点击次数：

论文类型：期刊论文

发表时间：2014-07-03

发表刊物：TOXICOLOGY

收录刊物：SCIE、PubMed、Scopus

卷号：321

期号：1

页面范围：89-95

ISSN号：0300-483X

关键字：Tamoxifen; Sex determination; Sex reversal; Endocrine-disrupting chemicals

摘要：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 17 beta-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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.