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

摘要 在胎盘在妊娠早期晚期完全发挥功能之前，人类胚胎的主要来源是 营养素是蛋黄--母体沉积的脂肪和蛋白质的储藏库。蛋黄的沉淀物 卵母细胞由受体介导的内吞作用控制，也就是由一种称为Merc的受体复合体控制。 对斑马鱼(Danio Rerio)的初步研究表明，母亲暴露在全氟化环境中 化合物(PFC)扰乱了Merc的表达，改变了卵母细胞的营养量和组成。此外， 这些先入为主的PFC暴露损害了胰腺器官的生成，减少了胰岛素的产生 所产生的胚胎的面积。在线虫(秀丽线虫)中，先入为主的卵子暴露出来 成年后甘油三酯水平升高，提示代谢功能障碍。这项研究的目标是 为了从机制上理解先入为主的PFC暴露损害卵母细胞的过程 营养沉积，引发营养压力，使人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 果蝇模型(如透明的，后代数量多，世代时间短， 以及转基因和突变品系)，以评估先入为主的营养和代谢后果 暴露于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。这项研究的第一个目的是阐明 这些母体先入为主的暴露扰乱Merc功能并损害营养的机制 在卵母细胞中沉积。第二个目标将评估这些暴露如何影响胚胎营养和 胰腺的发育--葡萄糖动态平衡和消化的主要调节器。第三个目标将是 通过在以后的生活中评估代谢功能障碍来描绘健康寿命的截断。总体而言，这个项目 将确定母体暴露于先孕会降低卵子质量和损害卵子质量的机制 整个生命过程中的代谢功能。该项目旨在实现NIEHS的目标：1)确定关键的“敏感” 暴露可能有助于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险。

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.