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

总结 在胎盘在前三个月后期完全发挥功能之前，人类胚胎的主要来源是胎盘。 营养物质是蛋黄--一种母体沉积的脂质和蛋白质的贮藏器。蛋黄沉积到 卵母细胞由受体介导的内吞作用控制，即由称为MERC的受体复合物控制。 对斑马鱼（Danio rerio）的初步研究表明， 化合物（PFCs）破坏MERC表达并改变卵母细胞的营养量和组成。此外，本发明还 这些孕前PFC暴露损害了胰腺器官的形成，减少了胰岛素分泌的胰岛细胞， 在所产生的胚胎中。在线虫（秀丽隐杆线虫）， 成年后甘油三酯水平升高，提示代谢功能障碍。本研究的目的是 获得一个机制的理解的过程中，孕前PFC暴露损害卵母细胞 营养沉积，诱发营养应激，使个体在以后的生活中易患代谢功能障碍。 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（Drosophilamelanogaster）模型（例如透明的、大量的后代、短的世代时间， 以及转基因和突变株系）来评估孕前的营养和代谢后果 接触两种持久性全氟化合物：遗留毒物全氟辛烷磺酸及其 新出现的替代化学品全氟丁磺酸。本研究的第一个目的是阐明 这些母亲的先入之见暴露破坏MERC功能， 在卵母细胞中沉积。第二个目标是评估这些暴露如何影响胚胎营养， 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截断。总的来说，这个项目 将确定一种机制，通过这种机制，母亲的孕前暴露会降低卵母细胞的质量， 在整个生命过程中的代谢功能。该项目涉及NIEHS目标，以1）确定关键的“敏感” 暴露可能导致健康和疾病的发育起源的窗口 范例，以及2）发现新出现的污染物造成的危害。

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.