title: Early-life glucocorticoids programme behaviour and metabolism in adulthood in zebrafish.
abstract: Glucocorticoids (GCs) in utero influence embryonic development with consequent programmed effects on adult physiology and pathophysiology and altered susceptibility to cardiovascular disease. However, in viviparous species, studies of these processes are compromised by secondary maternal influences. The zebrafish, being fertilised externally, avoids this problem and has been used here to investigate the effects of transient alterations in GC activity during early development. Embryonic fish were treated either with dexamethasone (a synthetic GC), an antisense GC receptor (GR) morpholino (GR Mo), or hypoxia for the first 120h post fertilisation (hpf); responses were measured during embryonic treatment or later, post treatment, in adults. All treatments reduced cortisol levels in embryonic fish to similar levels. However, morpholino- and hypoxia-treated embryos showed delayed physical development (slower hatching and straightening of head-trunk angle, shorter body length), less locomotor activity, reduced tactile responses and anxiogenic activity. In contrast, dexamethasone-treated embryos showed advanced development and thigmotaxis but no change in locomotor activity or tactile responses. Gene expression changes were consistent with increased (dexamethasone) and decreased (hypoxia, GR Mo) GC activity. In adults, stressed cortisol values were increased with dexamethasone and decreased by GR Mo and hypoxia pre-treatments. Other responses were similarly differentially affected. In three separate tests of behaviour, dexamethasone-programmed fish appeared 'bolder' than matched controls, whereas Mo and hypoxia pre-treated fish were unaffected or more reserved. Similarly, the dexamethasone group but not the Mo or hypoxia groups were heavier, longer and had a greater girth than controls. Hyperglycaemia and expression of GC responsive gene (pepck) were also increased in the dexamethasone group. We conclude that GC activity controls many aspects of early-life growth and development in the zebrafish and that, like other species, manipulating GC status pharmacologically, physiologically or genetically in early life leads to programmable metabolic and behavioural traits in adulthood.
authors.affiliation: The University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: K S
authors.initials: KS
authors.lastname: Wilson
authors.affiliation: The University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: C S
authors.initials: CS
authors.lastname: Tucker
authors.affiliation: The University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: E A S
authors.initials: EA
authors.lastname: Al-Dujaili
authors.affiliation: The University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: M C
authors.initials: MC
authors.lastname: Holmes
authors.affiliation: The University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: P W F
authors.initials: PW
authors.lastname: Hadoke
authors.affiliation: The University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Kenyon
authors.affiliation: The University/BHF Centre for Cardiovascular ScienceUniversity of Edinburgh, The Queen's Medical Research Institute, Edinburgh, UK Martin.Denvir@ed.ac.uk.
authors.forename: M A
authors.initials: MA
authors.lastname: Denvir
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D047108:Embryonic Development / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D006854:Hydrocortisone / Q000097:blood; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D006854:Hydrocortisone
keywords: adult; embryo; glucocorticoids; heart; zebrafish