Role of fetal TCDD-activited AHR in adult heart disease

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DESCRIPTION (provided by applicant): The primary objective of the proposed studies is to study the effects of toxicant exposures during fetal development on the adult cardiovascular (CV) system. Little is known of the etiology and progression of cardiovascular disease (CVD) in adults resulting from toxicant exposures to the pregnant mother, and the proposed studies seek to uncover early markers of disease vital in the identification of signaling pathways involved in CVD. The effect of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) in CVD from fetal exposure will be examined. TCDD, the prototypical dioxin, is pervasive in the environment and causes a large number of seemingly unrelated biological effects in humans. TCDD is one of the most potent ligands for the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor responsible for the regulation of many detoxification genes. Because the AHR plays a role in CV development and cross talks with other signaling pathways, and because TCDD causes ischemic heart disease in the adult and induces changes in cell signaling; the intent of this proposal is to test the hypothesis that activation of the AHR by TCDD in the fetus causes a reprogramming of gene expression in the fetal CV system that results in the adult onset of CVD. To test this hypothesis, the following specific aims are proposed. (1) Determine the window of fetal TCDD sensitivity and the effect that the TCDD-activated AHR during gestation has on CVD and CV global transcription of adult progeny from mouse strains that differ at the Ahr locus. We hypothesize that the genomic and physiological effects of an acute TCDD exposure on the fetus are dependent on the activation of the AHR during particular time frames of gestation. (2) Determine the effect of the activated AHR on the CV system of adult progeny following treatment with biologically relevant doses of TCDD during gestation. We hypothesize that the genomic and physiological effects of biologically relevant doses of TCDD on the fetus play a large role in adult CVD. We expect to link gene profiles of acute- and chronic-based TCDD exposures to specific CVDs and to integrate our data sets with other gene profiling data sets. The results will lead to a clearer understanding of the mechanisms that are initiated from fetal exposures that lead to adult disease, and with such knowledge, preventative measures can begin to be implemented to protect mother and fetus.