The overall goal of this project is to establish zebrafish as a faster and relevant model to study multigenerational and epigenetic consequences of developmental exposure to environmental toxicants. Because of their rapid development, fecundity and relatively lower culture cost, fish are a uniquely suited but underutilized model to study multi- and trans-generational, epigenetic effects of environmental contaminant exposure. Effects of benzo[a]pyrene an environmentally relevant carcinogenic and endocrine disrupting compound that causes multigenerational effects in mammals will be the focus of this study. Polycyclic aromatic hydrocarbons (PAHs), like BaP, are implicated in preterm deliveries, low birth weights, and childhood cancers in offspring of exposed mothers. However, a significant knowledge gap exists in the molecular mechanisms for reproductive, developmental and multi/trans-generational effects associated with these environmental exposures. We hypothesize that parental exposure to BaP will adversely affect reproduction, alter gene specific and global methylation status, and cause quantifiable pathologies. Importantly, we expect that these effects could be preserved in subsequent F1, F2 and F3 generations. With our experimental plan we expect to identify new pathways altered by BaP exposure and assess critical time periods, tissue specificities, and sex dependence for epigenetic changes. Most importantly we will validate the zebrafish model and identify critical biomarkers that will be able to be used to further screen other chemicals for the fetal basis of adult disease and multigenerational toxic effects.

Public Health Relevance

There is a new appreciation that environmental factors that act during key developmental stages can increase the risk of developing adult disease, and that this disease susceptibility can be passed on multi- or transgenerationally. Fish are a well suited, but underutilized, model organism for testing the multigenerational and epigenetic consequences of environmental contaminant exposure. This proposal will use zebrafish to probe mechanisms of multigenerational toxicity of an environmentally relevant endocrine disruptor benzo[a]pyrene.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES019940-02
Application #
8319336
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Chadwick, Lisa
Project Start
2011-08-12
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2012
Total Cost
$178,750
Indirect Cost
$53,750
Name
University of Mississippi
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
067713560
City
University
State
MS
Country
United States
Zip Code
38677
Corrales, J; Fang, X; Thornton, C et al. (2014) Effects on specific promoter DNA methylation in zebrafish embryos and larvae following benzo[a]pyrene exposure. Comp Biochem Physiol C Toxicol Pharmacol 163:37-46
Corrales, Jone; Thornton, Cammi; White, Mallory et al. (2014) Multigenerational effects of benzo[a]pyrene exposure on survival and developmental deformities in zebrafish larvae. Aquat Toxicol 148:16-26
Fang, Xiefan; Thornton, Cammi; Scheffler, Brian E et al. (2013) Benzo[a]pyrene decreases global and gene specific DNA methylation during zebrafish development. Environ Toxicol Pharmacol 36:40-50
Fang, Xiefan; Corrales, Jone; Thornton, Cammi et al. (2013) Global and gene specific DNA methylation changes during zebrafish development. Comp Biochem Physiol B Biochem Mol Biol 166:99-108