title: Gestational stress induces the unfolded protein response, resulting in heart defects.
abstract: Congenital heart disease (CHD) is an enigma. It is the most common human birth defect and yet, even with the application of modern genetic and genomic technologies, only a minority of cases can be explained genetically. This is because environmental stressors also cause CHD. Here we propose a plausible non-genetic mechanism for induction of CHD by environmental stressors. We show that exposure of mouse embryos to short-term gestational hypoxia induces the most common types of heart defect. This is mediated by the rapid induction of the unfolded protein response (UPR), which profoundly reduces FGF signaling in cardiac progenitor cells of the second heart field. Thus, UPR activation during human pregnancy might be a common cause of CHD. Our findings have far-reaching consequences because the UPR is activated by a myriad of environmental or pathophysiological conditions. Ultimately, our discovery could lead to preventative strategies to reduce the incidence of human CHD.
authors.affiliation: The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Shi
authors.affiliation: The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.
authors.forename: Victoria C
authors.initials: VC
authors.lastname: O'Reilly
authors.affiliation: The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.
authors.forename: Julie L M
authors.initials: JL
authors.lastname: Moreau
authors.affiliation: The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.
authors.forename: Therese R
authors.initials: TR
authors.lastname: Bewes
authors.affiliation: The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.
authors.forename: Michelle X
authors.initials: MX
authors.lastname: Yam
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Bogdan E
authors.initials: BE
authors.lastname: Chapman
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, New South Wales 2006, Australia Sydney Translational Imaging Laboratory, Sydney Medical School, University of Sydney, Sydney, New South Wales 2006, Australia Department of Radiology, Royal Prince Alfred Hospital, Sydney, New South Wales 2050, Australia.
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Grieve
authors.affiliation: The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Roland
authors.initials: R
authors.lastname: Stocker
authors.affiliation: The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Graham
authors.affiliation: The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia.
authors.forename: Gavin
authors.initials: G
authors.lastname: Chapman
authors.affiliation: The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia s.dunwoodie@victorchang.edu.au duncan.sparrow@dpag.ox.ac.uk.
authors.forename: Duncan B
authors.initials: DB
authors.lastname: Sparrow
authors.affiliation: The Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia School of Biotechnology and Biomolecular Sciences, Faculty of Science, University of New South Wales, Sydney, New South Wales 2052, Australia s.dunwoodie@victorchang.edu.au duncan.sparrow@dpag.ox.ac.uk.
authors.forename: Sally L
authors.identifier: 0000-0002-2069-7349
authors.initials: SL
authors.lastname: Dunwoodie
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000187:drug effects / Q000473:pathology; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000209:etiology* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000494:pharmacology; D010641:Phenotype; D011247:Pregnancy; D014176:Protein Biosynthesis / Q000187:drug effects; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D005346:Fibroblast Growth Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D010100:Oxygen
keywords: FGF signaling; Heart development; Hypoxia; Unfolded protein response