Toxicant disruption of receptor-mediated endocytosis in oogenesis and later life metabolic dysfunction

卵子发生和晚年代谢功能障碍中受体介导的内吞作用的毒性破坏

• 批准号: 9757769
• 负责人: Alicia R Timme-Laragy
• 金额: $ 38.6万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757769
• 关键词: Acids; Address; Adult; Affect; Alcohol consumption; Animal Model; Area; Biochemical; Caenorhabditis elegans; Chemicals; Cholesterol; Complex; Conceptions; Counseling; Data; Deposition; Development; Dietary Intervention; Digestion; Dimethyl Sulfoxide; Disease; Drosophila melanogaster; Elderly; Embryo; Endocytosis; Energy-Generating Resources; Environmental Pollution; Exposure to; First Pregnancy Trimester; Fishes; Food Packaging; Generations; Germ Cells; Glucose; Goals; Health; Heat-Shock Response; Homologous Gene; Human; Hypertriglyceridemia; Impairment; Incidence; Individual; Insulin; Investigation; Islets of Langerhans; Knowledge; LDL-Receptor Related Protein 2; Larva; Life; Life Cycle Stages; Lipids; Maternal Exposure; Measures; Mediating; Metabolic; Metabolic Syndrome Pathway; Metabolic dysfunction; Metabolic syndrome; Modeling; National Institute of Environmental Health Sciences; Nematoda; Nutrient; Nutritional; Oocytes; Oogenesis; Organogenesis; Outcome; Oxidation-Reduction; Oxidative Stress; Pancreas; Pathologic; Placenta; Placentation; Plant Roots; Process; Proteins; Public Health; RNA Interference; Reproductive Biology; Research; Risk; Role; Smoking; Solvents; Source; Speed; Stress; Study models; Suggestion; Surface; Testing; Time; Toxicant exposure; Toxicology; Transgenic Organisms; Zebrafish; adverse outcome; blood glucose regulation; comparative; cooking; detection of nutrient; deviant; drinking water; egg; fly; hazard; healthspan; intrinsic factor-cobalamin receptor; islet; knock-down; lipid biosynthesis; metabolic phenotype; mother nutrition; mutant; nutrition; offspring; oocyte maturation; oocyte quality; pancreas development; programs; protein complex; protein function; receptor; receptor expression; receptor mediated endocytosis; reproductive; response; sensor; tool; toxicant; transcription factor

Summary Before the placenta becomes fully functional late in the first trimester, the human embryo's primary source of nutrients is the yolk—a cache of maternally-deposited lipids and proteins. The deposition of yolk into the oocyte is governed by receptor-mediated endocytosis, namely by a receptor complex called MERC. Preliminary studies in zebrafish (Danio rerio) have shown that maternal exposures to perfluorinated compounds (PFCs) disrupted MERC expression and altered oocyte nutrient quantity and composition. Further, these preconception PFC exposures impaired pancreatic organogenesis, decreasing insulin-producing islet area in the resulting embryos. In the nematode (Caenorhabditis elegans), preconception exposed eggs developed elevated triglyceride levels as adults, suggestive of metabolic dysfunction. The goal of this study is to gain a mechanistic understanding of the process by which preconception PFC exposures impair oocyte nutrient deposition, induce nutritional stress and predispose individuals to metabolic dysfunction later in life. We will use an evolutionary, three-model approach combining the strengths of the zebrafish, nematode, and fruitfly (Drosophila melanogaster) models (e.g. transparent, high numbers of progeny, short generation time, and transgenic and mutant lines) to assess the nutritional and metabolic consequences of preconception exposures to two persistent perfluorinated compounds: the legacy toxicant perfluorooctanesulfonic acid, and its emerging replacement chemical perfluorobutanesulfonic acid. The first aim of this study will elucidate the mechanisms by which these maternal preconception exposures disrupt MERC function, and impair nutrient deposition in the oocyte. The second aim will assess how these exposures affect embryonic nutrition and development of the pancreas—a master regulator of glucose homeostasis and digestion. The third aim will delineate the truncation of the healthspan by assessing metabolic dysfunction later in life. Overall, this project will identify a mechanism by which maternal preconception exposures can reduce oocyte quality and impair metabolic function throughout the life course. This project addresses NIEHS goals to 1) identify key “sensitive” windows during which exposures may contribute to the Developmental Origins of Health and Disease paradigm, and 2) discover hazards posed by emerging contaminants.

概括 在妊娠早期晚期胎盘完全发挥功能之前，胎盘是人类胚胎的主要来源 营养物质是蛋黄——母体沉积的脂质和蛋白质的储藏室。蛋黄沉积到 卵母细胞由受体介导的内吞作用（即称为 MERC 的受体复合物）控制。 对斑马鱼（Danio rerio）的初步研究表明，母亲接触全氟化物 化合物 (PFC) 破坏 MERC 表达并改变卵母细胞营养物质的数量和组成。更远， 这些孕前 PFC 暴露会损害胰腺器官发生，减少产生胰岛素的胰岛 所得胚胎中的区域。在线虫（秀丽隐杆线虫）中，受孕前暴露的卵 成年后甘油三酯水平升高，提示代谢功能障碍。本研究的目标是 从机制上了解孕前 PFC 暴露损害卵母细胞的过程 营养沉积，引起营养应激，并使个体在以后的生活中容易出现代谢功能障碍。 我们将使用一种进化的三模型方法，结合斑马鱼、线虫和 果蝇（Drosophila melanogaster）模型（例如透明、后代数量多、世代时间短、 以及转基因和突变系）来评估先入为主的营养和代谢后果 接触两种持久性全氟化合物：遗留毒物全氟辛烷磺酸及其 新兴替代化学品全氟丁磺酸。本研究的第一个目的是阐明 这些母亲孕前暴露破坏 MERC 功能并损害营养的机制 沉积在卵母细胞中。第二个目标将评估这些暴露如何影响胚胎营养和 胰腺的发育——葡萄糖稳态和消化的主要调节器。第三个目标将 通过评估生命后期的代谢功能障碍来描绘健康寿命的缩短。总体来说，这个项目 将确定一种机制，通过这种机制，母亲孕前暴露会降低卵母细胞质量并损害 代谢功能贯穿整个生命过程。该项目旨在实现 NIEHS 的目标：1) 识别关键的“敏感” 暴露可能导致健康和疾病的发育起源的窗口 范式，2) 发现新兴污染物造成的危害。