Liu Kejun, Lehmann Kim P, Sar Madhabananda, Young S Stanley, Gaido Kevin W
CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709, USA.
Biol Reprod. 2005 Jul;73(1):180-92. doi: 10.1095/biolreprod.104.039404. Epub 2005 Feb 23.
Male reproductive tract abnormalities associated with testicular dysgenesis in humans also occur in male rats exposed gestationally to some phthalate esters. We examined global gene expression in the fetal testis of the rat following in utero exposure to a panel of phthalate esters. Pregnant Sprague-Dawley rats were treated by gavage daily from Gestational Days 12 through 19 with corn oil vehicle (1 ml/kg) or diethyl phthalate (DEP), dimethyl phthalate (DMP), dioctyl tere-phthalate (DOTP), dibutyl phthalate (DBP), diethylhexyl phthalate (DEHP), dipentyl phthalate (DPP), or benzyl butyl phthalate (BBP) at 500 mg/kg per day. Testes were isolated on Gestational Day 19, and global changes in gene expression were determined. Of the approximately 30 000 genes queried, expression of 391 genes was significantly altered following exposure to the developmentally toxic phthalates (DBP, BBP, DPP, and DEHP) relative to the control. The developmentally toxic phthalates were indistinguishable in their effects on global gene expression. No significant changes in gene expression were detected in the nondevelopmentally toxic phthalate group (DMP, DEP, and DOTP). Gene pathways disrupted include those previously identified as targets for DBP, including cholesterol transport and steroidogenesis, as well as newly identified pathways involved in intracellular lipid and cholesterol homeostasis, insulin signaling, transcriptional regulation, and oxidative stress. Additional gene targets include alpha inhibin, which is essential for normal Sertoli cell development, and genes involved with communication between Sertoli cells and gonocytes. The common targeting of these genes by a select group of phthalates indicates a role for their associated molecular pathways in testicular development and offers new insight into the molecular mechanisms of testicular dysgenesis.
与人类睾丸发育不全相关的男性生殖道异常也出现在孕期接触某些邻苯二甲酸酯的雄性大鼠中。我们检测了子宫内接触一组邻苯二甲酸酯后大鼠胎儿睾丸中的整体基因表达情况。怀孕的斯普拉格-道利大鼠从妊娠第12天至19天每天经口灌胃给予玉米油载体（1毫升/千克）或邻苯二甲酸二乙酯（DEP）、邻苯二甲酸二甲酯（DMP）、对苯二甲酸二辛酯（DOTP）、邻苯二甲酸二丁酯（DBP）、邻苯二甲酸二（2-乙基己基）酯（DEHP）、邻苯二甲酸二戊酯（DPP）或邻苯二甲酸苄基丁酯（BBP），剂量为每天500毫克/千克。在妊娠第19天分离睾丸，并确定基因表达的整体变化。在检测的约30000个基因中，与对照组相比，接触发育毒性邻苯二甲酸酯（DBP、BBP、DPP和DEHP）后391个基因的表达发生了显著改变。发育毒性邻苯二甲酸酯对整体基因表达的影响没有差异。在非发育毒性邻苯二甲酸酯组（DMP、DEP和DOTP）中未检测到基因表达的显著变化。被破坏的基因途径包括先前确定为DBP作用靶点的途径，如胆固醇转运和类固醇生成，以及新确定的参与细胞内脂质和胆固醇稳态、胰岛素信号传导、转录调控和氧化应激的途径。其他基因靶点包括对支持细胞正常发育至关重要的α抑制素，以及参与支持细胞与生殖母细胞之间通讯的基因。一组特定邻苯二甲酸酯对这些基因的共同靶向作用表明其相关分子途径在睾丸发育中起作用，并为睾丸发育不全的分子机制提供了新的见解。
