Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian, Liaoning 116024, China.
School of Life Science and Biotechnology, Dalian University of Technology, Dalian, Liaoning 116024, China.
Toxicology. 2014 Jul 3;321:89-95. doi: 10.1016/j.tox.2014.04.006. Epub 2014 Apr 24.
Tamoxifen, as well as most endocrine-disrupting chemicals, affects the reproductive system and sexual development, but little is known about its disruption of the molecular pathways regulating mammalian sex determination. In fetal mice, the expression levels and pattern of key genes involved in controlling sexually dimorphic balance were analyzed both in vivo and in vitro by using whole-mount in situ hybridization and quantitative-PCR. Developmental tamoxifen exposure induced abnormal up-regulation of the testis differentiation marker Pdfgra in Leydig cells and of Sox9 and Fgf9 in Sertoli cells in XX gonad. Immunohistochemistry analysis confirmed the over-expression of SOX9 protein. Accordingly, the ovary development marker Foxl2 was depressed at both the mRNA and protein levels. The increase in testosterone and the reduction in 17β-estradiol and progesterone were observed by using the in vitro assay with organotypic cultures. Taken together, results indicated that tamoxifen induced the ectopic expression of well-established sex-specific genes during the critical developmental period, thus resulting in abnormal testicular development in the XX gonad of mammals. This study facilitates a better understanding of the molecular mechanisms of antiestrogens and possibly of compounds that interrupt estrogen signaling by other modes of action, and the association with the pathogenesis of human sexual developmental disorders.
他莫昔芬和大多数内分泌干扰化学物质一样，会影响生殖系统和性发育，但人们对其扰乱调节哺乳动物性别决定的分子途径知之甚少。在胎鼠中，通过使用整体原位杂交和定量 PCR，在体内和体外分析了参与控制性别二态性平衡的关键基因的表达水平和模式。发育性他莫昔芬暴露诱导 XX 性腺中的睾丸分化标记物 Pdfgra 在 Leydig 细胞中以及 Sox9 和 Fgf9 在 Sertoli 细胞中的异常上调。免疫组织化学分析证实了 SOX9 蛋白的过表达。相应地，卵巢发育标记物 Foxl2 在 mRNA 和蛋白质水平上均受到抑制。通过使用器官培养的体外测定，观察到睾酮增加和 17β-雌二醇和孕酮减少。总之，结果表明他莫昔芬在关键发育时期诱导了既定的性别特异性基因的异位表达，从而导致哺乳动物 XX 性腺中睾丸发育异常。这项研究有助于更好地理解抗雌激素的分子机制，以及可能通过其他作用模式中断雌激素信号的化合物，并与人类性发育障碍的发病机制相关。
