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.

这个项目，人类和啮齿动物胎儿睾丸中邻苯二甲酸酯对维甲酸信号的干扰， 将通过提供有关破坏生殖系统的机械信息来改善男性生殖健康。 关键的胎儿睾丸发育途径的一类普遍存在的环境化学品。 视黄酸信号调节睾丸生殖细胞进入减数分裂， 视黄酸对涉及性腺性别决定的信号传导途径具有显著影响， 睾丸的分化。邻苯二甲酸酯与胎儿睾丸中视黄酸信号的相互作用 体外邻苯二甲酸盐和视黄酸都对胎儿生精索造成不良影响， 多个物种然而，关于这种相互作用的机制仍然存在疑问 以及破坏这种信号通路的长期影响。胎儿睾丸培养 实验证明外源性视黄酸破坏生精索的发育 和性别决定的信号，邻苯二甲酸酯与视黄酸相互作用， 增强和抑制其中一些效应。R00的研究将集中在大鼠之间的比较， 胎儿睾丸以及小鼠和人胎儿睾丸模型（具体目标1）。这将 允许重要的跨物种比较与实验中的胎儿睾丸培养和培养 支持细胞。这些实验将量化胎儿睾丸对视黄酸的反应 和邻苯二甲酸酯，使用组织学、免疫组织化学和基因表达作为终点。额外 实验将测量胎儿邻苯二甲酸酯和视黄酸暴露对小鼠的影响 睾丸在以后的生活中，包括睾丸的发育，成年小鼠的精子发生， DNA甲基化的变化（特异性目的2）。这将是澄清 邻苯二甲酸酯毒性产生持久和潜在跨代影响的机制 通过破坏胎儿睾丸中的视黄酸信号。该项目由工作指导， 假设：邻苯二甲酸酯通过破坏维甲酸干扰胎儿睾丸发育 生精索中的酸性信号。 拟议的实验提供了关于环境暴露和对环境的影响的关键信息。 男性生殖健康和服务于本项目的目标：描述机制， 邻苯二甲酸酯作用于视黄酸信号通路， 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：比较不同物种间破坏的视黄酸信号传导对睾丸发育的影响。第二章： 识别由改变的视黄酸信号介导的邻苯二甲酸酯暴露的持续不良后果。