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Effects of tamoxifen on autosomal genes regulating ovary maintenance in adult mice

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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.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China [No. 81273119], Water Pollution Control and Management Project [2012ZX07202-002], and “123” Project of Liaoning environment education research supported by the Geping Green Finance of China Environmental Protection Foundation [No. CEPF 2010-123-1-11].

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics statement

This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals (Ministry of Science and Technology of China, 2006) and was approved by the School of Environmental Science and Technology, Dalian University of Technology, China. All surgeries were performed under sodium pentobarbital anesthesia, and all efforts were made to minimize suffering.

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Authors and Affiliations

  1. 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

    Mingxi Yu, Wei Liu, Yongan Wang & Yu Wang

  2. School of Life Science and Biotechnology, Dalian University of Technology, No. 2 Linggong Road, 116024, Dalian, Liaoning, China

    Jingyun Wang

  3. Department of Developmental and Regenerative Biology, Key Laboratory for Regenerative Medicine (MOE), Jinan University, No. 601 West Huangpu Road, 510632, Guangzhou, Guangdong, China

    Junwen Qin

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  1. Mingxi Yu
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Correspondence to Jingyun Wang.

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Responsible editor: Philippe Garrigues

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Yu, M., Liu, W., Wang, J. et al. Effects of tamoxifen on autosomal genes regulating ovary maintenance in adult mice. Environ Sci Pollut Res 22, 20234–20244 (2015). https://doi.org/10.1007/s11356-015-5245-5

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  • DOI: https://doi.org/10.1007/s11356-015-5245-5

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