Developmental toxicants and congenital pancreas malformations

项目摘要 生命早期暴露于外源性物质可导致胰腺发育异常， 使个体易患胰腺炎和代谢功能障碍。一种常见的毒性模式， 许多化合物是产生活性氧（ROS）和氧化还原应激。ROS和细胞 氧化还原电位在正常胚胎发育和细胞信号传导中起着重要作用。摄动 这些由外源性暴露引起的过程可以改变细胞命运决定，导致功能性或 只有在随后的压力或年龄下才会变得明显的结构变化。然而，令人惊讶的是， 了解胚胎如何应对氧化还原应激，或外源性暴露对胰腺的影响， 发展 据估计，人类先天性胰腺畸形发生在大约10%的 肥胖、胰腺炎、1型和2型糖尿病与糖尿病的发病有关。的原因 这些畸形还没有被很好地理解，并且不能完全用遗传多态性来解释， 说明有很强的外源成分我们发现，早期接触PFAS化合物， 促氧化剂导致外分泌胰腺变短。这项资助在转基因方面采取了系统级的方法， 斑马鱼（Danio rerio）胚胎，以研究这种畸形中氧化应激的潜在机制， 试图建立截短的外分泌胰腺表型的功能结果。斑马鱼是一种- 已建立的、广泛使用的和强有力的用于研究脊椎动物体内胚胎发育的模式生物。 这项工作将有助于促进对早期生命中外源性暴露如何 氧化还原应激可损害发育中的胰腺并使人易患代谢疾病。

Project Summary Early life stage exposures to xenobiotics can result in aberrant pancreatic development, which may predispose an individual to pancreatitis and metabolic dysfunction. A common mode of toxicity shared by numerous compounds is the generation of reactive oxygen species (ROS) and redox stress. ROS and cellular redox potential play fundamental roles in normal embryonic development and cell signaling. Perturbation of these processes resulting from xenobiotic exposure can alter cell fate decisions, resulting in functional or structural alterations that only become apparent with subsequent stress or age. However, surprisingly little is known about how embryos respond to redox stress, or the impact of xenobiotic exposures on pancreas development. Congenital pancreas malformations in humans are estimated to occur in approximately ten percent of the population and are associated with obesity, pancreatitis, Type 1 and Type 2 diabetes mellitus. The causes of these malformations are not well understood, and cannot be fully explained by genetic polymorphisms, suggesting a strong exogenous component. We have found that early life exposures to PFAS compounds and pro-oxidants results in a short exocrine pancreas. This grant takes a systems-level approach in transgenic zebrafish (Danio rerio) embryos to investigate a potential mechanism of oxidative stress in this deformity, and seeks to establish the functional outcomes of the truncated exocrine pancreas phenotype. Zebrafish are a well- established, widely used, and powerful model organism for studying vertebrate embryonic development in vivo. This work will facilitate advancement of a mechanistic understanding of how early-life xenobiotic exposures and redox stress can damage the developing pancreas and predispose humans to metabolic diseases.