Molecular biomarkers of exposure to an endocrine disrupting herbicide

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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.