Mono(2-ethylhexyl)phthalate (MEHP) is both a male and female reproductive toxicant as determined in the NTP Reproductive Assessment by Continuous Breeding protocol. In the male, MEHP has been shown in vivo and in vitro to be a Sertoli cell (SC) toxicant. In vitro MEHP inhibited FSH-stimulated cAMP accumulation in cultured SCs. This inhibition occurred after a 6 hr preincubation period, with maximal inhibition (50%) by 24 hrs. Half-maximal inhibition is seen at 12-15 (mu)M MEHP. Since MEHP is also a female reproductive toxicant, and granulosa cells are thought to be the female counterpart to SCs, we examined the effect of MEHP on FSH-stimulated cAMP accumulation in cultured granulosa cells (GCs). GCs are harvested by ovarian puncture of DES-primed immature (19-22 d) F-344 rats and 300,000 viable cells were incubated in plastic tubes for up to four days. FSH, forskolin, and isoproterenol were shown to stimulate cAMP accumulation. MEHP inhibited FSH-stimulated cAMP accumulation in a dose- and time-dependent manner. Significant inhibition (30-50%) of GC cAMP accumulation occurred with 200 (mu)M MEHP after a 15 hr exposure, with maximal inhibition at 30 hrs. MEHP also inhibits progesterone production. Thus, the action of MEHP on GCs appears to be limited to an effect to decrease FSH-stimulated cAMP production. This decrease in cAMP levels then results in decreased progesterone production which may be an important part of the female reproductive toxicity of MEHP.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Intramural Research (Z01)
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