The teratogenic potential of alcohol is well known and the offspring of mothers who abuse alcohol have been shown to have a broad spectrum of anomalies that have been termed alcohol related birth defects (ARBD). The manifestation of ARB span from reduced birth weight to the unique constellation of features termed fetal alcohol syndrome (FAS). FAS children are the offspring of chronic alcoholic women. However, clinical studies have shown that even moderate drinking during pregnancy can affect fetal development suggesting that alcohol abuse may be one of the leading causes of birth defects. Most studies of the teratogenic effects of alcohol have focused on the morphological and neurological features of the affected infants. However, recent studies have shown ARBD children to be at high risk of having some degree of immune deficiency and consequent increased incidence and severity of infection. Since the immune system is not fully developed at birth the infant's ability to cope with infection is fragile. Therefore, it is important to identify environmental factors that might delay normal immune development and put infants at risk. Recent studies from this laboratory using a murine model of ARBD have shown that in utero exposure to alcohol caused a retarded development of B lymphocytes in fetal liver and neonatal bone marrow and spleen. Phenotypic analysis of developmental intermediates in the B lineage showed several to be affected by in utero alcohol exposure. In particular, the investigator's observed that a previously unreported B cell precursor was decreased in neonatal marrow and spleens of animals exposed in utero to alcohol. In this proposal the applicants will use a model consisting of fetal alcohol exposed and pair-fed and chow-fed control animals to assess the effects of alcohol on B lymphopoiesis during fetal and neonatal life. They will use multiparameter flow cytometry to ascertain the absolute number of B cell intermediates and the phenotype of these cells within the fetal liver and neonatal bone marrow and spleen. The developmental potential of the B cell intermediates will be determined by sorting B-lineage cells and other hematopoietic precursors and stem cells and using clonal analysis to determine if alcohol exposure alters the frequency of cells that are capable of differentiation. They will also follow fetal alcohol exposed animals in to adulthood to determine if the exposure affected the function of the humoral immune system and the longevity of the effect.
