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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL067306-03
Application #
6638768
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Schramm, Charlene A
Project Start
2001-05-01
Project End
2005-04-30
Budget Start
2003-09-30
Budget End
2004-04-30
Support Year
3
Fiscal Year
2003
Total Cost
$278,075
Indirect Cost
Name
University of South Florida
Department
Pediatrics
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
Han, Mingda; Neves, Ana Luisa; Serrano, Maria et al. (2012) Effects of alcohol, lithium, and homocysteine on nonmuscle myosin-II in the mouse placenta and human trophoblasts. Am J Obstet Gynecol 207:140.e7-19
Linask, Kersti K; Huhta, James (2010) Folate protection from congenital heart defects linked with canonical Wnt signaling and epigenetics. Curr Opin Pediatr 22:561-6
Linask, Kaari L; Linask, Kersti K (2010) Calcium channel blockade in embryonic cardiac progenitor cells disrupts normal cardiac cell differentiation. Stem Cells Dev 19:1959-65
Han, Mingda; Serrano, Maria C; Lastra-Vicente, Rosana et al. (2009) Folate rescues lithium-, homocysteine- and Wnt3A-induced vertebrate cardiac anomalies. Dis Model Mech 2:467-78
Wang, Jushuo; Thurston, Harold; Essandoh, Eugene et al. (2008) Tropomyosin expression and dynamics in developing avian embryonic muscles. Cell Motil Cytoskeleton 65:379-92
Chen, Jizhen; Han, Mingda; Manisastry, Shyam M et al. (2008) Molecular effects of lithium exposure during mouse and chick gastrulation and subsequent valve dysmorphogenesis. Birth Defects Res A Clin Mol Teratol 82:508-18
Han, Mingda; Trotta, Patrizia; Coleman, Carl et al. (2006) MCT-4, A511/Basigin and EF5 expression patterns during early chick cardiomyogenesis indicate cardiac cell differentiation occurs in a hypoxic environment. Dev Dyn 235:124-31
Manisastry, Shyam M; Han, Mingda; Linask, Kersti K (2006) Early temporal-specific responses and differential sensitivity to lithium and Wnt-3A exposure during heart development. Dev Dyn 235:2160-74
Du, Aiping; Sanger, Jean M; Linask, Kersti K et al. (2003) Myofibrillogenesis in the first cardiomyocytes formed from isolated quail precardiac mesoderm. Dev Biol 257:382-94