Ancestral Exposures/Modern Responses to EDCs

祖先的接触/现代对 EDC 的反应

• 批准号: 8595128
• 负责人: David P Crews
• 金额: $ 38.02万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8595128
• 关键词: Address; Affect; Animal Model; Animals; Anxiety; Attention deficit hyperactivity disorder; Autistic Disorder; Automobile Driving; Behavior; Behavior Disorders; Behavioral; Biological Assay; Body Burden; Body Weight; Brain; Brain region; Breeding; Cancer Biology; Cell Nucleus; Chemical Exposure; Chemicals; Child; DNA; DNA Methylation; Data; Development; Developmental Biology; Disease; Endocrine; Endocrine Disruptors; Environment; Environmental Pollution; Epidemiology; Epigenetic Process; Evolution; Exposure to; Female; Food Chain; Functional disorder; Future; Gene Expression; Gene Proteins; Generations; Germ Cells; Guide prevention; Health; Health Policy; Heritability; Hormones; Human; Individual; Industrial fungicide; Inherited; Learning; Life; Link; Longevity; Medical; Mental Depression; Metabolic; Metabolism; Methods; MicroRNAs; Modeling; Modification; Molecular; Mood Disorders; Nature; Neurobiology; Neurodevelopmental Disorder; Phenotype; Physiological; Polychlorinated Biphenyls; Preventive Intervention; Process; Production; Property; Prosencephalon; Public Health; Rattus; Recording of previous events; Research; Role; Simulate; Social Behavior; Stimulus; System; Testing; Toxic Environmental Substances; Transcend; Work; aroclor 1221; base; brain behavior; burden of illness; cognitive function; data modeling; dosage; driving force; experience; exposed human population; global environment; insight; life history; male; neurobehavioral; neurobehavioral disorder; novel; pregnant; prenatal exposure; pressure; public health relevance; remediation; response; sex; social; trait; transmission process; vinclozolin

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.

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的状态。虽然已经对污染进行了一些局部补救，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），因为它们能够扰乱人体的激素系统。储存不当、泄漏、故意和意外的扩散对野生动物和人类健康产生了有据可查的影响。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的永久组成部分，并产生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，开发新的方法和观点。这个新世界的生命是由于生殖细胞中DNA的可遗传表观遗传修饰（跨代）而导致的祖先暴露，以及个人一生中经历的暴露（身体负担）导致该个人的分子表观遗传变化的组合。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。挑战在于如何对跨越寿命和几代人的累积和渐进变化进行建模。我们提出了一个独特的研究多代暴露于连续的环境毒物，每一个已知的扰乱激素，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，这些因素从未被一起研究过。在6代的过程中，我们做出了打破传统的预测，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，后代对近距离化学刺激的反应与祖先不同。为了完成这项工作，我们建议对相隔3代的两次暴露进行建模；在与环境有关的层面上，将使用不同级别的电子废物处理系统，每一种都有不同的行动模式。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学分析，以及动物在社交、焦虑和认知功能等一系列行为中的行为特征。现实地模拟跨代和代内的生活挑战的本质