title: A naturally hypersensitive glucocorticoid receptor elicits a compensatory reduction of hypothalamus-pituitary-adrenal axis activity early in ontogeny.
abstract: We comprehensively characterized the effects of a unique natural gain-of-function mutation in the glucocorticoid receptor (GR), GRAla610Val, in domestic pigs to expand current knowledge of the phenotypic consequences of GR hypersensitivity. Cortisol levels were consistently reduced in one-week-old piglets, at weaning and in peripubertal age, probably due to a reduced adrenal capacity to produce glucocorticoids (GC), which was indicated by an adrenocortical thinning in GRAla610Val carriers. Adrenocorticotrophic hormone (ACTH) levels were significantly reduced in one-week-old piglets only. Expression analyses in peripubertal age revealed significant downregulation of hypothalamic expression of CRH and AVP, the latter only in females, and upregulation of hepatic expression of SERPINA6, by GRAla610Val Transcriptional repression of proinflammatory genes in peripheral blood mononuclear cells (PBMCs) from GRAla610Val carriers was more sensitive to dexamethasone treatment ex vivo However, no significant effects on growth, body composition, blood chemistry or cell counts were observed under baseline conditions. These results suggest that GRAla610Val-induced GR hypersensitivity elicits a compensatory reduction in endogenous, bioactive glucocorticoid levels via readjustment of the hypothalamus-pituitary-adrenal (HPA) axis early in ontogeny to maintain an adequate response, but carriers are more sensitive to exogenous GC. Therefore, GRAla610Val pigs represent a valuable animal model to explore GR-mediated mechanisms of HPA axis regulation and responses to glucocorticoid-based drugs.
authors.affiliation: Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany murani@fbn-dummerstorf.de.
authors.forename: Eduard
authors.initials: E
authors.lastname: Muráni
authors.affiliation: Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany.
authors.forename: Siriluck
authors.initials: S
authors.lastname: Ponsuksili
authors.affiliation: Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Jaeger
authors.affiliation: Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Görres
authors.affiliation: Genetics and Biometry, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Tuchscherer
authors.affiliation: Genome Biology, Leibniz Institute for Farm Animal Biology (FBN), Wilhelm-Stahl-Allee 2, 18196 Dummerstorf, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Wimmers
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D015536:Down-Regulation; D005260:Female; D006854:Hydrocortisone; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D008297:Male; D009154:Mutation; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism*; D013552:Swine; D014156:Transcortin / Q000235:genetics; D014667:Vasopressins / Q000235:genetics
chemical_list: D018019:Receptors, Corticotropin-Releasing Hormone; D011965:Receptors, Glucocorticoid; D014667:Vasopressins; D000324:Adrenocorticotropic Hormone; D014156:Transcortin; D006854:Hydrocortisone
keywords: corticosteroid-binding globulin; corticotropin-releasing hormone; gain-of-function mutation; glucocorticoid receptor; glucocorticoids; hypothalamus–pituitary–adrenal axis