Scholarlink

Background <p>It is well-known that epigenetic regulation is involved in the negative effects of environmental physical, chemical and biological factors exposures on organs. To investigate the effects and mechanisms of histone hyperacetylation caused by environmental stress on spermatogenesis, we used the histone deacetylase inhibitor Panobinostat (PANO) to establish the hyperacetylation models in mice.</p> Methods <p>To investigate the effects of PANO on testicular function of male reproductive system, we conducted the evaluation of sperm quality parameters in mice. The morphological changes of testes were observed through hematoxylin and eosin (H&amp;E) staining on paraffin sections and quantified by stereological measurements after treatment to explore the cause of infertility and figure out if PANO has any effect on the reproductive system of male mice. Immunofluorescence, immunohistochemistry and immunoblotting were utilized to elucidate the impact and mechanisms of PANO treatment on spermatogenesis. RNA-seq analysis was performed on mouse testes to elucidate the underlying mechanisms of PANO.</p> Results <p>The rates of sperm survival and movement were reduced while malformation rate of sperm increased in the 34.4-day PANO group. Gene Set Enrichment Analysis (GSEA) supported the significant role of PANO in modulating cilium movement, sperm axoneme assembly and flagellated sperm motility. Numbers of MVH<sup>+</sup> cells were decreased while the numbers of SCP3<sup>+</sup> cells were significantly increased after PANO treatment compared to those in the control (CTL) group. The protein levels of PLZF in PANO-treated testes were dramatically reduced along with the increased distribution changes of SOX9, F4/80 protein. Further data demonstrated that PANO impeded spermiogenesis at the stage XI in the 34.4-day PANO group and enhanced the transcriptome levels of histone variants <i>H2bc4</i> and <i>H1f2</i>.</p> Conclusions <p>We have reported that PANO exerts a negative impact on the spermatogonial stem cell pool in mouse testes by disrupting its niche. This disruption leads to a reduction in germ cell numbers and impairs sperm function in mice, ultimately resulting in infertility. Moreover, PANO destabilizes the nucleosomes by increasing the transcriptional levels of <i>H2bc4</i> and <i>H1f2</i>, affects the histone-to-protamine transition, and arrests spermiogenesis at the elongating spermatid stage. These findings also suggest that <i>H2bc4</i> and <i>H1f2</i> may be potential key biomarkers in the testis for diagnosing male infertility associated with aberrant histone hyperacetylation due to the exposure of environmental pollutants.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Histone hyperacetylation disrupts spermatogonial stem cells homeostasis and impairs spermiogenesis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年6月15日

查看全文
  • Xiangying Ou,
  • Juan Yang,
  • Guihua Du,
  • Linfeng Yang,
  • Rong Zhong,
  • Fei Long,
  • Haocong Huang,
  • Huihong Zeng,
  • Lijian Shao

摘要

Background

It is well-known that epigenetic regulation is involved in the negative effects of environmental physical, chemical and biological factors exposures on organs. To investigate the effects and mechanisms of histone hyperacetylation caused by environmental stress on spermatogenesis, we used the histone deacetylase inhibitor Panobinostat (PANO) to establish the hyperacetylation models in mice.

Methods

To investigate the effects of PANO on testicular function of male reproductive system, we conducted the evaluation of sperm quality parameters in mice. The morphological changes of testes were observed through hematoxylin and eosin (H&E) staining on paraffin sections and quantified by stereological measurements after treatment to explore the cause of infertility and figure out if PANO has any effect on the reproductive system of male mice. Immunofluorescence, immunohistochemistry and immunoblotting were utilized to elucidate the impact and mechanisms of PANO treatment on spermatogenesis. RNA-seq analysis was performed on mouse testes to elucidate the underlying mechanisms of PANO.

Results

The rates of sperm survival and movement were reduced while malformation rate of sperm increased in the 34.4-day PANO group. Gene Set Enrichment Analysis (GSEA) supported the significant role of PANO in modulating cilium movement, sperm axoneme assembly and flagellated sperm motility. Numbers of MVH+ cells were decreased while the numbers of SCP3+ cells were significantly increased after PANO treatment compared to those in the control (CTL) group. The protein levels of PLZF in PANO-treated testes were dramatically reduced along with the increased distribution changes of SOX9, F4/80 protein. Further data demonstrated that PANO impeded spermiogenesis at the stage XI in the 34.4-day PANO group and enhanced the transcriptome levels of histone variants H2bc4 and H1f2.

Conclusions

We have reported that PANO exerts a negative impact on the spermatogonial stem cell pool in mouse testes by disrupting its niche. This disruption leads to a reduction in germ cell numbers and impairs sperm function in mice, ultimately resulting in infertility. Moreover, PANO destabilizes the nucleosomes by increasing the transcriptional levels of H2bc4 and H1f2, affects the histone-to-protamine transition, and arrests spermiogenesis at the elongating spermatid stage. These findings also suggest that H2bc4 and H1f2 may be potential key biomarkers in the testis for diagnosing male infertility associated with aberrant histone hyperacetylation due to the exposure of environmental pollutants.