Involvement of thyroxine in ovarian toxicity of di-(2-ethylhexyl) phthalate

Forced ovulation induced by the administration of exogenous gonadotropin is a useful marker for studying the ovarian toxicity of chemicals in experimental animals. We examined the toxicity of di-(2-ethylhexyl) phthalate (DEHP) in the ovaries of immature F344 female rats. Superovulation was induced by injections of equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG) in rats dosed with 125, 250, 500, 1,000 or 2,000 mg/kg body weight of DEHP for 4 consecutive days. The number of ova shed during superovulation significantly decreased in rats treated with DEHP at 500 mg/kg as compared with control, but no changes were observed in the number of ova in groups given other doses of DEHP. In control rats treated with olive oil, hypophysectomy reduced significantly the number of ovulated ova. When 2,000 mg DEHP was given to hypophysectomized (hypox) rats, the number of ova in the hypox group was significantly smaller than that in the intact group administered with the same doses of DEHP. In contrast, the numbers of ova of the intact and hypox groups did not significantly differ in rats given 500 mg DEHP. The levels of circulating thyroxine (T4) were significantly decreased by 2,000 mg DEHP in intact rats, and a tendency for T4 to decrease in T4 was also observed in hypox rats given 2,000 mg DEHP. These results suggest that daily administration of 500 mg DEHP suppressed superovulation in immature F344 rats by disrupting the hypothalamic-pituitary-ovarian axis in a manner similar to that of hypophysectomy. Decreased circulating T4 levels seemed to negate this disruption as observed in recovered superovulation after treatment with 2,000 mg DEHP.