Molecular biomarkers of exposure to an endocrine disrupting herbicide

描述（由申请人提供）：产前暴露于内分泌干扰化学物质（EDCs）会导致后代组织分化和长期生殖潜力的不可逆转的变化。这些变化通常在性成熟之前并不明显，这使得在人群中追踪这些变化变得困难。脊椎动物模型系统的使用，如斑马鱼（Danio rerio），减轻了生命周期研究的许多困难，并允许在很短的时间内进行多代研究。传统的方法用来描述个体暴露于EDCs的影响，产生了相互矛盾的数据，阻碍了我们预防、预测和治疗疾病的能力。另一种方法是通过使用生物标志物面板来表征和量化对EDCs的暴露及其相关影响。我们研究的长期目标是开发和完善EDCs暴露和生物反应的遗传生物标志物。我们的中心假设是，暴露于EDCs将在一个可处理的动物模型系统中引发独特的转录组特征，并且这些分子标记将根据暴露特征而变化。此外，我们假设这些分子特征在脊椎动物中都很保守，因此可以从实验室动物模型推断到人类。首先，我们将利用斑马鱼脊椎动物模型开发一个强大的基因标记面板，斑马鱼脊椎动物模型受控制的早期发育暴露于与环境相关且高度流行的EDC，阿特拉津。候选基因生物标志物将被优先考虑，并与生理终点相关联，以进一步验证其作为暴露指标。接下来，我们将通过基因表达分析和评估许多生理和生殖终点，在多代研究中研究阿特拉津在多个生命阶段的发育暴露的表观遗传效应。斑马鱼模型系统允许在短时间内多代的可用性，因为斑马鱼在大约三个月大的时候性成熟。这些研究的长期结果旨在未来的研究，然后将这些发现转化为评估人类暴露于EDCs的独特分子特征，包括对暴露于阿特拉津高风险人群的选定遗传生物标志物面板进行测试。我们的跨学科团队将在环境毒理学、基因组学、内分泌干扰以及发育和生殖生物学方面拥有专业知识，从而实现这些目标。这些研究将大大提高我们目前对EDC暴露相关的剂量-反应关系的认识，从而开发出可靠、有效和经济上可行的遗传生物标志物面板，用于不同人群中EDC暴露的指示。此外，在整个研究过程中，研究生和本科生将在开展科研学习的各个方面发挥积极作用并获得丰富的经验。

DESCRIPTION (provided by applicant): Prenatal exposure to endocrine disrupting chemicals (EDCs) can result in irreversible changes in tissue differentiation and long-term reproductive potential of offspring. These changes are not usually evident until sexual maturity making tracking of these changes in human populations difficult. The use of vertebrate animal model systems, such as the zebra fish (Danio rerio), alleviates much of the difficulty in life span studies and allows for multi-generation studies to be conducted in a very short amount of time. Traditional approaches used to characterize exposure and effects of individuals to EDCs have produced conflicting data and hampered our ability to prevent, predict, and treat disease. Another approach is to characterize and quantify exposure and associated effects to EDCs through the use of panels of biomarkers. The long-term goal of our research is to develop and refine genetic biomarkers of exposure and biological response to EDCs. Our central hypothesis is that exposure to EDCs will elicit unique transcriptome signatures in a tractable animal model system, and that these molecular markers will vary depending on exposure characteristics. Furthermore, we hypothesize that these molecular signatures are well-conserved across vertebrates, and thus can be extrapolated from the laboratory animal model to humans. First, we will develop a robust panel of gene markers using the zebra fish vertebrate model subjected to controlled early developmental exposure to an environmentally relevant and highly prevalent EDC, atrazine. Candidate gene biomarkers will be prioritized and correlated to physiological endpoints for further validation as indicators of exposure. Next, we will investigate the epigenetic effects of atrazine developmental exposure at multiple life stages in a multi-generation study using gene expression analysis and assessment of numerous physiological and reproductive endpoints. The zebra fish model system allows for the availability of multiple generations in a short time span as zebra fish are sexually mature at approximately three months of age. The long-term outcome of these studies aims to future studies that then translate these findings to assess the unique molecular signatures of exposure to EDCs in humans including testing of the selected genetic biomarker panel on human populations at high risk of exposure to atrazine. Our interdisciplinary team will enable achievement of these aims with expertise in environmental toxicology, genomics, endocrine disruption, and developmental and reproductive biology. These studies will significantly advance our current knowledge on the dose-response relationships related to EDC exposure, resulting in the development of reliable, valid, and economically feasible genetic biomarker panels for indication of exposure to EDCs in diverse populations. Moreover, throughout this study graduate and undergraduate students will play an active role and gain extensive experience in all aspects of conducting a scientific research study. PUBLIC HEALTH RELEVANCE: Traditional approaches used to characterize exposure and effects of individuals to endocrine disrupting chemicals (EDCs) have produced conflicting data and hampered our ability to prevent, predict, and treat disease. The long-term goal of our research is to develop and refine biomarkers of exposure and biological response to EDCs. These studies will significantly advance our current knowledge on the dose-response relationships related to EDC exposure, resulting in the development of reliable, valid, and economically feasible biomarker panels for indication of exposure to EDCs in diverse populations.