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

邻苯二甲酸盐对人类和啮齿动物胎儿睾丸中视黄酸信号传导的干扰

• 批准号: 9766295
• 负责人: Daniel James Spade
• 金额: $ 24.18万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766295
• 关键词: Address; Adult; Adverse effects; Affect; Binding; Biological Models; CYP26B1 gene; Cell Death; Cell Differentiation process; Cell Proliferation; Cells; Chemicals; Computer Simulation; Congenital Disorders; Cryptorchidism; DNA Methylation; Data; Defect; Development; Elderly; Environmental Exposure; Epigenetic Process; Exposure to; Fetal Development; Functional disorder; Gene Expression; Germ Cells; Goals; Health; Histology; Human; Hypospadias; Immunohistochemistry; In Vitro; Industrialization; Link; Long-Term Effects; Maintenance; Male Genital Organs; Malignant neoplasm of testis; Measures; Mediating; Meiosis; Metabolism; Mission; Modeling; Mus; National Institute of Environmental Health Sciences; Outcome; Ovary; Pathology; Pathway interactions; Peroxisome Proliferators; Pregnancy; RXR; Rattus; Reproductive Health; Research; Research Personnel; Resistance; Risk; Rodent; Seminiferous Cord; Sex Differentiation; Signal Pathway; Signal Transduction; Spermatogenesis; Structure; Testicular Dysgenesis Syndrome; Testing; Testis; Testosterone; Toxic effect; Tretinoin; Xenobiotics; adverse outcome; androgenic; cancer risk; environmental chemical; environmental stressor; experimental study; fetal; fetal loss; gonad development; health knowledge; human male; improved; in utero; in vitro Model; in vivo; male; mono-(2-ethylhexyl)phthalate; phthalates; premature; prenatal exposure; prevent; reproductive; reproductive tract; response; retinoic acid receptor alpha; sertoli cell; sex determination; species difference; sperm cell

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.

该项目是人类和啮齿动物胎儿睾丸中邻苯二甲酸盐的视黄酸信号传导的破坏， 通过提供有关中断的机械信息，将改善男性生殖健康 一类无处不在的环境化学物质的关键胎儿睾丸发育途径。 视黄酸信号传导调节睾丸生殖细胞进入减数分裂和外源性 视黄酸对伴有性腺性别确定的信号通路具有巨大影响 睾丸的区分。邻苯二甲酸酯与胎儿睾丸中的视黄酸信号传导相互作用 体外。邻苯二甲酸盐和视黄酸都会对 多种物种。但是，关于负责互动的机制仍然存在问题 以及破坏此信号通路的长期影响。胎儿睾丸培养 实验表明，外源性视黄酸会破坏生精的绳索发育 和性别确定的信号传导，并且邻苯二甲酸酯与视黄酸相互作用 增强和抑制其中一些影响。 R00研究将集中于老鼠之间的比较 胎儿睾丸以及小鼠和人类胎儿睾丸模型（特定目标1）。这会 允许与胎儿睾丸培养的实验进行重要的跨物种比较和培养 Sertoli细胞。这些实验将量化胎儿睾丸对视黄酸的反应 并使用组织学，免疫组织化学和基因表达作为终点进行邻苯二甲酸盐。额外的 实验将测量胎儿邻苯二甲酸酯和视黄酸对小鼠的影响 晚年睾丸，包括睾丸的发展，成年小鼠的精子发生以及 DNA甲基化的变化（特定目标2）。这将是澄清的第一步 邻苯二甲酸盐毒性发挥持久性且潜在的转世效应的机制 通过破坏胎儿睾丸中的视黄酸信号传导。该项目以工作为指导 假设：邻苯二甲酸盐通过破坏视网膜而干扰胎儿睾丸发育 酸信号在生精线中。 提出的实验提供了有关环境暴露和对影响的关键信息 男性生殖健康并实现该项目的目标：描述该机制的机制 邻苯二甲酸盐对视黄酸信号通路行动，在人类期间产生不良结果 胎儿睾丸发育。实现以下特定目标将实现此目标。 1：比较视黄酸信号传导对跨物种睾丸发育的影响。 2： 确定因视黄酸信号改变而介导的邻苯二甲酸酯暴露的持续不良结果。