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Using pollutant-adapted fish populations to understand gene-environment interactions underlying developmental cardiotoxicity
Citation:
Clark, B., J. Miller, M. Hahn, A. Whitehead, AND D. Nacci. Using pollutant-adapted fish populations to understand gene-environment interactions underlying developmental cardiotoxicity. 9th Aquatic Models of Human Disease Conference, Woods Hole, Massachussetts, September 29 - October 04, 2018.
Impact/Purpose:
Congenital heart disease (CHD) is the most common birth defect worldwide, yet the origins of the complex suite of structural and functional problems are still not understood. Epidemiological studies show that the disease has both genetic and environmental components, including exposure to environmental contaminants. To better understand the role of gene-environment interactions in developmental heart disease, we use fish that have adapted to multi-generational exposure to classes of compounds that can cause CHD. By performing whole-genome sequencing in specially bred fish lines, we have identified genomic regions that are associated with sensitivity to the developmental heart effects caused by some chemicals. These findings are useful to the medical community and regulators in identifying both genetic and environmental risk factors for developmental and childhood heart disease.
Description:
Congenital heart disease (CHD), which encompasses a suite of structural and functional deficits, is the most common congenital malformation worldwide. Though the etiology of the majority of CHD is still poorly understood, it involves the interaction of both genetic and environmental risk factors, including environmental exposures. Among the factors associated with heart disease and CHD is exposure to traffic-related and industrial air pollution, which is a significant source of teratogenic and carcinogenic polycyclic aromatic hydrocarbons (PAHs). Exposure to dioxin-like compounds (DLCs), which act through the aryl hydrocarbon receptor (AHR) pathway, is also associated with CHD. Furthermore, these compounds affect cardiovascular development across vertebrates, including mammals and fish. To understand the interactions between environmental exposure and genetic variation (GxE) that contribute to CHD, we are taking advantage of extreme variation in sensitivity to contaminants among wild populations of the Atlantic killifish (Fundulus heteroclitus) whereby multiple populations of killifish from heavily polluted urban estuaries along the Atlantic coast of North America have repeatedly and rapidly evolved resistance to pollutants (DLCs and PAHs). Specifically, we are using a quantitative trait loci (QTL) approach to identify the functional role of gene variants in sensitivity to a suite of specific cardiovascular defects associated with CHD. Individuals from pollution-tolerant and sensitive populations were paired, and their subsequent F1 offspring bred to create QTL mapping families (F2) that were exposed to contaminants as embryos. Using this approach, we identified genomic regions associated with tolerance of killifish to embryonic toxicity caused by the DLC PCB-126 (3,3’,4,4’,5-pentachlorobiphenyl), including components of the AHR pathway. To further killifish as a model for study of the GxE interactions underlying CHD, we are working to identify loci associated with sensitivity to chemically induced alterations of specific aspects of cardiac developmental and functional endpoints. To compare mechanisms underlying response to PAHs and DLCs, we are comparing QTL lines derived from populations that differ in their pollutant exposure history. By taking advantage of natural selection in these genetically diverse wild populations, this approach has a unique advantage for detecting the genes and gene networks that are functionally connected to pollutant-induced cardiac disease susceptibility.