title: Ah Receptor Signaling Controls the Expression of Cardiac Development and Homeostasis Genes.
abstract: Congenital heart disease (CHD) is the most common congenital abnormality and one of the leading causes of newborn death throughout the world. Despite much emerging scientific information, the precise etiology of this disease remains elusive. Here, we show that the aryl hydrocarbon receptor (AHR) regulates the expression of crucial cardiogenesis genes and that interference with endogenous AHR functions, either by gene ablation or by agonist exposure during early development, causes overlapping structural and functional cardiac abnormalities that lead to altered fetal heart physiology, including higher heart rates, right and left ventricle dilation, higher stroke volume, and reduced ejection fraction. With striking similarity between AHR knockout (Ahr(-/-)) and agonist-exposed wild type (Ahr(+/+)) embryos, in utero disruption of endogenous AHR functions converge into dysregulation of molecular mechanisms needed for attainment and maintenance of cardiac differentiation, including the pivotal signals regulated by the cardiogenic transcription factor NKH2.5, energy balance via oxidative phosphorylation and TCA cycle and global mitochondrial function and homeostasis. Our findings suggest that AHR signaling in the developing mammalian heart is central to the regulation of pathways crucial for cellular metabolism, cardiogenesis, and cardiac function, which are potential targets of environmental factors associated with CHD.
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics and.
authors.forename: Vinicius S
authors.initials: VS
authors.lastname: Carreira
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics and.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Fan
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics and.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics and.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics and.
authors.forename: Hisaka
authors.initials: H
authors.lastname: Kurita
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics and.
authors.forename: Chia-I
authors.initials: CI
authors.lastname: Ko
authors.affiliation: Department of Internal Medicine, Cardiology Division, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors.forename: Mindi
authors.initials: M
authors.lastname: Naticchioni
authors.affiliation: Department of Internal Medicine, Cardiology Division, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Internal Medicine, Cardiology Division, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors.forename: Sheryl
authors.initials: S
authors.lastname: Koch
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics and.
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Internal Medicine, Cardiology Division, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267.
authors.forename: Jack
authors.initials: J
authors.lastname: Rubinstein
authors.affiliation: *Department of Environmental Health and Center for Environmental Genetics and alvaro.puga@uc.edu.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Puga
mesh_terms: D000818:Animals; D004452:Echocardiography; D005260:Female; D006321:Heart / Q000196:embryology* / Q000254:growth & development; D006706:Homeostasis / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000378:metabolism; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D018336:Receptors, Aryl Hydrocarbon
keywords: Ah receptor; NKX2-5; cardiogenesis; congenital heart disease; mitochondrial dysfunction