Inhibition of FSH-stimulated cAMP accumulation by mono(2-ethylhexyl) phthalate in primary rat Sertoli cell cultures.
High doses of phthalate esters in vivo cause testicular lesions. One initial target for these effects is the sustentacular Sertoli cell. Sertoli cells are unique in that they have surface membrane receptors for follicle-stimulating hormone (FSH), which couple to adenylate cyclase. As a means of investigating why phthalates appear specific for Sertoli cells, we evaluated possible effects of an active monoester [mono(2-ethylhexyl) phthalate, MEHP] on the ability of FSH to elevate intracellular levels of cAMP. MEHP reduced FSH-induced elevation of cAMP levels by approximately 40%. This inhibition by MEHP required a lag period of 6 hr and did not affect the dose of FSH which gave half-maximal stimulation, suggesting that MEHP does not compete with FSH for binding to its receptor. The MEHP inhibition was not affected by incubation in the presence of methylisobutylxanthine, a phosphodiesterase inhibitor, suggesting that MEHP does not stimulate the breakdown of cAMP. The MEHP-induced inhibition 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 MEHP action is independent of the inhibitory adenylate cyclase pathway. Further experiments will be necessary to define the specific mechanism of action of phthalates on Sertoli cells; however, these experiments do describe a specific site of action of MEHP in vitro which may be related to the in vivo testicular toxicity of phthalate esters.
Heindel
J J
JJ
Developmental and Reproductive Toxicology Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Chapin
R E
RE
D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives / Q000633:toxicity*; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D008297:Male; D010795:Phthalic Acids / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D012708:Sertoli Cells / Q000187:drug effects* / Q000378:metabolism
D010795:Phthalic Acids; C034171:di-n-pentyl phthalate; D005576:Colforsin; D005640:Follicle Stimulating Hormone; D004051:Diethylhexyl Phthalate; D000242:Cyclic AMP; C016599:mono-(2-ethylhexyl)phthalate