Blockade of ovulation in the rat by the fungicide sodium N-methyldithiocarbamate: relationship between effects on the luteinizing hormone surge and alterations in hypothalamic catecholamines.
Sodium N-methyldithiocarbamate (SMD), also known as metam sodium, is a commonly employed soil fungicide and nematocide. Structurally related dithiocarbamates have been found to decrease norepinephrine (NE) synthesis by suppressing the activity of dopamine-beta-hydroxylase. Because brain hypothalamic catecholamine (CA) activity is involved in generating the proestrus afternoon surge in blood luteinizing hormone (LH) which stimulates the final stages of ovulation, this study explored the effect of SMD on this hormonal trigger and its relationship to changes in hypothalamic CAs. Ovariectomized, steroid-primed Long-Evans rats showed a dose-related (25-100 mg/kg, IP) suppression of the surge and a drop in NE when SMD was given at 1100 h, a few h prior to the expected LH rise. The surge effect was reversed by the alpha-adrenergic agonist clonidine. With cycling rats, a decline with dose (50-300 mg/kg, 1300 h, proestrus) was seen in the percentage of ovulating females, with earlier injections (0900 h) being less effective at the highest dose. At all doses, low circulating levels of LH and prolactin at 1600 h suggested either a blockade in the proestrus surges of each hormone or a displacement in their time of occurrence. Anterior and posterior hypothalamic NE fell by 3 h postinjection and was accompanied by a rise in dopamine, while serotonin was unchanged. Although there was a distinct parallel between the alterations in regional CAs and the incidence of ovulation at the high doses of SMD, the relationship did not hold as the dose decreased. A similar dissociation between ovulation and CAs was seen when equimolar doses of SMD or methylisothiocyanate, a principal metabolite, were given by gavage. At the regional level of analysis employed, the data indicate that while IP injections of SMD are able to block the LH surge and ovulation in these rats, the dose-response relationship suggests that, along with induced alterations in CA metabolism, an additional factor may be involved in the observed effects.
Goldman
J M
JM
Reproductive Toxicology Branch, Developmental Toxicology Division, Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711.
Stoker
T E
TE
Cooper
R L
RL
McElroy
W K
WK
Hein
J F
JF
D000818:Animals; D002395:Catecholamines / Q000378:metabolism*; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism*; D010053:Ovary / Q000502:physiology; D010060:Ovulation / Q000187:drug effects*; D011359:Proestrus / Q000502:physiology; D011388:Prolactin / Q000097:blood; D051381:Rats; D012636:Secretory Rate / Q000187:drug effects; D013859:Thiocarbamates / Q000633:toxicity*
D002395:Catecholamines; D005659:Fungicides, Industrial; D013859:Thiocarbamates; C008435:methyldithiocarbamate; D011388:Prolactin; D007986:Luteinizing Hormone