ToxSci Advance Access originally published online on April 7, 2008
Toxicological Sciences 2008 104(1):107-112; 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
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, North Carolina 27711
1 To whom correspondence should be addressed. Fax: (919) 541-5138. E-mail: goldman.jerome{at}epa.gov.
Received February 8, 2008; accepted March 27, 2008
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Abstract |
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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 (DA) 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 (OVX), 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 DA at 2 h 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.
Disclaimer: The research described in this article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.