Retinoic Acid Signaling Disruption by Phthalates in Human and Rodent Fetal Testis

这个项目，邻苯二甲酸盐在人类和啮齿动物胚胎睾丸中对维甲酸信号的干扰， 将改善男性生殖健康，通过提供关于中断 一类普遍存在的环境化学物质对胎儿睾丸发育的关键途径。 维甲酸信号调节睾丸生殖细胞进入减数分裂，外源 维甲酸对参与性腺性别决定的信号通路有显著影响 睾丸的分化。邻苯二甲酸盐与胎儿睾丸中的维甲酸信号相互作用 在试管中。邻苯二甲酸酯和维甲酸均对胎儿输精管有不良影响 多种物种。然而，关于这种相互作用的机制仍然存在疑问 以及关于扰乱这一信号通路的长期影响。胎儿睾丸培养 实验证明，外源性维甲酸干扰生精索发育 以及性别决定的信号，邻苯二甲酸盐与维甲酸相互作用 增强和抑制其中的一些影响。R00研究将集中在大鼠之间的比较 胎儿睾丸及小鼠和人胎儿睾丸模型(特定目标1)。这将是 允许与胎儿睾丸培养和培养的实验进行重要的跨物种比较 支持细胞。这些实验将量化胎儿睾丸对维甲酸的反应。 和邻苯二甲酸盐，以组织学、免疫组织化学和基因表达为终点。其他内容 实验将测量胎儿邻苯二甲酸盐和维甲酸对小鼠的影响 睾丸，包括睾丸的发育，成年小鼠的精子发生，以及 DNA甲基化的变化(特定目标2)。这将是朝着澄清 邻苯二甲酸盐毒性产生持久和潜在的跨代影响的机制 通过干扰胎儿睾丸中的维甲酸信号。这个项目是以工作为指导的 假设：邻苯二甲酸盐通过破坏维甲酸干扰胎儿睾丸发育 生精索中的酸性信号。 拟议的实验提供了有关环境暴露及其影响的关键信息 男性生殖健康和服务于本项目的目标：描述 邻苯二甲酸盐作用于维甲酸信号通路，在人体内产生不良后果 胎儿睾丸发育。这一目标将通过实现以下具体目标来实现。 1：比较维甲酸信号中断对不同物种睾丸发育的影响。2： 确定由改变的维甲酸信号介导的邻苯二甲酸盐暴露的持续不良后果。

This project, Retinoic Acid Signaling Disruption by Phthalates in Human and Rodent Fetal Testis, will improve male reproductive health by providing mechanistic information about disruption of a critical fetal testis developmental pathway by a ubiquitous class of environmental chemicals. Retinoic acid signaling regulates the entry of testicular germ cells into meiosis, and exogenous retinoic acid has dramatic effects on signaling pathways involved in gonadal sex determination and differentiation of the testis. Phthalates interact with retinoic acid signaling in the fetal testis in vitro. Phthalates and retinoic acid both cause adverse effects on the fetal seminiferous cord of multiple species. However, questions remain about the mechanisms responsible for the interaction and about the long-term effects of disrupting this signaling pathway. Fetal testis culture experiments have demonstrated that exogenous retinoic acid disrupts seminiferous cord development and signaling for sex determination, and that phthalates interact with retinoic acid to both enhance and inhibit some of these effects. R00 research will focus on comparisons between the rat fetal testis and both mouse and human fetal testis models (Specific Aim 1). This will allow for important cross-species comparison with experiments in fetal testis cultures and cultured Sertoli cells. These experiments will quantify the response of the fetal testis to retinoic acid and phthalates using histology, immunohistochemistry, and gene expression as endpoints. Additional experiments will measure the impact of fetal phthalate and retinoic acid exposure on the mouse testis in later life, including development of the testis, spermatogenesis in adult mice, and changes in DNA methylation (Specific Aim 2). This will be a first step toward clarifying the mechanisms by which phthalate toxicity exerts persistent and potentially transgenerational effects by disrupting retinoic acid signaling in the fetal testis. This project is guided by the working hypothesis: phthalates interfere with fetal testicular development through disruption of retinoic acid signaling in the seminiferous cord. The proposed experiments provide critical information about environmental exposures and effects on male reproductive health and serve the goal of this project: to describe the mechanism by which phthalates act on the retinoic acid signaling pathway to produce adverse outcomes during human fetal testicular development. This goal will be achieved by fulfilling the following Specific Aims. 1: Compare the impact of disrupted retinoic acid signaling on testis development across species. 2: Identify persistent adverse outcomes of phthalate exposure mediated by altered retinoic acid signaling.