Grant: Operating Grant

My laboratory studies the ways in which environmental chemicals and drugs produce birth defects. We have shown that the overproduction of certain chemically reactive forms of oxygen, called reactive oxygen species, produce DNA damage within the developing embryo. Valproic acid is a commonly prescribed antiepileptic drug, used to treat a wide variety of seizure disorders. Despite its effectiveness and widespread use, valproic acid can cause birth defects when taken during pregnancy. Since it is well known that uncontrolled seizures are also harmful to the developing fetus, a pregnant woman with epilepsy will be advised to continue to take her anticonvulsant therapy during her pregnancy. It is therefore important to learn how drugs like valproic acid cause birth defects, and how to prevent this from occurring. We have shown that metabolism of valproic acid generates reactive oxygen species, which causes breaks to occur in the DNA in cells, and this in turn causes the DNA to become rearranged in a process called DNA recombination. DNA recombination can lead to genetic changes that can kill cells in the fetus and stop important developmental genes from functioning properly. We hypothesize that an increase in chemical-initiated DNA recombination is responsible for at least some of the birth defects seen in children born to mothers who are exposed to toxic chemicals during pregnancy. We propose to test this hypothesis using both in vitro (cell cultures) and animal models. Ultimately, the understanding of how this drug causes birth defects will lead to the design and development of safer therapeutic strategies to reduce birth defects.