Ancestral Exposures/Modern Responses to EDCs

描述（由申请人提供）：世界被污染，永远不会回到化学革命之前存在的条件。虽然当地已经对污染采取了一些补救措施，但在全球一级，这是根本不可能的。一类污染物被称为内分泌干扰化学物质（EDC），因为它们能够干扰人体的激素系统。储存不善、泄漏、故意和意外的散布对野生动物和人类健康产生了有充分记录的影响。然而，EDC研究领域仍然存在高度争议和两极分化。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内分泌干扰物对未来的影响，我们必须超越传统的毒理学测试，开发新的方法和观点。 在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（跨代）而引起的祖先暴露，以及在个体自身一生中经历的暴露（身体负担），这些暴露导致该个体的分子表观遗传变化。这些过程在推动包括人类在内的所有物种的进化变化方面是一种未被充分认识的力量。挑战在于如何模拟跨寿命和代内的累积和渐进变化。我们提出了一个独特的研究多代暴露于连续的环境毒物，每一个已知的扰动激素，大脑和行为。我们提出的模型研究了祖先和直接表观遗传修饰的相互作用，这些因素从未一起研究过。在6代人的过程中，我们做出了偶像崇拜的预测，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祖先不同。为了完成这项工作，我们建议对两种暴露进行建模，每种暴露间隔3代;不同的EDC类别将用于环境相关水平，每种类别具有不同的作用模式。终点将是体重、生理参数、神经生物学基因表达和分子表观遗传测定，以及动物在涉及社交、焦虑和认知功能的一系列行为中的行为表征。现实地模拟几代人之间和几代人之内生活挑战的性质， 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.