title: Effects of tamoxifen on autosomal genes regulating ovary maintenance in adult mice.
abstract: Environmental endocrine-disrupting chemicals (EDCs), known to bind to estrogen/androgen receptors and mimic native estrogens, have been implicated as a main source for increasing human reproductive and developmental deficiencies and diseases. Tamoxifen (TAM) is one of the most well-known antiestrogens with defined adverse effects on the female reproductive tract, but the mechanisms related to autosomal gene regulation governing ovary maintenance in mammals remain unclear. The expression pattern and levels of key genes and proteins involved in maintaining the ovarian phenotype in mice were analyzed. The results showed that TAM induced significant upregulation of Sox9, which is the testis-determining factor gene. The results showed that TAM induced significant upregulation of Sox9, the testis-determining factor gene, and the expression level of Sox9 mRNA in the ovaries of mice exposed to 75 or 225 mg/kg bw TAM was 2- and 10-fold that in the control group, respectively (p < 0.001). Furthermore, the testicular fibroblast growth factor gene, Fgf9, was also elevated in TAM-treated ovaries. Accordingly, expression of the ovary development marker, forkhead transcription factor (FOXL2), and WNT4/FST signaling, were depressed. The levels of protein expression changed consistently with the target genes. Moreover, the detection of platelet/endothelial cell adhesion molecule 1 (PECAM-1) in TAM-treated ovaries suggested the formation of vascular endothelial cells, which is a further evidence for the differentiation of the ovaries to a testis-like phenotype. During this period, the level of 17β-estradiol, progesterone, and luteinizing hormone decreased, while that of testosterone increased by 3.3-fold (p = 0.013). The activation of a testis-specific molecular signaling cascade was a potentially important mechanism contributing to the gender disorder induced by TAM, which resulted in the differentiation of the ovaries to a testis-like phenotype in adult mice. Limited with a relatively higher exposure, the present study provided preliminary molecular insights into the sexual disorder induced by antiestrogens and compounds that interrupted estrogen signaling by other modes of action.
authors: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, No. 2 Linggong Road, 116024, Dalian, Liaoning, China.
authors: Mingxi
authors: M
authors: Yu
authors: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, No. 2 Linggong Road, 116024, Dalian, Liaoning, China.
authors: Wei
authors: W
authors: Liu
authors: School of Life Science and Biotechnology, Dalian University of Technology, No. 2 Linggong Road, 116024, Dalian, Liaoning, China. wangjingyun67@dlut.edu.cn.
authors: Jingyun
authors: J
authors: Wang
authors: Department of Developmental and Regenerative Biology, Key Laboratory for Regenerative Medicine (MOE), Jinan University, No. 601 West Huangpu Road, 510632, Guangzhou, Guangdong, China.
authors: Junwen
authors: J
authors: Qin
authors: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, No. 2 Linggong Road, 116024, Dalian, Liaoning, China.
authors: Yongan
authors: Y
authors: Wang
authors: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, No. 2 Linggong Road, 116024, Dalian, Liaoning, China.
authors: Yu
authors: Y
authors: Wang
mesh_terms: D000818:Animals; D052244:Endocrine Disruptors / Q000378:metabolism / Q000633:toxicity*; D004967:Estrogens / Q000097:blood / Q000235:genetics; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000097:blood / Q000235:genetics; D005640:Follicle Stimulating Hormone / Q000097:blood / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood / Q000235:genetics; D051379:Mice; D008813:Mice, Inbred ICR; D010053:Ovary / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013629:Tamoxifen / Q000378:metabolism / Q000633:toxicity*
chemical_list: D052244:Endocrine Disruptors; D004967:Estrogens; D051525:Fibroblast Growth Factor 9; D012333:RNA, Messenger; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D013629:Tamoxifen; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone
keywords: Endocrine-disrupting chemicals; FOXL2; Ovary maintenance; SOX9/FGF9; Tamoxifen; WNT4/FST