060:Ovulation / Q000187:drug effects*; D010902:Pituitary Gland / Q000378:metabolism; D011247:Pregnancy; D011388:Prolactin / Q000097:blood; D051381:Rats; D020318:Rats, Long-Evans; D013859:Thiocarbamates / Q000633:toxicity*; D013997:Time Factors
chemical_list: D001381:Azepines; D004343:Drug Implants; D004967:Estrogens; D006540:Herbicides; D013859:Thiocarbamates; D007987:Gonadotropin-Releasing Hormone; C009821:molinate; D011388:Prolactin; D007986:Luteinizing Hormone; D002802:Cholinesterases; D004298:Dopamine; D009638:Norepinephrine