Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate.
Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate.
复制标题
DOI：
10.1289/ehp.01109229
复制
发表时间：
2001-03
影响因子：
10.4
通讯作者：
Peterson RE
中科院分区：
文献类型：
--
作者：
Moore RW;Rudy TA;Lin TM;Ko K;Peterson RE
邻苯二甲酸酯家族的几个成员具有抗雄激素的特性，但很少有人知道如何暴露于这些无处不在的环境污染物在发展早期可能会影响性发育。我们进行了实验，以确定子宫内和哺乳期暴露于最常见的邻苯二甲酸酯，邻苯二甲酸二（2-乙基己基）酯（DEHP）对男性生殖系统发育和性行为的影响。Sprague-Dawley大鼠从妊娠第3天至出生后第21天（PND）口服玉米油或DEHP（0、375、750或1，500 mg/kg/天）。对雄性后代的剂量相关影响包括肛门生殖器距离缩短、乳晕和乳头保留、隐睾和永久性包皮不完全分离。在PND 21、63和/或105-112时，睾丸、附睾、阴茎头、腹侧前列腺、背外侧前列腺、前前列腺和精囊重量降低。其他剂量相关效应包括前列腺前部发育不全的发生率较高，部分或完全腹侧前列腺发育不全的发生率较低，偶尔背外侧前列腺和精囊发育不全，精子计数减少以及睾丸、附睾和阴茎畸形。许多DEHP暴露的男性在接受控制女性的存在下性活动不活跃，但性活动不活跃与男性生殖器官异常无关。这些结果表明，子宫内和哺乳期DEHP暴露也抑制了性二态中枢神经系统发育。在8只对照窝仔中均未发现重大异常，但DEHP在375 mg/kg/天剂量组8只窝仔中的5只、750 mg/kg/天剂量组8只窝仔中的7只和1，500 mg/kg/天剂量组5只窝仔中引起了严重的雄性生殖系统毒性。这些结果表明，雄性生殖系统在发育早期对DEHP的敏感性远远高于幼年或成年动物。DEHP对雄性生殖器官和性行为的影响，以及对同窝仔的阴道张开和首次发情时间无显著影响，表明DEHP（和/或其代谢物）主要通过作为抗雄激素影响雄性生殖系统的发育。子宫内和哺乳期DEHP暴露的影响模式与其他邻苯二甲酸酯引起的模式不同，前列腺前发育不全的优势似乎是所有化学品中唯一的。这些结果表明，DEHP的作用机制部分不同于其他抗雄激素。
Several members of the phthalate ester family have antiandrogenic properties, yet little is known about how exposure to these ubiquitous environmental contaminants early in development may affect sexual development. We conducted experiments to determine effects of in utero and lactational exposure to the most prevalent phthalate ester, di(2-ethylhexyl) phthalate (DEHP), on male reproductive system development and sexual behavior. Sprague-Dawley rats were dosed with corn oil or DEHP (0, 375, 750, or 1,500 mg/kg/day, per os) from gestation day 3 through postnatal day (PND) 21. Dose-related effects on male offspring included reduced anogenital distance, areola and nipple retention, undescended testes, and permanently incomplete preputial separation. Testis, epididymis, glans penis, ventral prostate, dorsolateral prostate, anterior prostate, and seminal vesicle weights were reduced at PND 21, 63, and/or 105-112. Additional dose-related effects included a high incidence of anterior prostate agenesis, a lower incidence of partial or complete ventral prostate agenesis, occasional dorsolateral prostate and seminal vesicle agenesis, reduced sperm counts, and testicular, epididymal, and penile malformations. Many DEHP-exposed males were sexually inactive in the presence of receptive control females, but sexual inactivity did not correlate with abnormal male reproductive organs. These results suggest that in utero and lactational DEHP exposure also inhibited sexually dimorphic central nervous system development. No major abnormalities were found in any of eight control litters, but DEHP caused severe male reproductive system toxicity in five of eight litters at 375 mg/kg/day, seven of eight litters at 750 mg/kg/day, and five of five litters at 1,500 mg/kg/day. These results demonstrate that the male reproductive system is far more sensitive to DEHP early in development than when animals are exposed as juveniles or adults. The effects of DEHP on male reproductive organs and sexual behaviors and the lack of significant effects on time to vaginal opening and first estrus in their littermates demonstrate that DEHP (and/or its metabolites) affects development of the male reproductive system primarily by acting as an antiandrogen. The pattern of effects of in utero and lactational DEHP exposure differed from patterns caused by other phthalate esters, and the preponderance of anterior prostate agenesis appears to be unique among all chemicals. These results suggest that DEHP acts partly by mechanisms distinct from those of other antiandrogens.