In Vitro Analysis of the Effects of Acute and Chronic Phthalate Exposures on Leydig Cell Testosterone Production, and the Molecular Mechanisms Involved

急性和慢性邻苯二甲酸盐暴露对间质细胞睾酮产生的影响以及所涉及的分子机制的体外分析

• 批准号: 10797467
• 负责人: Kassim Traore
• 金额: $ 15.61万
• 依托单位: DUQUESNE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2023-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10797467
• 关键词: Vitro; Analysis; Effects; Acute; Chronic

Project Summary By interfering with hormone function and action, endocrine-disrupting chemicals (EDCs) such as the plasticizer di-(2-ethylhexyl) phthalate (DEHP) can have negative effects on development and reproduction. With the support of a Research Enhancement (SC2) Award, when he was a faculty member at Elizabeth City State University, Dr. Traore found that in vivo exposure to DEHP during gestation had negative effects on testosterone (T) production in the adult, and that early exposure exacerbated the effects of subsequent exposures. Now at Duquesne University School of Medicine, Dr. Traore is proposing to conduct in vitro mechanistic studies of both acute and chronic DEHP effects on T production by Leydig cells. Until recently, Leydig cells isolated and cultured by available methods have been able to produce and maintain high levels of T production for only 3-5 days. Therefore, it has not yet been feasible to use primary cells in vitro to examine the direct, long-term effects of environmentally relevant concentrations of EDCs or to critically evaluate mechanisms involved in their actions on Leydig cells. However, Dr. Zirkin’s lab at the Johns Hopkins Bloomberg School of Public Health (JHSPH) has recently developed a method by which Leydig cells derived from the differentiation of Leydig stem cells are able to produce and sustain high levels of T production for longer periods, several months. Dr. Zirkin, who served in a mentorship position for the SC2 Award, is continuing to collaborate with Dr. Traore and his students. The availability of primary Leydig cells able to sustain high levels of T production will be of great value for our proposed studies of the chronic effects of environmentally relevant phthalate concentrations under highly controlled conditions, and the mechanisms by which they function. With the availability of these cells, we will conduct in vitro studies of the direct effects of MEHP on Leydig cell formation from stem cells, the effects of MEHP exposure on the adult Leydig cells, and the effects of early exposures on the consequences of subsequent exposures. We also will conduct mechanistic studies of acute and long-term effects of phthalate- induced oxidative stress on T production. Duquesne University has the equipment and facilities necessary for the proposed studies, as well as outstanding medical students, graduate students and undergraduates who will be involved in this research project. With funds of this REAP grant, Dr. Traore will be able to support and expand ongoing research in his lab at Duquesne University, an institution located in an underserved area of Pennsylvania. The extensive collaboration between the Johns Hopkins School of Public Health and Duquesne University will not only help excite Duquesne University students but also increase their interest in considering careers in basic science or clinical research. Moreover, the project undoubtedly will attract other Duquesne University faculty to seek funding to develop their research.

项目摘要 通过干扰骑马功能和动作，内分泌干扰化学物质（EDC），例如增塑剂 Di-（2-乙基己基）邻苯二甲酸酯（DEHP）可能对发育和繁殖产生负面影响。在支持下 在伊丽莎白市州立大学的教职员工时，颁发了研究增强奖（SC2）奖 Traore博士发现，妊娠期间体内暴露于DEHP对睾丸激素有负面影响（t） 成年人的生产，以及早期暴露使后续暴露的影响。现在在 Duquesne大学医学院，Traore博士提议对两者进行体外机械研究 Leydig细胞对T产生T的急性和慢性DEHP影响。直到最近，Leydig细胞分离和培养 通过可用的方法，仅3-5天就可以生产和维持高水平的T生产。 因此，在体外使用原代细胞来检查的直接，长期影响 EDC的环境相关浓度或严格评估其行动中涉及的机制 在leydig细胞上。但是，约翰·霍普金斯彭博公共卫生学院（JHSPH）的Zirkin博士实验室 最近开发了一种方法 生产和维持高水平的T生产长时间，几个月。 Zirkin博士，在 SC2奖的一项精神职位，正在继续与Traore博士及其学生合作。这 原发性Leydig细胞的可用性可以维持高水平的T生产将具有很大的价值 我们提出的对环境相关邻苯二甲酸酯浓度的慢性影响的研究 高度控制的条件及其功能的机制。这些可用性 细胞，我们将在体外研究MEHP对干细胞的Leydig细胞形成的直接影响， MEHP暴露对成年Leydig细胞的影响，以及早期暴露对 随后的暴露。我们还将对邻苯二甲酸酯的急性和长期作用进行机械研究 诱导氧化应激对T产生。杜肯大学有必要的设备和设施 拟议的研究以及杰出的医学生，研究生和本科生 参与该研究项目。通过这笔收获赠款的资金，Traore博士将能够支持和扩展 他在他在杜肯大学实验室的正在进行的研究，该机构位于一个服务不足的地区 宾夕法尼亚州。约翰·霍普金斯公共卫生学院与杜奎斯内的广泛合作 大学不仅会帮助杜肯大学的学生兴奋，而且还会增加他们考虑的兴趣 基础科学或临床研究的职业。此外，该项目无疑会吸引其他杜肯 大学教师寻求资金来发展他们的研究。