Developmental toxicants and congenital pancreas malformations

项目摘要 生命早期接触外源生物会导致胰腺发育异常，这可能 易患胰腺炎和代谢功能障碍。一种常见的毒性模式， 众多化合物是产生活性氧物种(ROS)和氧化还原应激反应的产物。ROS和蜂窝 氧化还原电位在正常胚胎发育和细胞信号转导中起着重要作用。摄动 这些由外来生物暴露引起的过程可以改变细胞命运的决定，导致功能性或 只有随着随后的压力或年龄而变得明显的结构变化。然而，令人惊讶的是，几乎没有 了解胚胎对氧化还原压力的反应，或外来生物暴露对胰腺的影响 发展。 据估计，人类先天性胰腺畸形发生在大约10%的 并与肥胖、胰腺炎、1型和2型糖尿病有关。原因是什么？ 这些畸形并没有被很好地理解，也不能完全用遗传多态来解释， 暗示有很强的外源成分。我们发现，早年接触全氟辛烷磺酸化合物和 促氧化剂会导致胰腺外分泌变短。这项资助采用了转基因技术的系统级方法。 斑马鱼(Danio Rerio)胚胎，研究这种畸形中氧化应激的潜在机制，以及 寻求建立截短外分泌胰腺表型的功能结果。斑马鱼是一口井- 建立、广泛使用和强大的模式生物，用于研究脊椎动物胚胎的体内发育。 这项工作将有助于从机制上理解早期生命中的外源生物如何暴露 氧化还原压力会损害发育中的胰腺，使人类容易患上代谢性疾病。

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.