Ethylene dimethanesulfonate effects on gene promoter activities related to the endocrine function of immortalized Leydig cell lines R2C and MA-10

IF 2.9 Q2 TOXICOLOGY
Jorge W.F. de Barros , Kenley Joule Pierre , Wilma De G. Kempinas , Jacques J. Tremblay
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Abstract

Ethylene dimethanesulfonate (EDS) is a molecule with known selective cytotoxicity on adult Leydig cells. A single intraperitoneal injection in rats but not mice, leads to male androgen deprivation and infertility. In vitro studies using rat and mouse immortalized Leydig cell lines, showed similar effects of cell death promoted by EDS in rat cells as seen in vivo, and suggest that EDS affects gene transcription, which could firstly compromise steroidogenesis before the apoptosis process. Using gene reporter assay, this study aimed to investigate EDS effects on the promoter activity of genes important for endocrine function (Star, Insl3) and response to toxic agents (Gsta3) in immortalized Leydig cell lines (rat R2C and mouse MA-10 cells), as well as identify possible EDS-responsive elements in the Star gene promoter. EDS exposure of R2C and MA-10 Leydig cells increased Gsta3 promoter activity after 4 h of treatment and decreased Insl3 promoter activity only in R2C cells after 24 h of treatment. EDS also decreased Star promoter activity in both Leydig cell lines. Using R2C cells, the EDS-responsive region in the Star promoter was located between −400 and −195 bp. This suggests that this region and the associated transcription factors, which include MEF2, might be targeted by EDS. Additional somatic gonadal cell lines expressing Star were used and EDS did not affect Star promoter activity in DC3 granulosa cells while Star promoter activity was increased in MSC-1 Sertoli cells after 24 h of treatment. This study contributes to the knowledge regarding the mechanism of EDS action in Leydig cells, and in other gonadal cell lineages, and brings new light regarding the rats and mice differential susceptibility to EDS effects, in addition to providing new avenues for experimental approaches to better understand Leydig cell function and dynamics in different rodent species.

Abstract Image

二甲苯磺酸乙烯酯对永生化莱德细胞系R2C和MA-10与内分泌功能有关的基因启动子活性的影响
二甲苯磺酸乙烯酯(EDS)是一种已知对成年髓质细胞具有选择性细胞毒性的分子。大鼠腹腔注射一次就会导致雄性雄性激素缺乏和不育,小鼠则不会。使用大鼠和小鼠永生化 Leydig 细胞系进行的体外研究显示,EDS 在大鼠细胞中促进细胞死亡的效果与在体内看到的相似,并表明 EDS 会影响基因转录,这可能会在细胞凋亡过程之前首先影响类固醇的生成。本研究采用基因报告分析法,旨在研究EDS对永生化Leydig细胞系(大鼠R2C和小鼠MA-10细胞)中对内分泌功能(Star、Insl3)和对毒物反应(Gsta3)有重要影响的基因启动子活性的影响,并确定Star基因启动子中可能存在的EDS反应元件。R2C和MA-10 Leydig细胞暴露于EDS后,Gsta3启动子活性在处理4小时后增加,而Insl3启动子活性在处理24小时后仅在R2C细胞中降低。EDS 还降低了两种 Leydig 细胞系中 Star 启动子的活性。利用 R2C 细胞,Star 启动子中的 EDS 反应区位于 -400 和 -195 bp 之间。这表明该区域及相关转录因子(包括 MEF2)可能是 EDS 的靶标。研究人员还使用了其他表达Star的体细胞系,结果表明EDS并不影响DC3颗粒细胞中Star启动子的活性,而MSC-1 Sertoli细胞中Star启动子的活性在处理24小时后有所增加。这项研究有助于了解 EDS 在 Leydig 细胞和其他性腺细胞系中的作用机制,并为大鼠和小鼠对 EDS 影响的不同易感性带来了新的启示,此外还为实验方法提供了新的途径,以更好地了解不同啮齿动物物种中 Leydig 细胞的功能和动态。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Current Research in Toxicology
Current Research in Toxicology Environmental Science-Health, Toxicology and Mutagenesis
CiteScore
4.70
自引率
3.00%
发文量
33
审稿时长
82 days
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