Davis B J, Maronpot R R, Heindel J J
Department of Microbiology, College of Veterinary Medicine, North Carolina State University, Raleigh 27606.
Toxicol Appl Pharmacol. 1994 Oct;128(2):216-23. doi: 10.1006/taap.1994.1200.
Di-(2-ethylhexyl) phthalate (DEHP) is a known reproductive toxicant and a carcinogen in rodent animal models. DEHP may also be a reproductive toxicant in women. Its action in female animal models is undetermined, although its potential to target the ovary has recently been shown. We have identified the ovarian toxicity and target cells of DEHP in the 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. Ovarian 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 proestrus/estrus after metestrus-initiated dosing. Microscopic evaluation of the ovaries determined that 7 of 10 DEHP-exposed rats had not ovulated by vaginal estrus, whereas 13 of 13 control rats had ovulated by vaginal estrus. Thus, DEHP treatment significantly altered natural ovulation times. Preovulatory follicles were also quantitatively smaller in DEHP-exposed rats than in controls because the granulosa cells were smaller. The mean control rat preovulatory follicle granulosa cell area was 16 +/- 3 x 10(3) microns, whereas the mean DEHP-treated rat preovulatory follicle granulosa cell area was 12 +/- 4 x 10(3) microns. DEHP exposure significantly suppressed preovulatory follicle granulosa cell estradiol production over 8 days of exposure. Suppressed serum estradiol levels caused secondary increases in FSH levels and did not stimulate the LH surge necessary for ovulation. Consequently, ovulation did not occur in DEHP-treated rats, although DEHP-treated rats ovulated after treatment with human chorionic hormone. Vaginal lavage cytology from rats treated with DEHP did not detect the ovarian toxicity as shown by histology and hormone analysis. In summary, exposure to DEHP resulted in hypoestrogenic anovulatory cycles and polycystic ovaries in adult female rats.
邻苯二甲酸二（2-乙基己基）酯（DEHP）在啮齿动物模型中是一种已知的生殖毒性物质和致癌物。DEHP在女性中也可能是一种生殖毒性物质。尽管最近已显示其对卵巢有潜在作用，但其在雌性动物模型中的作用仍未确定。我们已确定了DEHP在雌性大鼠中的卵巢毒性和靶细胞。成年、月经周期规律的斯普拉格-道利大鼠每天经口灌胃给予2 g/kg DEHP的玉米油溶液，持续1至12天。分析卵巢形态以及血清促卵泡生成素（FSH）、促黄体生成素（LH）、雌二醇和孕酮水平。DEHP暴露导致动情周期延长。具体而言，42只经DEHP处理的大鼠中有35只动情周期为5或6天，42只中只有7只动情周期为4天，而45只对照大鼠中有44只动情周期为4天。DEHP处理还抑制或延迟了在动情后期开始给药后的首次动情前期/动情期的排卵。对卵巢的显微镜评估确定，10只经DEHP处理的大鼠中有7只在阴道出现动情期时未排卵，而13只对照大鼠中有13只在阴道出现动情期时已排卵。因此，DEHP处理显著改变了自然排卵时间。与对照组相比，经DEHP处理的大鼠排卵前卵泡在数量上也较小，因为颗粒细胞较小。对照大鼠排卵前卵泡颗粒细胞的平均面积为16±3×10³微米，而经DEHP处理的大鼠排卵前卵泡颗粒细胞的平均面积为12±4×10³微米。在暴露的8天内，DEHP暴露显著抑制了排卵前卵泡颗粒细胞的雌二醇分泌。血清雌二醇水平降低导致FSH水平继发性升高，且未刺激排卵所需的LH高峰。因此，经DEHP处理的大鼠未排卵，尽管经DEHP处理的大鼠在用人绒毛膜促性腺激素治疗后排卵。经DEHP处理的大鼠的阴道灌洗细胞学检查未检测到组织学和激素分析所显示的卵巢毒性。总之，暴露于DEHP会导致成年雌性大鼠出现低雌激素无排卵周期和多囊卵巢。
