Specific inhibition of FSH-stimulated cAMP accumulation by delta 9-tetrahydrocannabinol in cultured rat granulosa cells.
delta 9-Tetrahydrocannabinol (THC), the major psychoactive component in marihuana has been shown to affect male and female reproduction in both humans and animals. THC has effects at the level at the pituitary-hypothalamic axis as well as a direct effect on the testis and ovary. A specific gonadal effect of THC is inhibition of steroidogenesis in cultured granulosa cells from immature, estrogen-treated rats that depends in part on a post-cyclic AMP site of action. The effect of THC on cAMP accumulation itself, however, has not yet been examined in this cell type. The aim of the present study was to examine the effect of THC on granulosa cell cAMP accumulation, a process that is important for several granulosa cell functions, including steroidogenesis. THC inhibited FSH-stimulated cAMP accumulation in a dose-dependent manner at concentrations which were not cytotoxic. This inhibition was evident by 2 hr and did not affect the dose of FSH which gave half-maximal stimulation, suggesting that THC does not compete with FSH for binding to its receptor. Detailed investigations regarding the mechanism of THC inhibition were conducted using forskolin and isoproterenol. In contrast to its effect on FSH stimulation, THC did not inhibit forskolin- or isoproterenol-stimulated cAMP accumulation, indicating a specific effect for the FSH receptor. In addition, inhibition of FSH-stimulated cAMP accumulation occurred in the presence of a phosphodiesterase inhibitor, indicating that THC does not decrease cAMP accumulation through an increase in the cAMP degradative pathway. These data indicate that a part of the reproductive toxicity seen with THC may be due to a specific alteration of the hormonal control of granulosa cell function via a specific inhibition of FSH-stimulated cAMP accumulation.
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
K A
KA
Treinen
J L
JL
Sneeden
J J
JJ
Heindel
D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology*; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
D013759:Dronabinol; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP; D007545:Isoproterenol