Parks L G, Ostby J S, Lambright C R, Abbott B D, Klinefelter G R, Barlow N J, Gray L E
Endocrinology Branch, MD-72, U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Reproductive Toxicology Division, Research Triangle Park, North Carolina 27711, USA.
Toxicol Sci. 2000 Dec;58(2):339-49. doi: 10.1093/toxsci/58.2.339.
Phthalate esters (PE) such as DEHP are high production volume plasticizers used in vinyl floors, food wraps, cosmetics, medical products, and toys. In spite of their widespread and long-term use, most PE have not been adequately tested for transgenerational reproductive toxicity. This is cause for concern, because several recent investigations have shown that DEHP, BBP, DBP, and DINP disrupt reproductive tract development of the male rat in an antiandrogenic manner. The present study explored whether the antiandrogenic action of DEHP occurs by (1) inhibiting testosterone (T) production, or by (2) inhibiting androgen action by binding to the androgen receptor (AR). Maternal DEHP treatment at 750 mg/kg/day from gestational day (GD) 14 to postnatal day (PND) 3 caused a reduction in T production, and reduced testicular and whole-body T levels in fetal and neonatal male rats from GD 17 to PND 2. As a consequence, anogenital distance (AGD) on PND 2 was reduced by 36% in exposed male, but not female, offspring. By GD 20, DEHP treatment also reduced testis weight. Histopathological evaluations revealed that testes in the DEHP treatment group displayed enhanced 3ss-HSD staining and increased numbers of multifocal areas of Leydig cell hyperplasia as well as multinucleated gonocytes as compared to controls at GD 20 and PND 3. In contrast to the effects of DEHP on T levels in vivo, neither DEHP nor its metabolite MEHP displayed affinity for the human androgen receptor at concentrations up to 10 microM in vitro. These data indicate that DEHP disrupts male rat sexual differentiation by reducing T to female levels in the fetal male rat during a critical stage of reproductive tract differentiation.
邻苯二甲酸酯（PE），如邻苯二甲酸二（2-乙基己基）酯（DEHP），是产量高的增塑剂，用于乙烯基地板、食品包装、化妆品、医疗产品和玩具。尽管它们被广泛且长期使用，但大多数PE尚未针对跨代生殖毒性进行充分测试。这令人担忧，因为最近的几项研究表明，DEHP、邻苯二甲酸丁苄酯（BBP）、邻苯二甲酸二丁酯（DBP）和邻苯二甲酸二异壬酯（DINP）以抗雄激素的方式破坏雄性大鼠的生殖道发育。本研究探讨了DEHP的抗雄激素作用是否通过以下方式发生：（1）抑制睾酮（T）的产生，或（2）通过与雄激素受体（AR）结合来抑制雄激素作用。从妊娠第14天（GD）至出生后第3天（PND），以750 mg/kg/天的剂量对母鼠进行DEHP处理，导致T的产生减少，并使妊娠第17天至出生后第2天的胎儿和新生雄性大鼠的睾丸及全身T水平降低。结果，出生后第2天，暴露组雄性后代的肛门生殖器距离（AGD）减少了36%，而雌性后代未出现这种情况。到妊娠第20天，DEHP处理也使睾丸重量减轻。组织病理学评估显示，与妊娠第20天和出生后第3天的对照组相比，DEHP处理组的睾丸在3β-羟基类固醇脱氢酶（3β-HSD）染色增强，出现多灶性睾丸间质细胞增生区域的数量增加，以及多核生殖母细胞数量增加。与DEHP对体内T水平的影响相反，在体外浓度高达10 μM时，DEHP及其代谢产物单（2-乙基己基）邻苯二甲酸酯（MEHP）对人雄激素受体均无亲和力。这些数据表明，在生殖道分化的关键阶段，DEHP通过将胎儿雄性大鼠体内的T降低至雌性水平来破坏雄性大鼠的性分化。
