Suppression of the steroid-primed luteinizing hormone surge in the female rat by sodium dimethyldithiocarbamate: relationship to hypothalamic catecholamines and GnRH neuronal activation.
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-beta-hydroxylase (DbetaH) which contains a copper cofactor. Sodium dimethyldithiocarbamate (DMDC) is a pesticide with metal chelating properties that has been found to reduce DbetaH 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.
Goldman
Jerome M
JM
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, USA. goldman.jerome@epa.gov
Murr
Ashley S
AS
Buckalew
Angela R
AR
Cooper
Ralph L
RL
D000818:Animals; D004125:Dimethyldithiocarbamate / Q000633:toxicity*; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007986:Luteinizing Hormone / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D010575:Pesticides / Q000633:toxicity*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D004125:Dimethyldithiocarbamate; D010575:Pesticides; D016760:Proto-Oncogene Proteins c-fos; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D009638:Norepinephrine