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Supression of the steroid-primed luteinizing hormone surge in the female rat by sodium dimethyldithiocarbamate: Relationship to hypothalamic catecholamines and GnRH neuronal activation
Citation:
GOLDMAN, J. M., A. E. MURR, A. R. BUCKALEW, AND R. L. COOPER. Supression of the steroid-primed luteinizing hormone surge in the female rat by sodium dimethyldithiocarbamate: Relationship to hypothalamic catecholamines and GnRH neuronal activation. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 1(104):107-112, (2008).
Impact/Purpose:
Sodium dimethyldithiocarbamate (DMDC) is a compound that has been employed in a variety of pesticidal applications It has been employed as an insecticide, fungicide, miticide and microbicide. The ability of DMDC to act as a metal chelator has been found to underlie many of its adverse physiological effects, given that a large number of enzymes rely on metal cofactors for their activity. Previous results have shown that DMDC is able to block the ovulatory surge of luteinizing hormone in the female rat. The effect is likely associated with a depletion in the neurotransmitter norepinephrine (NE), by suppressing the activity of the copper-containing enzyme necessary for NE synthesis. The current study investigated the associations among DMDC-induced alterations in brain hypothalamic NE, the subsequent effects on gonadotropin-releasing hormone neuronal activation, and the suppression of the LH surge, all of which are functional prerequisistes to ovulation. This work represents the first demonstration of a dose relationship among these three measures following a single exposure to an environmental toxicant known to target the synthesis of a neurotransmitter critical to normal regulatory activity within the female reproductive system.
Description:
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 requires the presence of dopamine--hydroxylase (DH) and its copper cofactor. Sodium dimethyldithiocarbamate (DMDC) is a pesticide with metal chelating properties, and along with other dithiocarbamates, it is able to reduce DH activity. The resultant decrease in NE causes a suppression of both the LH surge and ovulation. The present study examined the impact of DMDC on hypothalamic GnRH neuronal activation, indicated by the nuclear presence of the early gene product c-fos. A marked reduction or absence of c-fos would be an essential link between effects on NE and suppression of the surge. For this work, ovariectomized, estradiol- and progesterone-primed Sprague-Dawley rats were given a single IP injection of 0, 0.025, 0.05, 0.1 or 0.2 mM/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 0.05 mM/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 that a partial activation of GnRH neuronal activity is consistent with the presence of a fully-developed surge.
