Ancestral Exposures/Modern Responses to EDCs

祖先的接触/现代对 EDC 的反应

基本信息

批准号：
8898800
负责人：
David P Crews
金额：
$ 38.03万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898800
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 Social Behavior Stimulus System Testing Toxic Environmental Substances Transcend Work 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 remediation response sex social anxiety trait transgenerational epigenetic inheritance transmission process vinclozolin

项目摘要

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）：世界被污染了，永远不会回到化学革命之前的状态。尽管已经进行了一些局部污染修复，但在全球范围内这是根本不可能的。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。这些化合物现在已成为我们环境中永久的一部分，并产生了以前未知的进化压力。如果我们要预测和了解 EDC 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。这个新世界的生活是由于生殖细胞中 DNA 的可遗传表观遗传修饰（跨代）而导致的祖先暴露，以及个体一生中经历的暴露（身体负担）的组合，这些暴露导致个体的分子表观遗传变化。这些过程是推动包括人类在内的所有物种进化变化的一股未被充分认识的力量。挑战在于如何对生命周期和代际内的累积和渐进变化进行建模。我们提出了一项独特的研究，针对多代人连续暴露于环境毒物的情况，已知每种毒物都会扰乱激素、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。在六代人的过程中，我们做出了反传统的预测，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。为了完成这项工作，我们建议对相隔 3 代的两次暴露进行建模；不同的 EDC 类别将在环境相关水平上使用，每种类别都有不同的作用模式。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学测定，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特征。真实地模拟几代人之间和几代人内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。