Toxicological Sciences, Vol 51, 9-18, Copyright © 1999 by Society of Toxicology
AS Tischler, JF Powers, M Pignatello, P Tsokas, JC Downing and RM McClain
Adrenal medullary hyperplasia and pheochromocytomas are induced in rats by
a variety of non-genotoxic agents, and we have hypothesized that these
agents induce lesions indirectly by stimulating chromaffin cell
proliferation. Vitamin D3, which has not been previously associated with
adrenal medullary proliferative lesions, is the most potent in vivo
stimulus to chromaffin cell proliferation yet identified. The present
investigation utilized the vitamin D3 model to prospectively test the
relationship between mitogenicity and focal proliferative lesions in the
adrenal medulla and to determine early events in the pathogenesis of these
lesions. Charles River Crl:CD BR rats were treated with 0; 5000; 10,000; or
20,000 IU/kg/day of vitamin D3 in corn oil (5 ml/kg) by oral intubation.
Rats were killed after 4, 8, 12, or 26 weeks of treatment, following a
final week of labeling with bromodeoxyuridine (BrdU) using a mini-pump.
Adrenal sections were double-stained for BrdU and
phenylethanolamine-N-methyl transferase (PNMT) to discriminate epinephrine
(E) from norepinephrine (NE) cells or for vesicular acetylcholine
transporter (VAchT) to identify cholinergic nerve endings. Vitamin D3
caused a 4-5-fold increase in BrdU labeling at week 4, diminishing to a
2-fold increase by week 26. An initial preponderance of labeled E cells
gave way to a preponderance of labeled NE cells. By week 26, 17/19 (89%)
animals receiving the 2 highest doses of vitamin D3 had focal adrenal
medullary proliferative lesions, in contrast to an absence of lesions in
control rats. The lesions encompassed a spectrum including BrdU-labeled
"hot spots" not readily visible on H and E sections, hyperplastic nodules,
and pheochromocytomas. Lesions were usually multicentric, bilateral, and
peripheral in location, and almost all were PNMT-negative. The lesions were
not cholinergically innervated, suggesting autonomous proliferation. Hot
spots, hyperplastic nodules, and pheochromocytomas appear to represent a
continuum rather than separate entities. Their development might involve
selective responses of chromaffin cell subsets to mitogenic signals,
influenced by both innervation and corticomedullary interactions. A number
of non-genotoxic compounds that induce pheochromocytomas in rats are known
to affect calcium homeostasis. The results of this study provide further
evidence to support the hypothesis that altered calcium homeostasis is
indirectly involved in the pathogenesis of pheochromocytomas, via effects
on chromaffin cell proliferation.
ARTICLES
Vitamin D3-induced proliferative lesions in the rat adrenal medulla
Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts, USA. arthur.tischler@es.nemc.org
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