title: Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult.
abstract: The Developmental Origins of Health and Disease (DOHaD) Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr-/- and in utero TCDD-exposed Ahr+/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr-/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease.
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, United States of America.
authors.forename: Vinicius S
authors.initials: VS
authors.lastname: Carreira
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, United States of America.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, United States of America.
authors.forename: Hisaka
authors.initials: H
authors.lastname: Kurita
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, United States of America.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, United States of America.
authors.forename: Chia-I
authors.initials: CI
authors.lastname: Ko
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, United States of America.
authors.forename: Mindi
authors.initials: M
authors.lastname: Naticchioni
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, United States of America.
authors.forename: Sheryl
authors.initials: S
authors.lastname: Koch
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, United States of America.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, United States of America.
authors.forename: Jacek
authors.initials: J
authors.lastname: Biesiada
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, United States of America.
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, United States of America.
authors.forename: Jack
authors.initials: J
authors.lastname: Rubinstein
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, United States of America.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Puga
mesh_terms: D000818:Animals; D005260:Female; D006330:Heart Defects, Congenital / Q000378:metabolism* / Q000503:physiopathology; D006706:Homeostasis; D018811:Maternal Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000378:metabolism; D011247:Pregnancy; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018336:Receptors, Aryl Hydrocarbon