Poster Sessions

Dev-16

Robert Prentice

R. Prentice, J. Keyser, S. Burgess, L. Brody

A Zebrafish Model for Folate-Associated Congenital Heart Defects

Periconceptual folic acid consumption reduces the risk of having a child with a neural tube defect. Folate supplementation also appears to reduce the incidence of congenital heart defects. The biological mechanisms through which folate reduces birth defects are not well understood. Because early developmental processes are difficult to study in mammals, we used zerbrafish, Danio rerio, to investigate the role of folate metabolism in developing embryos. We disrupted folate metabolism by exposing zebrafish embryos to methotrexate (MTX), a potent inhibitor of dihydrofolate reductase (DHFR), the initial enzyme in the folate metabolic pathway. Inhibiting DHFR activity creates functional folate deficiency. Approximately 60% of embryos incubated with 300 µM MTX developed cardiac malformations, pericardial edema, decreased pigmentation and craniofacial abnormalities. Affected hearts frequently remained linear tubes or failed to complete cardiac looping. To determine the developmental window in which these defects originate, embryos were exposed to MTX during overlapping time intervals. Data suggest that the developmental processes affected occur within 9 hours post-fertilization (hpf), before the major organ structures have begun to form. We have developed an in vivo zebrafish model of a common human birth defect. Our data suggest that folate levels play an important role during zebrafish embryonic development.