Toxicology Assessment Division, Reproductive Toxicology Branch, U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Research Triangle Park, North Carolina 27711, USA.
Toxicol Sci. 2011 Sep;123(1):206-16. doi: 10.1093/toxsci/kfr146. Epub 2011 Jun 1.
Several phthalate esters have been linked to the Phthalate Syndrome, affecting male reproductive development when administered to pregnant rats during in utero sexual differentiation. The goal of the current study was to enhance understanding of this class of compounds in the Sprague Dawley (SD) fetal rat following exposure on gestational days (GDs) 14-18 by determining the relative potency factors for several phthalates on fetal testes endpoints, the effects of a nine phthalate mixture on fetal testosterone (T) production, and differences in SD and Wistar (W) strain responses of fetal T production and testicular gene expression to di(2-ethylhexyl) phthalate (DEHP). We determined that diisobutyl phthalate (DIBP) and diisoheptyl phthalate (DIHP) reduced fetal testicular T production with similar potency to DEHP, whereas diisononyl phthalate (DINP) was 2.3-fold less potent. DINP was also less potent at reducing StAR and Cyp11a gene expression levels, whereas DIBP was slightly more potent than DEHP. We observed that administration of dilutions of a mixture of nine phthalates (DEHP, DIHP, DIBP, dibutyl-, benzyl butyl-, dicyclohexyl-, diheptyl-, dihexyl-, and dipentyl phthalate) reduced fetal T production in a dose-dependent manner best predicted by dose addition. Finally, we found that the differential effects of in utero DEHP treatment on epididymal and gubernacular differentiation in male SD and W rats (0, 100, 300, 500, 625, 750, or 875 mg DEHP/kg/day) are likely due to tissue-specific strain differences in the androgen and insl3 signaling pathways rather than differential effects of DEHP on fetal testis T and insl3 production.
几种邻苯二甲酸酯已被证明与邻苯二甲酸酯综合征有关，当在宫内性分化期间给怀孕的大鼠施用时，会影响雄性生殖发育。本研究的目的是通过确定几种邻苯二甲酸酯对胎儿睾丸终点的相对效力因子、九种邻苯二甲酸酯混合物对胎儿睾酮（T）产生的影响，以及在 Sprague Dawley（SD）和 Wistar（W）品系胎儿 T 产生和睾丸基因表达对邻苯二甲酸二（2-乙基己基）酯（DEHP）的反应差异，来增强对宫内妊娠第 14-18 天暴露于此类化合物的认识。我们发现，邻苯二甲酸二异丁酯（DIBP）和邻苯二甲酸二异庚酯（DIHP）降低胎儿睾丸 T 产生的效力与 DEHP 相似，而邻苯二甲酸二异壬酯（DINP）的效力则低 2.3 倍。DINP 还降低 StAR 和 Cyp11a 基因表达水平的效力也较低，而 DIBP 比 DEHP 略高。我们观察到，用 9 种邻苯二甲酸酯混合物（DEHP、DIHP、DIBP、二丁基、苄基丁基、二环己基、二庚基、二己基和二戊基邻苯二甲酸酯）的稀释液处理，以剂量加和方式最佳预测的剂量依赖性方式降低胎儿 T 产生。最后，我们发现宫内 DEHP 处理对雄性 SD 和 W 大鼠附睾和 gubernacular 分化的差异影响（0、100、300、500、625、750 或 875 mg DEHP/kg/天）可能是由于组织特异性品系在雄激素和 insl3 信号通路中的差异，而不是 DEHP 对胎儿睾丸 T 和 insl3 产生的差异影响。
