Steroid Profiling Reveals Widespread Local Regulation of Glucocorticoid Levels During Mouse Development

Abstract

Glucocorticoids (GCs) are produced by the adrenal glands and circulate in the blood to coordinate organismal physiology. In addition, different tissues may independently regulate their local GC levels via local GC synthesis. Here, we find that in the mouse, endogenous GCs show tissue-specific developmental patterns, rather than mirroring GCs in the blood. Using solid-phase extraction, HPLC, and specific immunoassays, we quantified endogenous steroids and found that in tissues of female and male mice, (1) local GC levels can be much higher than systemic GC levels, (2) local GCs follow age-related patterns different from those of systemic GCs, and (3) local GCs have identities different from those of systemic GCs. For example, whereas corticosterone is the predominant circulating adrenal GC in mice, high concentrations of cortisol were measured in neonatal thymus, bone marrow, and heart. The presence of cortisol was confirmed with liquid chromatography-tandem mass spectrometry. In addition, gene expression of steroidogenic enzymes was detected across multiple tissues, consistent with local GC production. Our results demonstrate that local GCs can differ from GCs in circulating blood. This finding suggests that steroids are widely used as local (paracrine or autocrine) signals, in addition to their classic role as systemic (endocrine) signals. Local GC regulation may even be the norm, rather than the exception, especially during development.

Evidence for an immune signature of prenatal alcohol exposure in female rats

“…Total serum corticosterone levels were measured using the ImmuChem Double Antibody Corticosterone 125 I radioimmunoassay kit (MP Biomedicals, LLC, Orangeburg, NY, USA, according the manufacturer's instructions with one modification – the lowest standard was further diluted to detect lower corticosterone concentrations (Taves et al, 2015). The minimum detectable corticosterone concentration was approximately 7.7 ng/mL, and the intra- and inter-assay coefficients of variation were <10 % and <7 %, respectively.…”

Neuroendocrine-immune circuits, phenotypes, and interactions

“…However, in thymic tissue, cortisol is the predominant glucocorticoid (Schmidt et al, 2009, 2010; Schmidt and Soma, 2008; Taves et al 2016a), which suggests that local steroids may produce different effects from those of systemic steroids. In neonatal and postnatal mice, local concentrations of corticosterone are elevated in thymus, liver, spleen, and/or brain relative to circulating levels (Taves et al 2015). Lymphoid-derived corticosterone is not produced de novo from cholesterol, but regenerated from adrenal metabolites (Taves et al 2016b), which does not alter circulating levels since inactive metabolites (11-deoxycorticosterone) with little glucocorticoid activity are used.…”

“…Conversely, this regeneration mechanism permits higher glucocorticoid concentrations to accrue locally that would otherwise passively track circulating levels. Local elevation of glucocorticoids regulates selection of immunocompetent T-cells, while systemic levels are low to presumably minimize the detrimental effects of chronic glucocorticoid exposure during development (Taves et al 2015). Taken together, the relationship between glucocorticoids and immune function is altered depending upon which NEI circuit is employed (long-loop (peripheral) versus local circuit).…”

Evolution of corticosteroid specificity for human, chicken, alligator and frog glucocorticoid receptors

“…This is important because more than one corticosteroid may be a physiological glucocorticoid in terrestrial vertebrates [33][34][35]. Reports of transcriptional activation by corticosteroids of the GR for other terrestrial vertebrates: amphibians, reptiles and birds, are limited [36,37].…”