Specific inhibition of FSH-stimulated cAMP accumulation by delta 9-tetrahydrocannabinol in cultures of rat Sertoli cells.
delta 9-Tetrahydrocannabinol (THC), the major psychoactive component in marihuana, is a reproductive toxicant in both man and animals. THC acts at both the level of the pituitary-hypothalamic axis and the testis, specifically the Leydig cell; an effect on the Sertoli cell has not been shown. Since THC inhibits cAMP accumulation in several cell types, we have examined the effect of THC on Sertoli cell function using altered cAMP accumulation as a marker of toxicity. THC reduced the FSH-induced accumulation of cAMP at concentrations which were neither cytotoxic nor affected cellular ATP levels. This inhibition was evident after 3 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. The ability of THC to inhibit cAMP accumulation was not affected by incubation in the presence of phosphodiesterase inhibitors, making it unlikely that it acts via stimulation of phosphodiesterase activity. This THC-induced inhibition of Sertoli cell cAMP is specific for FSH; it does not affect the ability of forskolin, cholera toxin, isoproterenol, or prostaglandin E1 to stimulate Sertoli cell cAMP. Furthermore, inhibition occurs in the presence of pertussis toxin, suggesting that this effect of THC is independent of the inhibitory adenylate cyclase pathway. Inhibition of Sertoli cell cAMP also occurs with other cannabinoids which are present in marihuana, but which are not psychoactive. These data indicate that a part of the testicular toxicity of THC may be due to a specific alteration of the hormonal control of Sertoli cell function via an inhibition of FSH-stimulated cAMP accumulation.
Heindel
J J
JJ
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Keith
W B
WB
D000255:Adenosine Triphosphate / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D013759:Dronabinol / Q000494:pharmacology*; D005640:Follicle Stimulating Hormone / Q000037:antagonists & inhibitors*; D008297:Male; D008855:Microscopy, Electron, Scanning; D051381:Rats; D011916:Rats, Inbred F344; D015290:Second Messenger Systems / Q000187:drug effects*; D012708:Sertoli Cells / Q000187:drug effects* / Q000378:metabolism
D000067956:Adenylyl Cyclase Inhibitors; D002186:Cannabinoids; D013759:Dronabinol; D000255:Adenosine Triphosphate; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP