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Pubertal exposure to di-(2-ethylhexyl)-phthalate inhibits G9a-mediated histone methylation during spermatogenesis in mice

  • Reproductive Toxicology
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Abstract

The increasing incidence of male reproductive impairments has been associated with di-(2-ethylhexyl)-phthalate (DEHP) exposure. However, mechanisms involved are lacking. We exposed 4-week-old male C57BL/6j mice to DEHP by gavage at 0, 125, 250 or 500 mg/kg body weight/day for 28 consecutive days. Our data showed that pubertal exposure to DEHP induces sperm count reduction as well as histological abnormalities in seminiferous epithelium and apoptosis of post-meiotic germ cells, and these effects are concomitant with reduction of testosterone levels and its steroidogenic gene expression. Moreover, the expressions of estrogen receptor ERβ and nuclear receptors Nr0b1, Nr0b2 are increased. The expression of Nr5a2 which is the inducer of steroidogenesis is significantly reduced. Furthermore, spermatogonial stem cell (SSC) self-renewal, differentiation and meiosis were significantly impaired, and the epigenetic regulator G9a-mediated histone methylation was decreased following DEHP exposure. Our results suggest that the DEHP-induced male reproductive impairments may depend on its estrogenic action on estrogen receptor and nuclear receptor, and involve inhibition of steroidogenesis, SSC self-renewal and meiosis, which may be attributed to the down-regulation of G9a-mediated histone methylation.

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Acknowledgments

This work was supported by the National Basic Research Program of China (National 973 Program) (Grant No: 2011CB503700) and the National Natural Science Foundation of China (Grant No: 31170800).

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The authors declare no conflict of interest.

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    Authors and Affiliations

    1. Department of Occupational Health, Third Military Medical University, Chongqing, 400038, People’s Republic of China

      Chuan Liu, Peng Qian, Lingling Yang, Lei Zhang, Chunhai Chen, Mindi He, Yonghui Lu, Min Li, Yanwen Zhang, Min Zhong, Zhengping Yu & Zhou Zhou

    2. Department of Occupational and Environmental Health, School of Public Health and Health Management, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

      Wei Feng

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    1. Chuan Liu
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    Correspondence to Zhou Zhou.

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    Chuan Liu and Peng Qian have contributed equally to this work.

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    Liu, C., Qian, P., Yang, L. et al. Pubertal exposure to di-(2-ethylhexyl)-phthalate inhibits G9a-mediated histone methylation during spermatogenesis in mice. Arch Toxicol 90, 955–969 (2016). https://doi.org/10.1007/s00204-015-1529-2

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