Many environmental, industrial and therapeutic chemicals perturb female reproduction. The ovary is clearly a target for many of these chemicals, but mechanisms of ovarian toxicants are poorly defined. Therefore, this proposal will elucidate mechanisms by which primary ovarian toxicants damage cells essential for reproduction. The ovarian response to chemical insult is evaluated using three specific ovarian toxicants as probes. Cyclophosphamide is used to kill rapidly proliferating cells. Di(2-ethylhexyl) phthalate is used to perturb granulosa cell growth and differentiation. Ethylene glycol monomethyl ether is used to target oocytes. Perturbations in ovarian morphology (quantitative light and electron microscopy studies), and ovarian function (estradiol, progesterone, androstenedione) and pituitary function (FSH, LB) are evaluated with respect to the estrous cycle and time of chemical exposure. The granulosa cell is a central link in the exchange of intraovarian and extraovarian communication; thus, toxic insult to the granulosa cell could result in ovarian dysfunction. Work from this laboratory has determined that the female reproductive toxicant mono(2-ethylhexyl) phthalate decreases FSH mediated cAMP accumulation in cultured rat granulosa cells. Cyclic AMP and estradiol, a cAMP-dependent granulosa cell product and a critical regulatory hormone, will be measured in cultured FSH-stimulated granulosa cells to test the hypothesis that the primary toxicity of mono (2-ethylhexyl) phthalate on granulosa cells is mediated through alterations in FSH-stimulated cAMP accumulation. Structure-activity relationships will then be examined to test the hypothesis that alterations in FSH-stimulated cAMP accumulation is the primary mechanism of female reproductive toxicity of the class of phthalates.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Physician Scientist Award (K11)
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Environmental Health Sciences Review Committee (EHS)
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North Carolina State University Raleigh
Schools of Veterinary Medicine
United States
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Davis, B J; Almekinder, J L; Flagler, N et al. (1997) Ovarian luteal cell toxicity of ethylene glycol monomethyl ether and methoxy acetic acid in vivo and in vitro. Toxicol Appl Pharmacol 142:328-37
Heindel, J J; Sneeden, J; Powell, C J et al. (1996) A novel hypothalamic peptide, pituitary adenylate cyclase-activating peptide, regulates the function of rat granulosa cells in vitro. Biol Reprod 54:523-30
Davis, B J; Weaver, R; Gaines, L J et al. (1994) Mono-(2-ethylhexyl) phthalate suppresses estradiol production independent of FSH-cAMP stimulation in rat granulosa cells. Toxicol Appl Pharmacol 128:224-8
Davis, B J; Maronpot, R R; Heindel, J J (1994) Di-(2-ethylhexyl) phthalate suppresses estradiol and ovulation in cycling rats. Toxicol Appl Pharmacol 128:216-23