This application is directed at the study of gene-environment interactions regulated by the Ah receptor (AHR) during embryonic development and at their consequences in adult disease. Human exposure to organ chlorinated Ah receptor ligands, such as dioxin, has been epidemiologically associated with a number of toxicological outcomes and diseases, of which developmental abnormalities and mortality from cardiovascular disease are preeminent. While prevailing scientific evidence suggests that these outcomes are mediated by AHR activation, the molecular mechanisms by which AHR ligands exert their effects in humans remain to be identified. We propose to identify these mechanisms and to provide a biological test of the causal connection between AHR, fetal exposure to dioxin and cardiovascular disease. Our immediate objectives are, (i) to determine if developmental exposure of mice to TCDD or ablation of the Ahr gene causes cardiac changes associated with physiological deficits in adult life; (ii) to assess if these changes result from modifications to he the normal heart-specific developmental epigenetic program; (iii) to characterize gene-gene-environment interactions that exacerbate cardiac disease resulting from known haploin sufficiency caused by mutations in genes that regulate cardiac development; and (iv) to use computational tools to build causal relationships between variant cardiac epigenetic programs, gene expression regulatory changes, and TCDD exposure in utero. We have found that the AHR coordinates a complex regulatory target network during development responsible for attainment and maintenance of cardiac homeostasis. Key in this network is Nkx2-5, coding for a cardiac homeobox transcription factor that lies genetically upstream of multiple genes essential for heart development. Nkx2-5 is repressed by TCDD-dependent AHR activation in mouse ES cells and in differentiating mouse embryos. In humans and mice, NKX2.5 polymorphisms cause NKX2-5 haploinsufficiency associated with congenital cardiac malformations which, in independent epidemiologic studies have been associated with maternal exposure to dioxins and polychlorinated biphenyls during pregnancy. We propose to explore the hypothesis that exposure to dioxin during development redirects endogenous AHR functions towards toxic/adaptive responses that depress expression of NKX2-5 and its target genes and disrupt cardiomyocyte differentiation, recapitulating the congenital cardiac malformations and adult cardiac disease resulting from NKX2.5 haploinsufficiency in humans. Congenital cardiac disease is the most common type of human birth defect, the leading cause of neonatal/infant mortality, and a major source of adult cardiac insufficiency. Results from this work will establish the role of AHR in cardiac development and in mediating in utero toxicity and heart disease, characterize how in utero exposure to an environmental agent, TCDD, affects the epigenetic programing of heart development, and identify gene-environment interactions that may aggravate heart disease susceptibility.

Public Health Relevance

Congenital cardiovascular malformations are the leading cause of neonatal and infant death and a major cause of adult cardiac insufficiency. This fact underscores the critical need to understand the mechanisms that cause these diseases. While TCDD is a prototypical AHR ligand, the precise pathogenesis and phenotype of AHR-agonist induced developmental toxicity remains poorly characterized. Our work aims to characterize how developmental perturbations of the AHR pathway (i.e. agonist exposure or ablation of the receptor) affect the cardiovascular system in the mammalian embryo, how such effects may underlie congenital heart disease, and what ramifications this has for adult health.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Special Emphasis Panel (ZRG1)
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Reinlib, Leslie J
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University of Cincinnati
Public Health & Prev Medicine
Schools of Medicine
United States
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Koch, Sheryl E; Nieman, Michelle L; Robbins, Nathan et al. (2018) Tranilast Blunts the Hypertrophic and Fibrotic Response to Increased Afterload Independent of Cardiomyocyte Transient Receptor Potential Vanilloid 2 Channels. J Cardiovasc Pharmacol 72:40-48
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