Ancestral Exposures/Modern Responses to EDCs

描述(申请人提供)：世界被污染，永远不会回到化学革命之前存在的条件。虽然已经对污染进行了一些局部补救，但在全球层面上，这根本是不可能的。一类污染物被称为内分泌干扰化学品(EDC)，因为它们能够扰乱人体的激素系统。储存不良、泄漏、故意和意外扩散对野生动物和人类健康的影响有据可查。然而，EDC的研究领域仍然存在很大的争议和两极分化。这些化合物现在是我们环境中永久的一部分，并创造了以前未知的进化压力。如果我们要预测和了解EDCs对未来的影响，我们必须超越传统的毒理学测试，开发新的方法和视角。这个新世界中的生命是由于生殖细胞中DNA的可遗传表观遗传修饰而导致的祖先暴露的组合(跨代)，以及在个体自身一生中经历的导致该个体的分子表观遗传变化的暴露(身体负担)。在推动包括人类在内的所有物种的进化变化方面，这些过程是一种被低估的力量。挑战是如何对跨越生命周期和世代之间的累积和渐进变化进行建模。我们提出了一项关于连续几代人接触环境毒物的独特研究，每种毒物都会扰乱荷尔蒙、大脑和行为。我们提出的模型研究了祖先和即刻表观遗传修饰的相互作用，这些因素从未被一起研究过。在六代人的过程中，我们做出了颠覆传统的预测，即由于当代环境驱动力(化学污染)，个体将以独特的方式进化，后代对近端化学刺激的反应与他们的祖先不同。为了做这项工作，我们建议对被三代分开的两种暴露建立模型；不同的EDC类别将在与环境相关的水平上使用，每一种类别都有不同的行动模式。终点是体重、生理参数、神经生物学基因表达和分子表观遗传学分析，以及动物在一系列涉及社交、焦虑和认知功能的行为中的行为特征。现实地模拟跨代和跨代人生活挑战的本质将 为理解和预测环境污染将如何影响所有物种的进化提供框架。

DESCRIPTION (provided by applicant): The world is contaminated, never to return to conditions that existed prior to the chemical revolution. Although some local remediation of contamination has occurred, at a global level this is simply not possible. A class of contaminants is known as Endocrine Disrupting Chemicals (EDC) because of their ability to perturb the body's hormone systems. Poor storage, spills, deliberate and accidental dispersal have had well-document effects on wildlife and human health. However, the field of EDC research remains highly controversial and polarized. Such compounds are now a permanent part of our environment and creating previously unknown evolutionary pressures. We must transcend traditional toxicological testing to develop new methods and perspectives if we are to anticipate and understand EDCs' impact on the future. Life in this new world is a combination of ancestral exposures due to heritable epigenetic modifications to DNA in germ cells (transgenerational), together with exposures experienced during the individual's own lifetime (body burden) that cause molecular epigenetic changes to that individual. These processes are an underappreciated force in driving evolutionary change in all species, including humans. The challenge is how to model the cumulative and progressive changes both across lifespans and within generations. We propose a unique study of multigenerational exposures to sequential environmental toxicants, each known to perturb hormones, brain and behavior. Our proposed model investigates interactions of ancestral and immediate epigenetic modifications, factors that have never been studied together. Over the course of 6 generations, we make the iconoclastic prediction that individuals will evolve in unique ways due to contemporary environmental driving forces (chemical contamination), with descendants responding differently to proximal chemical stimuli than their ancestors. To do this work, we propose to model two exposures separated by 3 generations; different EDC classes will be used at environmentally relevant levels, each with a different mode of action. Endpoints will be body weight, physiological parameters, neurobiological gene expression and molecular epigenetic assays, together with behavioral characterization of the animals in a suite of behaviors involved in social, anxiety, and cognitive function. Realistically simulating the nature of life challenges across and within generations will provide the framework for understanding and anticipating how environmental contamination will affect the evolution of all species.