The long-term goal of this research project is to define the role of embryonic folate metabolism and reactive metabolites in chemical-induced teratogenicity. The immediate objective is two-fold. One objective is to study the embryotoxic risks of folate deficiency induced by the anticonvulsant drug, phenytoin and the anesthetic drug, nitrous oxide. Phenytoin and nitrous oxide are clinically important drugs and they both disrupt folate metabolism in humans and they are embryotoxic in laboratory animals. In these studies, the effects of these drugs on embryo folate metabolism will be determined. Embryotoxicity will be measured by morphological examinations and by biochemical assays such as DNA synthesis. The studies will be conducted in vivo with rats and mice and by the use of various culture systems, including whole embryo culture and organ cultures of embryonic secondary palatal shelves. The second immediate objective of the research project is to study the role of potentially toxic metabolites, namely catecholic metabolites, in toxicity and to determine the mechanism of catechol formation. The role of reactive metabolites in phenytoin teratogenicity will be studied in various mammalian culture systems. Additional chemicals which are both important environmental chemicals and model compounds for more complex aromatic chemicals will also be studied. These chemicals are benzene, naphthalene, biphenyl, 4-chlorobiphenyl, chlorobenzene and bromobenzene. An understanding of catechol formation is important to teratogenicity research because of the reactive metabolites which can be formed from catechols by further oxidative reactions, i.e. Sigma-quinones and semiquinones. These experiments will be conducted with isolated rat hepatocytes as a model system.
