Reproductive functions and hypothalamic catecholamines in response to the soil fumigant metam sodium: adaptations to extended exposures.

Jerome M Goldman, Ralph L Cooper, Ashley S Murr

Endocrinology Branch, Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. goldman.jerome@epa.gov

Neurotoxicology and teratology 2007 May-Jun

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Metam sodium (MS) is a soil fumigant and Category II pesticide with a relatively low toxicity in mammals. Previous data have shown an ability to impair reproductive mechanisms in ovariectomized, estradiol-primed rats. A single i.p. injection blocked the luteinizing hormone (LH) surge that in gonadal-intact females initiates the final stages of follicular and oocytic maturation and serves as the trigger for ovulation. The effect paralleled a fall in hypothalamic norepinephrine (NE) and rise in hypothalamic dopamine (DA) that was likely due to a suppression in dopamine-beta-hydroxylase activity. In addition to determining the influence on catecholamine (CA) concentrations from a single oral exposure to MS, the present study explored effects of longer, 3-week treatments on estrous cyclicity, the LH surge, ovulation and hypothalamic CAs. Normally cycling 90 d S-D rats were administered MS (0-200 mg/kg/d, oral) and cyclicity was monitored daily. At the end of the 3rd week, proestrous blood was sampled over the afternoon from regular 4-day cyclers for a determination of LH. These animals were then killed on the following day of estrus (treatment days 21-26) for oocyte retrieval and assessment of hypothalamic CAs. Results showed that shortly after treatment began there occurred a dose-related period of persistent diestrus that typically lasted 8-16 d before regular cycles were reinstated. After 3 weeks, no effects were seen on the magnitude/timing of the LH surge or ovulated oocyte numbers. Anterior and posterior hypothalamic NE and DA were not significantly different from controls, although DA turnover (reflected by the ratio of DOPAC {3,4-dihydroxy-phenylacetic acid} to DA) in both anterior hypothalamic and caudate regions was decreased at all dosages. The data indicate that a 3 week oral exposure to MS induced an initial period of extended diestrus before the resumption of apparently normal reproductive activity, with previously reported CA alterations (apart from a persistent alteration in the DOPAC/DA ratio) being normalized by the end of dosing.

Citation

Jerome M Goldman, Ralph L Cooper, Ashley S Murr. Reproductive functions and hypothalamic catecholamines in response to the soil fumigant metam sodium: adaptations to extended exposures. Neurotoxicology and teratology. 2007 May-Jun;29(3):368-76