Cardiovascular disease is the major mortality risk associated with secondhand smoke (environmental tobacco smoke, ETS). The developing fetus is particularly at risk from exposure to environmental toxins such as ETS, but the long-term health effects are not known. One well-studied effect of maternal exposure to ETS during pregnancy is intrauterine growth retardation. Low birthweight is a risk factor for cardiovascular disease, stroke, and type II diabetes in the adult. It is therefore reasonable to suspect that fetal ETS exposure may cause or predispose towards the development of adult cardiovascular disease. ETS could directly cause cardiovascular disease, or its development could be due to adaptive responses to lower birth weight. Additionally, it is unknown whether intrauterine growth retardation is itself a direct effect of ETS exposure on the developing fetus, or whether it is a result of impaired maternal nutrient transfer. This proposal describes an experimental system that uses zebrafish as a model organism to study the direct effects of ETS exposure on embryo development and subsequent cardiovascular function, independent of the placental environment and maternal factors. The interdisciplinary approach will utilize state-of-the-art genomics and proteomics to identify gene and protein expression changes that result from exposure of zebrafish embryos to ETS (Aim 1). Heart rate, blood pressure, and EKG will be measured in the adult zebrafish and used as indices to determine if embryonic ETS exposure produces deficits in cardiovascular function (Aim 2). Finally, genes and proteins identified in Specific Aim 1 will be knocked down during the embryonic ETS exposure using antisense morpholino technology, and the indices of cardiovascular function will be measured in these morphants to determine if gene knock-down rescues cardiovascular deficits (Aim 3). This proposal will establish a novel model system for the study of the physiological consequences of exposure to ETS and will identify and validate potential gene targets for therapeutic intervention. ? ?
