Adrenomedullary function is severely impaired in 21-hydroxylase-deficient mice.
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.
Bornstein
S R
SR
Section on Endocrine Physiology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892. Bornstes@mail.nih.gov
Tajima
T
T
Eisenhofer
G
G
Haidan
A
A
Aguilera
G
G
D000312:Adrenal Hyperplasia, Congenital / Q000201:enzymology / Q000503:physiopathology; D000313:Adrenal Medulla / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D001483:Base Sequence; D002395:Catecholamines / Q000378:metabolism; D019439:Chromaffin Cells / Q000201:enzymology / Q000378:metabolism / Q000648:ultrastructure; D002851:Chromatography, High Pressure Liquid; D003345:Corticosterone / Q000097:blood; D017931:DNA Primers; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008854:Microscopy, Electron; D010625:Phenylethanolamine N-Methyltransferase / Q000235:genetics; D011374:Progesterone / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D002395:Catecholamines; D017931:DNA Primers; D012333:RNA, Messenger; D011374:Progesterone; D010625:Phenylethanolamine N-Methyltransferase; D003345:Corticosterone