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.

LUMAN/CREB3 Plays a Dual Role in Stress Responses as a Cofactor of the Glucocorticoid Receptor and a Regulator of Secretion

“…An increase in GR expression would lead to enhanced negative feedback in the HPA axis, resulting in decreased circulating CORT levels ( Mizoguchi et al, 2003 ). Previous GR hyperactivity models have corroborated these findings, showing that early in ontology the HPA axis is able to remodel itself to decrease ACTH and cortisol release to allow for normal basal GR reactivity ( Murani et al, 2016 ). The mechanism through which this remodeling occurs has been suggested to happen at the epigenetic level, leading to the need to identify factors that alter gene expression and even chromatin structure to allow a better understanding of the molecular basis of stress sensitivity ( Hunter et al, 2015 ).…”

Omics Application in Animal Science—A Special Emphasis on Stress Response and Damaging Behaviour in Pigs

“…The QTN segregates in diverse commercial pig breeds (German Landrace, German Large White, Pietrain, Duroc) and shows consistent association with cortisol production [ 61 ]. Because GR is involved in negative feedback regulation of the HPA axis activity, the enhanced receptor sensitivity (i.e., hypersensitivity) likely leads to compensatory downregulation of the HPA axis early in ontogeny [ 113 ]. While the effect on adrenal function is most pronounced, the mutation influences also activity of the central branch of the HPA axis, including corticotropin releasing hormone ( CRH ) and vasopressin expression [ 113 ].…”

“…Because GR is involved in negative feedback regulation of the HPA axis activity, the enhanced receptor sensitivity (i.e., hypersensitivity) likely leads to compensatory downregulation of the HPA axis early in ontogeny [ 113 ]. While the effect on adrenal function is most pronounced, the mutation influences also activity of the central branch of the HPA axis, including corticotropin releasing hormone ( CRH ) and vasopressin expression [ 113 ]. Since these latter neuropeptides are involved also in the regulation of behaviour and SAM, the mutation might have a broader impact on stress responses.…”

Does Maternal Stress Affect the Early Embryonic Microenvironment? Impact of Long-Term Cortisol Stimulation on the Oviduct Epithelium

“…Two concentrations of cortisol (100 and 250 nM), as measured in the plasma of sows under moderate and severe stressors, were employed for the stimulation experiment [41,42]. The 10 mg/mL cortisol stock solution was prepared in 100% ethanol and stored in aliquots at −20 • C until use.…”