piRNA array analysis provide insight into the mechanism of DEHP-induced testicular toxicology in pubertal male rats

IF 6.2 2区 环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES Ecotoxicology and Environmental Safety Pub Date : 2024-11-05 DOI:10.1016/j.ecoenv.2024.117282
Guoqing Fu , Qinru Wu , Juan Dai , Siqi Lu , Ting Zhou , Zhongcheng Yang , Yuqin Shi
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Abstract

Di-(2-ethylhexyl) phthalate (DEHP), a widely used plasticizer, could cause male reproductive toxicity by disrupting spermatogenesis. Piwi-interacting RNAs (piRNAs) are a small non-coding RNAs specifically highly expressed in the germline and interact with PIWI proteins to regulate spermatogenesis. Accumulating studies have confirmed that environmental poisons could induce male reproductive injury via altering piRNA expression. However, it remains unclear whether DEHP causes male reproductive dysfunction by perturbing piRNA expression levels. In this study, we conducted piRNA microarray expression analyses on testes of DEHP-exposed and control male rats and performed some in vitro and in vivo studies to explore the role of piRNA on DEHP-induced male reproductive toxicity. Our results showed that DEHP exposure leaded to changed expression profiles of piRNAs in pubertal male rat testes. And bioinformatics analyses revealed that down-regulated piR-rno-26751 probably targeted Insr mRNA expression regulation. Results from gene and protein expression tests demonstrated that DEHP caused decreased expression level of INSR mainly in spermatogonia. Moreover, MEHP, the main metabolite of DEHP resulted in cell apoptosis and down-regulation of INSR and its downstream p-IRS1, p-PI3K, p-AKT and p-FOXO1 in GC-1spg cells. Conversely, overexpression of INSR restored cell apoptosis and the down-regulation of the above proteins in GC-1spg cells. In conclusion, these findings suggest that DEHP-induced down-regulation of piR-rno-26751 targets the suppression of INSR, leading to apoptosis of spermatogonia in pubertal male rats.
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piRNA 阵列分析有助于深入了解 DEHP 诱导青春期雄性大鼠睾丸中毒的机制
邻苯二甲酸二(2-乙基己基)酯(DEHP)是一种广泛使用的增塑剂,可通过干扰精子发生而导致男性生殖毒性。Piwi-interacting RNAs(πRNAs)是一种小型非编码 RNAs,在生殖细胞中特异性高表达,与 PIWI 蛋白相互作用,调控精子发生。大量研究证实,环境毒物可通过改变 piRNA 的表达诱发男性生殖损伤。然而,DEHP 是否会通过扰乱 piRNA 的表达水平而导致男性生殖功能障碍,目前仍不清楚。在本研究中,我们对暴露于DEHP的雄性大鼠和对照组大鼠的睾丸进行了piRNA芯片表达分析,并进行了一些体外和体内研究,以探讨piRNA在DEHP诱导的雄性生殖毒性中的作用。结果表明,DEHP 暴露导致青春期雄性大鼠睾丸中 piRNA 的表达谱发生了变化。生物信息学分析表明,下调的 piR-rno-26751 可能是针对 Insr mRNA 表达的调控。基因和蛋白质表达检测结果表明,DEHP主要在精原细胞中导致INSR表达水平下降。此外,DEHP 的主要代谢产物 MEHP 会导致 GC-1spg 细胞凋亡,并下调 INSR 及其下游的 p-IRS1、p-PI3K、p-AKT 和 p-FOXO1。相反,过表达 INSR 可恢复 GC-1spg 细胞的细胞凋亡和上述蛋白的下调。总之,这些研究结果表明,DEHP 诱导的 piR-rno-26751 下调会抑制 INSR,从而导致青春期雄性大鼠精原细胞凋亡。
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来源期刊
CiteScore
12.10
自引率
5.90%
发文量
1234
审稿时长
88 days
期刊介绍: Ecotoxicology and Environmental Safety is a multi-disciplinary journal that focuses on understanding the exposure and effects of environmental contamination on organisms including human health. The scope of the journal covers three main themes. The topics within these themes, indicated below, include (but are not limited to) the following: Ecotoxicology、Environmental Chemistry、Environmental Safety etc.
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