Phthalate-induced testicular mitochondrial dysfunction

邻苯二甲酸盐诱导的睾丸线粒体功能障碍

• 批准号: 6789817
• 负责人: THOMAS M ONORATO
• 金额: $ 4.11万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6789817
• 关键词: SDS polyacrylamide gel electrophoresis; Sertoli cells; antioxidants; apoptosis; cytochrome c; diethylhexylphthalate; flow cytometry; free radical oxygen; gene expression; immunoprecipitation; laboratory mouse; laboratory rat; messenger RNA; mitochondrial disease /disorder; northern blottings; oxidative stress; peroxidases; phosphorylation; phthalates; polymerase chain reaction; postdoctoral investigator; terminal nick end labeling; testis disorder; toxicology; western blottings

DESCRIPTION (provided by applicant): Phthalates, widely used as plasticizers in food and biomedical packing, present a hazard to male reproductive health. DEHP, the most common phthalate, is metabolized to its active monoester, MEHP. In the testis, MEHP's primary testicular target is Sertoli cells (SC). However, germ cells (GC) undergo dramatic MEHP-induced changes such as detachment from SC and subsequent GC apoptosis. The long-term objective of this study is to elucidate the role of oxidative stress-induced GC mitochondrial dysfunction in MEHP toxicity and characterize the molecular targets involved. The specific aims to carry out this objective are to: (1) test the postulate that MEHP affects testicular expression of the antioxidant peroxiredoxins (Prx), (2) determine whether MEHP exposure leads to Prx3 inactivation in GC, but not in SC, (3) establish whether Prx3 inactivation leads to increased ROS generation and mitochondrial dysfunction in GC, but not in SC, and (4) characterize whether Prx3 plays a role in toxicant-mediated cytochrome c release from GC mitochondria. Mechanistic studies involving state of the art molecular cell biology techniques will be used to elucidate the role that mitochondrial dysfunction plays in phthalate-induced testicular toxicity and infertility.

描述（由申请人提供）：邻苯二甲酸盐，广泛用作食物和生物医学包装中的增塑剂，对男性生殖健康构成危害。 DEHP是最常见的邻苯二甲酸酯，已代谢其活跃的单酯MEHP。在睾丸中，MEHP的主要睾丸靶标是Sertoli细胞（SC）。然而，生殖细胞（GC）经历了MEHP引起的戏剧性变化，例如SC脱离以及随后的GC凋亡。这项研究的长期目标是阐明氧化应激诱导的GC线粒体功能障碍在MEHP毒性中的作用，并表征所涉及的分子靶标。 The specific aims to carry out this objective are to: (1) test the postulate that MEHP affects testicular expression of the antioxidant peroxiredoxins (Prx), (2) determine whether MEHP exposure leads to Prx3 inactivation in GC, but not in SC, (3) establish whether Prx3 inactivation leads to increased ROS generation and mitochondrial dysfunction in GC, but not in SC, and (4)表征PRX3是否在毒物介导的细胞色素C从GC线粒体释放中起作用。涉及ART分子细胞生物学技术的机械研究将用于阐明线粒体功能障碍在邻苯二甲酸酯引起的睾丸毒性和不育的作用。