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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
1R15ES019137-01
Application #
7940339
Study Section
Special Emphasis Panel (ZRG1-CB-N (52))
Program Officer
Humble, Michael C
Project Start
2010-06-10
Project End
2013-05-31
Budget Start
2010-06-10
Budget End
2013-05-31
Support Year
1
Fiscal Year
2010
Total Cost
$441,124
Indirect Cost
Name
Purdue University
Department
Other Health Professions
Type
Schools of Public Health
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Horzmann, Katharine A; Reidenbach, Leeah S; Thanki, Devang H et al. (2018) Embryonic atrazine exposure elicits proteomic, behavioral, and brain abnormalities with developmental time specific gene expression signatures. J Proteomics 186:71-82
Wirbisky-Hershberger, Sara E; Sanchez, Oscar F; Horzmann, Katharine A et al. (2017) Atrazine exposure decreases the activity of DNMTs, global DNA methylation levels, and dnmt expression. Food Chem Toxicol 109:727-734
Wirbisky, Sara E; Freeman, Jennifer L (2017) Atrazine exposure elicits copy number alterations in the zebrafish genome. Comp Biochem Physiol C Toxicol Pharmacol 194:1-8
Horzmann, Katharine A; Freeman, Jennifer L (2016) Zebrafish Get Connected: Investigating Neurotransmission Targets and Alterations in Chemical Toxicity. Toxics 4:
Wirbisky, Sara E; Sepúlveda, Maria S; Weber, Gregory J et al. (2016) Embryonic Atrazine Exposure Elicits Alterations in Genes Associated with Neuroendocrine Function in Adult Male Zebrafish. Toxicol Sci 153:149-64
Wirbisky, Sara E; Weber, Gregory J; Sepúlveda, Maria S et al. (2016) An embryonic atrazine exposure results in reproductive dysfunction in adult zebrafish and morphological alterations in their offspring. Sci Rep 6:21337
Wirbisky, Sara E; Weber, Gregory J; Schlotman, Kelly E et al. (2016) Embryonic atrazine exposure alters zebrafish and human miRNAs associated with angiogenesis, cancer, and neurodevelopment. Food Chem Toxicol 98:25-33
Wirbisky, Sara E; Weber, Gregory J; Sepúlveda, Maria S et al. (2015) Developmental origins of neurotransmitter and transcriptome alterations in adult female zebrafish exposed to atrazine during embryogenesis. Toxicology 333:156-67
Wirbisky, Sara E; Freeman, Jennifer L (2015) Atrazine Exposure and Reproductive Dysfunction through the Hypothalamus-Pituitary-Gonadal (HPG) Axis. Toxics 3:414-450
Weber, Gregory J; Sepulveda, Maria S; Peterson, Samuel M et al. (2013) Transcriptome alterations following developmental atrazine exposure in zebrafish are associated with disruption of neuroendocrine and reproductive system function, cell cycle, and carcinogenesis. Toxicol Sci 132:458-66