Effect of mono-(2-ethylhexyl)phthalate on follicle-stimulating hormone responsiveness of cultured rat Sertoli cells.
Mono-(2-ethylhexyl)phthalate (MEHP) is one of a number of phthalate esters known to damage the rat testis with the Sertoli cell as its target. These effects can be modeled using primary testicular cell cultures. Stimulation of rat Sertoli cells by follicle-stimulating hormone (FSH) results in an increase in release of cAMP into the culture medium. However, cultures pretreated with MEHP (10(-7)-10(-4) M) showed a dose-related reduction in FSH-stimulated cAMP production (maximally greater than 50%), suggesting that MEHP is interfering with the FSH receptor-adenyl cyclase system. Detailed investigations of the system were conducted utilizing forskolin and choleratoxin, which both stimulate adenyl cyclase but bypass the FSH receptor to produce an increase in cAMP secretion. Cultures pretreated with MEHP (10(-9)-10(-5)M) showed no reduction in either forskolin- or choleratoxin-stimulated cAMP production. However, at low doses (10(-8)-10(-6)M) MEHP produced a potentiation (up to three times) of both forskolin- and choleratoxin-stimulated cAMP secretion, but gave slight inhibition at 5 X 10(-5) and 10(-4) M. These data indicate that MEHP produces a perturbation at the level of the FSH receptor, causing an inhibition of FSH action. This finding may be related to the age-dependent toxicity of the compound, since FSH is critical for the initiation of spermatogenesis in young animals, but is not necessary for the maintenance of spermatogenesis in adults. Thus an effect on FSH responsiveness in vitro may provide an indication of the mode of action of MEHP in vivo.
Lloyd
S C
SC
Imperial Chemical Industries PLC, Central Toxicology Laboratory, Macclesfield, Cheshire, United Kingdom.
Foster
P M
PM
D000818:Animals; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D008297:Male; D010795:Phthalic Acids / Q000494:pharmacology*; D051381:Rats; D011962:Receptors, FSH / Q000187:drug effects; D012708:Sertoli Cells / Q000187:drug effects* / Q000378:metabolism
D010795:Phthalic Acids; D011962:Receptors, FSH; D005576:Colforsin; D005640:Follicle Stimulating Hormone; D002772:Cholera Toxin; D004051:Diethylhexyl Phthalate; D000242:Cyclic AMP; C016599:mono-(2-ethylhexyl)phthalate