title: Early-life perturbations in glucocorticoid activity impacts on the structure, function and molecular composition of the adult zebrafish (Danio rerio) heart.
abstract: BACKGROUND
  Transient early-life perturbations in glucocorticoids (GC) are linked with cardiovascular disease risk in later life. Here the impact of early life manipulations of GC on adult heart structure, function and gene expression were assessed.
  
  
  RESULTS
  Zebrafish embryos were incubated in dexamethasone (Dex) or injected with targeted glucocorticoid receptor (GR) morpholino knockdown (GR Mo) over the first 120 h post fertilisation (hpf); surviving embryos (>90%) were maintained until adulthood under normal conditions. Cardiac function, heart histology and cardiac genes were assessed in embryonic (120 hpf) and adult (120 days post fertilisation (dpf)) hearts. GR Mo embryos (120 hpf) had smaller hearts with fewer cardiomyocytes, less mature striation pattern, reduced cardiac function and reduced levels of vmhc and igf mRNA compared with controls. GR Mo adult hearts were smaller with diminished trabecular network pattern, reduced expression of vmhc and altered echocardiographic Doppler flow compared to controls. Dex embryos had larger hearts at 120 hpf (Dex 107.2 ± 3.1 vs. controls 90.2 ± 1.1 μm, p < 0.001) with a more mature trabecular network and larger cardiomyocytes (1.62 ± 0.13 cells/μm vs control 2.18 ± 0.13 cells/μm, p < 0.05) and enhanced cardiac performance compared to controls. Adult hearts were larger (1.02 ± 0.07 μg/mg vs controls 0.63 ± 0.06 μg/mg, p = 0.0007), had increased vmhc and gr mRNA levels.
  
  
  CONCLUSIONS
  Perturbations in GR activity during embryonic development results in short and long-term alterations in the heart.
authors.affiliation: The British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
authors.forename: K S
authors.initials: KS
authors.lastname: Wilson
authors.affiliation: The British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
authors.forename: J
authors.initials: J
authors.lastname: Baily
authors.affiliation: The British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
authors.forename: C S
authors.initials: CS
authors.lastname: Tucker
authors.affiliation: The British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
authors.forename: G
authors.initials: G
authors.lastname: Matrone
authors.affiliation: The British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
authors.forename: S
authors.initials: S
authors.lastname: Vass
authors.affiliation: The British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
authors.forename: C
authors.initials: C
authors.lastname: Moran
authors.affiliation: The British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
authors.forename: K E
authors.initials: KE
authors.lastname: Chapman
authors.affiliation: The British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
authors.forename: J J
authors.initials: JJ
authors.lastname: Mullins
authors.affiliation: The British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
authors.forename: C
authors.initials: C
authors.lastname: Kenyon
authors.affiliation: The British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK.
authors.forename: P W F
authors.initials: PW
authors.lastname: Hadoke
authors.affiliation: The British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, Edinburgh EH16 4TJ, UK. Electronic address: martin.denvir@ed.ac.uk.
authors.forename: M A
authors.initials: MA
authors.lastname: Denvir
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000009:adverse effects*; D046149:Embryo Culture Techniques; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism*; D006321:Heart / Q000187:drug effects* / Q000196:embryology / Q000503:physiopathology; D006334:Heart Function Tests / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011965:Receptors, Glucocorticoid / Q000008:administration & dosage*; D013002:Somatomedins / Q000235:genetics; D024723:Ventricular Myosins / Q000235:genetics; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D013002:Somatomedins; D029961:Zebrafish Proteins; C431139:igf1 protein, zebrafish; D003907:Dexamethasone; D024723:Ventricular Myosins
keywords: Development; Echocardiography; Glucocorticoids; Heart; Zebrafish