Lithium (Li++) is widely used in the prophylaxis and treatment of bipolar disorder (manic depression) which for women clusters during childbearing years. Controversy continues to exist on the use of lithium during pregnancy and teratogenic effects of during cardiac embryogenesis. Data from lithium birth registries and clinical studies indicate an increased risk in congenital abnormalities with the heart predominantly affected. There have been no cellular and molecular studies addressing lithium's role specifically in cardiac teratogenicity in animal models. Good informative epidemiologic studies among children of women treated with Li++ during pregnancy are difficult to perform. Li++ has been shown to have dramatic effects on morphogenesis in the vertebrate embryo through the Wnt/B-catenin signaling pathway by its inhibition of glycogen synthase kinase-3. How Li++ may exert its teratogenic effects during cardiogenesis is not known. Our research indicates that Li++ affects cytoplasmic 8-catenin in precardiac cells and that these effects are amplified during development. The broad goals are: 1) To determine how Li++ is responsible for the increased incidence of congenital cardiac defects in humans, by analyzing on the cell and molecular level Li++ effects on avian and mouse heart development. 2) Using echocardiography and microarray analyses to determine the effects and pathways by which Li++ acts on the embryonic mouse heart. The hypotheses to be tested are: Hypothesis: Li++ affects cell reorganization into an epithelium and results in wider hearts (2) Hypothesis: Li++ effects on the cardiac compartment are related to its mimicking Wnt signaling and the resulting increased cytoplasmic B-catenin pools. Hypothesis: Elevation of B-catenin by misexpression in the precardiac mesoderm leads to abnormal cardiac cell differentiation and compartmentalization. (2B): Hypothesis: Misexpression of LEF1 inhibits the activation of specific genes that are necessary for subsequent normal cardiac morphogenetic processes to take place. (3) Hypothesis: Li++ exposure in mouse embryos affects cardiac cell function and gene expression. Such studies will provide important insights on a molecular level into the use of Li++ on embryonic human cardiac development during pregnancy. Until the safety of lithium is conclusively proven, one must assume teratogenic potential and harm to the fetus.
