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Principal Investigator: Horzmann, Katharine Ann Marie
Institute Receiving Award Auburn University At Auburn
Location Auburn, AL
Grant Number R15ES033361
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 11 Aug 2021 to 31 Jul 2024
DESCRIPTION (provided by applicant): Project Summary: Trichloroethylene (TCE) and tetrachloroethylene (perchloroethylene; PERC) are two volatile organic compounds (VOCs) that significantly contaminate the environment after a legacy of industrial use in the mid-twentieth century. TCE and PERC are known or suspected carcinogens and are linked to congenital defects and neurodegenerative disease. The US EPA regulates TCE and PERC in drinking water with a maximum contaminant level of 5 ppb (parts per billion; µg/L); however, ground water levels can be greater than 300,000 ppb at Superfund sites. The proposed research seeks to address gaps in knowledge about the developmental, delayed, multigenerational, and transgenerational toxicity of TCE and PERC though focused experiments using the zebrafish (Danio rerio) model. A second goal is to determine how zebrafish metabolize these VOCs, as species differences in metabolism represent an obstacle in modeling human health outcomes in laboratory animals. The overarching hypothesis is that developmental exposure to VOCs like TCE and PERC causes acute, delayed, and epigenetic toxicity that affects body system development and behavioral outcomes throughout the zebrafish life-course and subsequent generations. It is further hypothesized that metabolism of TCE and PERC is necessary for some of the toxic effects and the metabolites produced are dependent on the intrinsic metabolic profile of the zebrafish model. The first aim of the proposed research will test the hypothesis that the VOCs TCE and PERC cause acute toxicity in larvae and delayed toxicity in adult zebrafish after developmental exposure. Developmental toxicity will be evaluated in larvae through acute toxicity assays, tests of behavior, and morphologic measurements, while delayed toxicity will be assessed through reproductive, behavioral, and morphologic endpoints. The second aim will test the hypothesis that TCE and PERC cause multi- and transgenerational toxicity through the measuring of similar endpoints in F1 and F2 generation progeny and also seeks to identify a mechanism of epigenetic toxicity through the evaluation of DNA methyltransferase expression and global DNA methylation status in TCE exposed fish and their progeny. Finally, the third aim will test the hypothesis that metabolites of TCE and PERC are partially responsible for toxicity and will characterize the metabolism of TCE in zebrafish. The exposure water will be monitored via GC-MS and HPLC analysis to determine the change in TCE concentration over time and the predominant metabolites excreted by zebrafish. The developmental toxicity of major metabolites of TCE and PERC will be determined. Additionally, the gene expression of common metabolic enzymes will be evaluated to determine how the expression of these enzymes changes over time and after embryonic TCE exposure. The proposed studies would significantly address key gaps in the VOC literature and inform toxicity modeling and regulatory efforts. Additionally, the proposed experiments are designed to be approachable and intuitive to undergraduate, graduate, and professional students, according to the goal of the R15 REAP grant program.
Science Code(s)/Area of Science(s) Primary: 71 - Alternative Model Development
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Thaddeus Schug
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