The objective of this project is to investigate the role of DNMT3s in the long-term effects of developmental exposure to toxicants. Recent studies have implicated epigenetic mechanisms such as DNA methylation in the persistent effects of developmental exposure to toxicants. But, the mechanism by which DNA methylation patterns are altered is not known. Using zebrafish as a model system, we are investigating the role of DNMT3 genes in toxicant-induced alterations in DNA methylation patterns. In contrast to mammals (DNMT3A and DNMT3B), zebrafish possess multiple DNMT3s, due to a genome duplication event in the fish lineage shortly after their divergence from tetrapods. They are all the homologs of mammalian DNMTs. Genome duplication often leads to subfunction partitioning among the duplicated genes. This provides an unique opportunity for obtaining new mechanistic insights into the multiple functions of a single human gene. Using individual DNMT3 knockout animals, we are studying the role of DNMT3s in toxicant-induced alterations in DNA methylation.