Cell Communication and Signaling
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2024
·Vol. 22
·期 1
·1-16
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IF 8.2
Zhai Wenhui,Tian Hairui,Liang Xuemei,Wu Yunqiang,Wen Jian,Liu Zhipeng,Zhao Xiaodong,Tao Li,Zou Kang
Background Androgens are essential hormones for testicular development and the maintenance of male fertility. Environmental factors, stress, aging, and psychological conditions can disrupt androgen production, impacting the androgen signaling pathway and consequently spermatogenesis. Within the testes, testosterone is produced by Leydig cells and acts on Sertoli cells by activating the androgen receptor (AR), which then translocates to the nucleus to function as a transcription factor. Despite clinical correlations between low testosterone levels and diminished sperm quality, the precise mechanism remains unclear. Methods This study explores the hypothesis that reduced androgen levels impair Sertoli cell function by disrupting AR transcriptional regulation. Using an androgen blockade model with enzalutamide, we investigated the impact of low androgen levels on AR target genes in Sertoli cells through ChIP-seq and RNA-seq assays. Results Our results reveal that androgen blockage increases AR enrichment on the promoter region of Wee1 , promoting Wee1 expression, while decreasing binding to the promoter region of Lfng , inhibiting its expression. Increased WEE1 protein inhibits Sertoli cell proliferation, whereas reduced LFNG affects Notch modification, leading to decreased production of glial cell line-derived neurotrophic factor (GDNF), a key growth factor for spermatogonial stem cell self-renewal. Conclusions These findings provide new insights into the molecular mechanisms by which low androgen levels interfere with Sertoli cell functions, offering novel perspectives for the clinical treatment of male reproductive disorders.
研究领域:
生殖生物学
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内分泌学
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产品关联
DOI
PubMed
高影响因子
Toxics
·
2025
·Vol. 13
·期 4
·285
·
IF 4.1
Yonggang Zhao,Mo Peng,Honglei Liu,Xiaoyu Zhang,Dan Fu
Tris(2-chloroethyl) phosphate (TCEP) is a representative chlorinated organophosphate flame retardant (OPFR) that demonstrates greater persistence than other non-halogenated alkyl or aryl OPFRs. Although TCEP has been shown to accumulate significantly in the environment and contribute to testicular toxicity and spermatogenic dysfunction, the precise underlying factors and mechanisms of action remain unclear. Herein, male ICR mice were gavaged with corn oil, 50 mg/kg body weight (bw) TCEP, or 100 mg/kg bw TCEP from postnatal day (PND) 22 to PND 35. TCEP exposure resulted in the disruption of blood-testis barrier (BTB) integrity and in abnormal testicular development. Considering that Sertoli cells constitute the primary target of toxicants and that TCEP induces oxidative stress in the testis and other organs, we focused on ferroptosis in Sertoli cells. Our findings revealed a significant increase in ferroptosis in the testes and Sertoli cells following TCEP exposure, and we observed functional restoration of Sertoli cell junctions upon treatment with the ferroptosis inhibitor ferrostatin-1. Furthermore, ferritin heavy chain 1 (FTH1) was markedly reduced in TCEP-exposed testes and Sertoli cells. Since nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy is essential for the degradation of FTH1, we assessed ferritinophagic activity and found significant upregulation of NCOA4, ATG5, ATG7, and LC3B II/I in TCEP-exposed testes and Sertoli cells. These results strongly suggest that TCEP triggers Sertoli cell ferroptosis by activating ferritinophagy that leads to reduced expression of BTB-associated proteins, ultimately causing BTB disruption and testicular developmental toxicity.
研究领域:
生殖毒理学
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环境健康科学
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DOI
PubMed
高影响因子
DNA AND CELL BIOLOGY
·
2025
·
IF 2.6
Lijiang Zhao,Xueqing Wu,Qiang Li,Yan Shen,Sheng Zeng,Jinbao Wang,Qian Liu
Bisphenol A (BPA) is the most common endocrine disruptor that has toxicity to the reproductive system and male infertility. However, the underlying mechanisms of BPA’s toxicity to Sertoli cells remain poorly understood. Cellular communication network factor 5 (CCN5) is reported to regulate cell proliferation, apoptosis, and differentiation. Our study demonstrated a significant elevation of CCN5 expression in the testis of nonobstructive azoospermia patients and TM4 Sertoli cells exposed to BPA. Knockdown of CCN5 reduced apoptotic cells after BPA treatment, as determined by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling assays. Cells exposed to BPA showed increased expressions of Bax and cleaved poly(ADP-ribose) polymerase, decreased expression of Bcl-2, as well as elevated activities of caspase-3 and caspase-9 in BPA-induced TM4 cells, which were reversed by CCN5 inhibition. Loss of CCN5 declined phosphorylation of protein kinase R-like endoplasmic reticulum kinase and eukaryotic translation initiation factor 2A and decreased activating transcription factor 4 and C/EBP-homologous protein in BPA-treated cells. Furthermore, silencing CCN5 blocked BPA-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK). Administration of anisomycin, a mitogen-activated protein kinase (MAPK) activator, reversed the effects of CCN5 knockdown on BPA-induced endoplasmic reticulum (ER) stress and apoptosis. Taken together, CCN5 promotes apoptosis and ER stress in Sertoli cells exposed to BPA by activating the p38/JNK MAPK signaling pathway.
研究领域:
生殖生物学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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