Dissection of the corticotroph transcriptome in a mouse model of glucocorticoid-induced suppression of the HPA axis

Romano, N.; Duncan, P.; McClafferty, H.; Nolan, O.; Ding, Q.; Homer, N. Z.; Le Tissier, P.; Walker, B. R.; Shipston, M. J.; Chambers, T. J. G.

doi:10.1101/2020.07.29.227330

bioRxiv · 10.1101/2020.07.29.227330

Dissection of the corticotroph transcriptome in a mouse model of glucocorticoid-induced suppression of the HPA axis

Romano, N.·Duncan, P.·McClafferty, H.·Nolan, O.·Ding, Q.·Homer, N. Z.·Le Tissier, P.·Walker, B. R.·Shipston, M. J.·Chambers, T. J. G.

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Abstract

Glucocorticoids (GC) are prescribed for periods >3 months to 1-3% of the UK population; 10-50% of these patients develop hypothalamus-pituitary-adrenal (HPA) axis suppression, which may last over 6 months and is associated with morbidity and mortality. Recovery of higher nodes of the axis is necessary for recovery of adrenal function. We developed a mouse model of Dexamethasone (DEX)-induced HPA axis dysfunction in order to further explore recovery in the pituitary. Adult male C57BL6/J or those crossed with Pomc-eGFP mice were randomly assigned to receive DEX (~0.4 mg/kg bodyweight/day) or vehicle via drinking water for 4 weeks following which treatment was withdrawn. Tissues were harvested at 0, 1, and 4 weeks following withdrawal of treatment. Corticotrophs were isolated from Pomc-eGFP pituitaries using FACS, and RNA extracted for RNA-seq. DEX treatment suppressed corticosterone production, which remained partially suppressed at least 1 week following DEX withdrawal. In the adrenal, at time 0, Hsd3b2, Cyp11a1, and Mc2r mRNA levels were significantly reduced, with Mc2r and Cyp11a1 remaining reduced 1 week following DEX withdrawal. The corticotroph transcriptome was modified by DEX treatment with some differences between groups persisting 4 weeks following withdrawal. No genes supressed by DEX exhibited ongoing attenuation 1 and 4 weeks following withdrawal, whilst only 2 genes were upregulated and remained so following withdrawal. A pattern of rebound at 1 and 4 weeks was observed in 14 genes that increased following suppression, and 6 genes that were reduced by DEX and then increased. Chronic GC treatment may induce persistent changes in the pituitary that may influence future response to GC treatment or stress.

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Romano, N., Duncan, P., McClafferty, H., Nolan, O., Ding, Q., Homer, N. Z., Le Tissier, P., Walker, B. R., Shipston, M. J., Chambers, T. J. G.. 2020-07-30. Dissection of the corticotroph transcriptome in a mouse model of glucocorticoid-induced suppression of the HPA axis. https://doi.org/10.1101/2020.07.29.227330

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