Mu Xueyan, Liu Kejun, Kleymenova Elena, Sar Madhabananda, Young S Stanley, Gaido Kevin W
CIIT Centers for Health Research, Research Triangle Park, NC 27709, USA.
J Biochem Mol Toxicol. 2006;20(1):7-17. doi: 10.1002/jbt.20110.
The androgen receptor (AR) is expressed in the fetal testis; however, the role of AR in fetal testicular development is poorly understood. Disrupted AR activity and subsequent gene expression alterations may disturb developmental programming of the fetal testis and result in testicular abnormalities later in life. The present study was performed to examine global gene expression patterns in rat fetal testis following in utero exposure to various AR antagonists. Pregnant Sprague-Dawley rats were treated with flutamide (50 mg/kg/day), linuron (50 mg/kg/day), vinclozolin (200 mg/kg/day), p,p'-DDE (100 mg/kg/day) or corn oil vehicle by gavage daily from gestation day (GD) 12-19. Testes were isolated on GD 19, and AR immunostaining, histology, and global changes in gene expression were determined. There were no alterations in the pattern or expression level of AR and no apparent histological changes in the fetal testes in any treatment group. Microarray analysis using Dunnett's test with multiple testing correction revealed no significant gene expression alterations following exposure to flutamide, linuron, vinclozolin, and p,p'-DDE. A less stringent analysis yielded some chemical specific effects on gene expression, and these effects were further evaluated by real-time RT-PCR. Vinclozolin treatment reduced the expression of several genes involved in cholesterol biosynthesis, though the testosterone levels were unchanged in the fetal testes in any treatment group. In flutamide, linuron, and p,p'-DDE treatment groups, the expression of hemoglobin Y, beta-like embryonic chain (Hbb-y) was reduced. Myomesin 2 (Myom2) expression was increased following linuron treatment. Given the lack of a common set of genes and the absence of overt histopathology, we conclude that the fetal testis is not a major target for AR activity at this stage of development although some cell-type specific gene expression changes cannot be ruled out.
雄激素受体（AR）在胎儿睾丸中表达；然而，AR在胎儿睾丸发育中的作用仍知之甚少。AR活性的破坏及随后的基因表达改变可能会干扰胎儿睾丸的发育程序，并导致日后生活中的睾丸异常。本研究旨在检测子宫内暴露于各种AR拮抗剂后大鼠胎儿睾丸中的整体基因表达模式。从妊娠第12天至19天，每天通过灌胃给怀孕的Sprague-Dawley大鼠施用氟他胺（50 mg/kg/天）、利谷隆（50 mg/kg/天）、乙烯菌核利（200 mg/kg/天）、p,p'-滴滴涕（100 mg/kg/天）或玉米油载体。在妊娠第19天分离睾丸，并进行AR免疫染色、组织学检查以及基因表达的整体变化测定。在任何治疗组中，胎儿睾丸中AR的模式或表达水平均无改变，也没有明显的组织学变化。使用Dunnett检验并进行多重检验校正的微阵列分析显示，暴露于氟他胺、利谷隆、乙烯菌核利和p,p'-滴滴涕后，基因表达没有显著改变。不太严格的分析产生了一些化学物质对基因表达的特异性影响，并通过实时RT-PCR进一步评估了这些影响。乙烯菌核利处理降低了几个参与胆固醇生物合成的基因的表达，尽管任何治疗组中胎儿睾丸中的睾酮水平均未改变。在氟他胺、利谷隆和p,p'-滴滴涕治疗组中，血红蛋白Y、β样胚胎链（Hbb-y）的表达降低。利谷隆处理后肌间蛋白2（Myom2）的表达增加。鉴于缺乏一组共同的基因且没有明显的组织病理学变化，我们得出结论，在这个发育阶段，胎儿睾丸不是AR活性的主要靶点，尽管不能排除一些细胞类型特异性的基因表达变化。
