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Small Molecule Screening and Toxicity Testing in Early-stage Zebrafish Larvae
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Zebrafish embryos as a screen for DNA methylation modifications after compound exposure
Manon C Bouwmeester1, Sander Ruiter1, Tobias Lommelaars1
1Center for Health Protection, National Institute for Public Health and the Environment (RIVM), PO Box 1, 3720 BA Bilthoven, The Netherlands.
Toxicology and Applied Pharmacology
|December 30, 2015
Summary
The zebrafish embryo can screen for environmental toxins that alter DNA methylation, supporting the Developmental Origins of Health and Disease (DOHaD) concept. This model helps identify epigenetic risks from chemical exposures.
Area of Science:
- Environmental Epigenetics
- Developmental Toxicology
- Comparative Toxicology
Background:
- The Developmental Origins of Health and Disease (DOHaD) concept links early-life epigenetic changes to adult health outcomes.
- Environmental contaminants are increasingly recognized as factors that can modify the developing epigenome.
- Systematic screening for the epigenome-modifying potential of compounds is crucial.
Purpose of the Study:
- To evaluate the zebrafish embryo as a screening model for detecting DNA methylation modifications induced by environmental contaminants.
- To assess the impact of various xenobiotics on global and site-specific DNA methylation in zebrafish embryos.
- To investigate the potential of zebrafish embryos to distinguish between different classes of chemical toxicants based on their epigenetic effects.
Main Methods:
- Zebrafish embryos were exposed to a range of subtoxic environmental compounds, including bisphenol-A (BPA), metals, and endocrine disruptors, from 0 to 72 hours post-fertilization.
- Global DNA methylation levels were assessed.
- Site-specific methylation in promoter regions of key genes (vasa, vtg1, cyp19a2) was analyzed using techniques including Digital Restriction Enzyme Analysis of Methylation (DREAM) and pyrosequencing.
Main Results:
- Only 5-azacytidine (5AC) significantly affected global DNA methylation.
- Genome-wide analysis for BPA revealed minimal large-scale methylation changes.
- Site-specific analysis identified the vasa (ddx4) gene promoter as responsive, with estrogenic compounds and metals showing distinct effects on methylation direction and sensitivity relative to embryotoxicity.
Conclusions:
- The zebrafish embryo serves as a viable screening tool for identifying xenobiotic-induced DNA methylation modifications.
- The model demonstrated potential in differentiating epigenetic effects of various chemical classes.
- Future research should correlate these early epigenetic findings with adult phenotypes to further support the DOHaD hypothesis.
