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.

概括在妊娠晚期，plapeta变得完全实用之前，人类胚胎的主要来源营养成分是蛋黄 - 母体沉积的脂质和蛋白质的缓存。蛋黄的沉积卵母细胞受受体介导的内吞作用，即由称为MERC的受体复合物。斑马鱼（Danio rerio）的初步研究表明，物质暴露于全氟化化合物（PFC）破坏了MERC表达和卵母细胞营养量和成分的改变。更远，这些预智的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，先选暴露的卵成年后，甘油三酸酯水平升高，表明代谢功能障碍。这项研究的目的是为了获得对先入为主PFC暴露损害卵母细胞的过程的机械理解营养沉积，诱导营养应激和倾向的个体会在以后的生活中代谢功能障碍。我们将使用一种进化的三模型方法，结合了斑马鱼，线虫和果蝇（果蝇Melanogaster）模型（例如，透明，进度较高，短生成时间，以及转基因和突变品），以评估先入为主的营养和代谢后果暴露于两种持续的全氟化化合物：遗产毒物的全氟辛磺酸及其新兴的替代化学全氟二硫酸。这项研究的第一个目的将阐明这些孕产妇的感受暴露于中断MERC功能并损害营养的机制卵母细胞中的沉积。第二个目标将评估这些暴露如何影响胚胎营养和胰腺的开发 - 葡萄糖稳态和消化的主要调节剂。第三个目标通过评估生命后期的代谢功能障碍来描述健康范围的截断。总体而言，这个项目将确定一种机制，通过材料先入暴露可以降低卵母细胞质量和损害在整个生命过程中，代谢功能。该项目解决了NIEHS目标1）确定关键“敏感” 在此期间暴露可能有助于健康和疾病的发展起源范式和2）发现新兴污染物构成的危害。