Adrenomedullary function is severely impaired in 21‐hydroxylase‐deficient mice

Abstract

Deficiency of 21-hydroxylase (21-OH), one of the most common genetic defects in humans, causes low glucocorticoid and mineralocorticoid production by the adrenal cortex, but the effect of this disorder on the adrenomedullary system is unknown. Therefore, we analyzed the development, structure, and function of the adrenal medulla in 21-OH-deficient mice, an animal model resembling human congenital adrenal hyperplasia. Chromaffin cells of 21-OH-deficient mice exhibited ultrastructural features of neuronal transdifferentiation with reduced granules, increased rough endoplasmic reticulum and small neurite outgrowth. Migration of chromaffin cells in the adrenal to form a central medulla was impaired. Expression of phenylethanolamine-N-methyltransferase (PNMT) was reduced to 27 +/- 9% (P<0.05), as determined by quantitative TaqMan polymerase chain reaction, and there was a significant reduction of cells staining positive for PNMT in the adrenal medulla of the 21-OH-deficient mice. Adrenal contents of epinephrine were decreased to 30 +/- 2% (P<0. 01) whereas norepinephrine and dopamine levels were reduced to 57 +/- 4% (P<0.01) and 50 +/- 9% (P<0.05), respectively. 21-OH-deficient mice demonstrate severe adrenomedullary dysfunction, with alterations in chromaffin cell migration, development, structure, and catecholamine synthesis. This hitherto unrecognized mechanism may contribute to the frequent clinical, mental, and therapeutic problems encountered in humans with this genetic disease.

Restoration of adrenal steroidogenesis by adenovirus-mediated transfer of human cytochromeP450 21-hydroxylase into the adrenal gland of21-hydroxylase-deficient mice

“…17 Therefore, systemic administration of the gene resulting in little, if any, expression of the enzyme in the adrenal would be unlikely to provide adequate levels of circulating glucocorticoids in case of increased demand, and would be insufficient for local adrenal regulation. The mitochondrial abnormalities in 21-OH-deficient mice resemble those described in humans with CAH, 18 and differ from the increase in mitochondrial vesicular membranes that occurs following ACTH or CRH administration.…”

Approaching the shared biology of obesity and depression: the stress axis as the locus of gene–environment interactions

“…Gene deletions for CRH receptors, transcription factors (such as steroidogenic factors), and steroidogenic enzymes (such as 21-hydroxylase) that play a crucial role in the release and regulation of glucocorticoids also affect the release and regulation of catecholamines and neuropeptides. 50,51 Those different transgenic animals display conspicuous alterations in ultrastructure (Figure 2c, d) and hormone expression in various neuroendocrine cell systems. Impairment of catecholamine and neuropeptide release and regulation therefore appear to contribute to the metabolic and behavioral symptoms seen in animal models and patients with altered HPA axis function.…”

Expression Levels of mRNAs for Catecholamine Biosynthetic Enzymes as Markers of Acute Response to Contusion Stress during the Early Postmortem Period

“…On the other hand, measurement of sympathoadrenal activity based on expression levels of mRNAs for catecholamine biosynthetic enzymes has been performed in the field of molecular biology (Nankova et al 1994;Nankova et al 1996;Brooks et al 1997;Levenson and Moore 1998;Rusnák et al 1998;Bornstein et al 1999;Lai et al 2000;Sabban and Kvetnanský 2001;Gallara et al 2004;Kubovcakova et al 2004;Klimes et al 2005;Lai et al 2005;Herradón et al 2006). However, earlier animal studies on some stresses such as immobilization, cold exposure, forced exercise, and insulininduced hypoglycemia (Brooks et al 1997;Lai et al 2000;Sabban and Kvetnanský 2001;Gallara et al 2004;Klimes et al 2005;Lai et al 2005), did not cover all forms of stresses encountered in forensic practice.…”

“…Moreover, most of the methods in the analysis including Southern blotting and semi-quantitative reverse trancrptional polymerase chain reaction (RT-PCR) (Nankova et al 1994;Nankova et al 1996;Brooks et al 1997;Lai et al 2000;Kubovcakova et al 2004;Gallara et al 2004;Lai et al 2005), require some experience to produce reliably reproducible results. In recent years, real-time quantitative PCR (RQ-PCR) has been established as a simplified and reproducible method for the quantification of mRNA expression, and some investigators have used this technique for assaying levels of catecholamine mRNA expression (Bornstein et al 1999;Kvetnansky et al 2004;Herradón et al 2006). However, these authors only compared catecholamine levels between stress and nonstress conditions, and not between different stress conditions.…”