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ToxSci Advance Access published online on April 7, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn074
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Published by Oxford University Press 2008.

Suppression of the Steroid-primed Luteinizing Hormone Surge in the Female Rat by Sodium Dimethyldithiocarbamate: Relationship to Hypothalamic Catecholamines and GnRH Neuronal Activation

Jerome M. Goldman, Ashley S. Murr, Angela R. Buckalew and Ralph L. Cooper

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

Corresponding author: J. M. Goldman, Ph.D., Endocrinology Br., MD72, RTD, NHEERL, ORD, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711.

Received February 8, 2008; revision received March 26, 2008; accepted March 27, 2008


  Abstract

In female rodents, hypothalamic norepinephrine (NE) has a role in stimulating the secretion of gonadotropin-releasing hormone (GnRH) that triggers the ovulatory surge of luteinizing hormone (LH). NE synthesis from dopamine is catalyzed by dopamine-β-hydroxylase (DβH) which contains a copper cofactor. Sodium dimethyldithiocarbamate (DMDC) is a pesticide with metal chelating properties that has been found to reduce DβH activity. The resultant decrease in NE causes a suppression of both the LH surge and ovulation. The present study examined the dose-related impact of DMDC on hypothalamic GnRH neuronal activation, indicated by the nuclear presence of the early gene product c-fos. It represents an essential link between effects on NE and suppression of the surge. Ovariectomized, estradiol- and progesterone-primed Sprague-Dawley rats were given a single IP injection of 0, 3.6, 7.1, 14.2 or 28.4 mg/kg DMDC in separate groups of females to assess tissue GnRH/c-fos immunostaining, hypothalamic catecholamines and serial blood samplings for LH. A dose-related decline in hypothalamic NE and increase in dopamine at two hours after DMDC administration were consistent with a decrease in c-fos positive GnRH neurons, with an almost complete absence of c-fos at the two highest doses. The effects correlated well with a suppression of the surge, although the percentage decrease in c-fos neurons at 7.1 mg/kg only attenuated the surge peak, not the overall amount of circulating LH. The present data offer further evidence that the impact of DMDC on the LH surge is central in origin and in doing so defines the toxic pathway for this effect on ovulation.

Key Words: sodium dimethyldithiocarbamate; gonadotropin-releasing hormone; luteinizing hormone; norepinephrine; c-fos.


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