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

基本信息

批准号：
10008145
负责人：
Alicia R Timme-Laragy
金额：
$ 15.37万
依托单位：
UNIVERSITY OF MASSACHUSETTS AMHERST
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-06 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10008145
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

项目摘要

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，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。卵母细胞受受体介导的内吞作用（即称为 MERC 的受体复合物）的控制。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成分。这些先入为主的 PFC 暴露会损害胰腺器官发生，减少产生胰岛素的胰岛在线虫（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。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的替代化学品全氟丁磺酸。本研究的首要目的是阐明全氟丁磺酸。这些母亲孕前暴露破坏 MERC 功能并损害营养的机制第二个目标是评估这些暴露如何影响胚胎营养和发育。胰腺的发育——葡萄糖稳态和消化的主要调节器。总体而言，该项目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。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该项目致力于实现 NIEHS 的目标：1) 识别关键的“敏感”功能。暴露可能导致健康和疾病的发育起源的窗口范例，2) 发现新兴污染物造成的危害。