DI-(2-ETHYLHEXYL) PHTHALATE SUPPRESSES ESTRADIOL AND OVULATION IN CYCLING RATS

Di-(2-ethylhexyl) phthalate (DEHP) is a known reproductive toxicant an d a carcinogen in rodent animal models. DEHP may also be a reproductiv e toxicant in women. Its action in female animal models is undetermine d, although its potential to target the ovary has recently been shown. We have identified the ovarian toxicity and target cells of DEHP in t he female rat. Adult, regularly cycling Sprague-Dawley rats were dosed daily with 2 g/kg DEHP in corn oil by gavage for 1 to 12 days. Ovaria n morphology and serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone levels were analyzed. DEHP exposure resulted in prolonged estrous cycles. Specifically. 35 of 42 DEHP-treated rats had 5- or 6-day cycles and only 7 of 42 had a 4-day cycle compared to 44 of 45 control rats with 4-day cycle lengths. DEHP treatment also suppressed or delayed ovulations by the first proestru s/estrus after metestrus-initiated dosing. Microscopic evaluation of t he ovaries determined that 7 of 10 DEHP-exposed rats had not ovulated by vaginal estrus, whereas 13 of 13 control rats had ovulated by vagin al estrus. Thus, DEHP treatment significantly altered natural ovulatio n times. Preovulatory follicles were also quantitatively smaller in DE HP-exposed rats than in controls because the granulosa cells were smal ler. The mean control rat preovulatory follicle granulosa cell area wa s 16 +/- 3 X 10(3) mu m, whereas the mean DEHP-treated rat preovulator y follicle granulosa cell area was 12 +/- 4 X 10(3) mu m. DEHP exposur e significantly suppressed preovulatory follicle granulosa cell estrad iol production over 8 days of exposure. Suppressed serum estradiol ler els caused secondary increases in FSH levels and did not stimulate th e LH surge necessary for ovulation. Consequently, ovulation did not oc cur in DEHP-treated rats, although DEHP-treated rats ovulated after tr eatment with human chorionic hormone. Vaginal lavage cytology from rat s treated with DEHP did not detect the ovarian toxicity as shown by hi stology and hormone analysis. In summary, exposure to DEHP resulted in hypoestrogenic anovulatory cycles and polycystic ovaries in adult fem ale rats. (C) 1994 Academic Press, Inc.