Vitamin D3-induced proliferative lesions in the rat adrenal medulla.
Vitamin D3-induced proliferative lesions in the rat adrenal medulla.
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维生素 D3 诱导的大鼠肾上腺髓质增殖性病变。
DOI：
10.1093/toxsci/51.1.9
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
McClain,RM
中科院分区：
文献类型：
--
作者：
Tischler,AS;Powers,JF;Pignatello,M;Tsokas,P;Downing,JC;McClain,RM
肾上腺髓质增生和嗜铬细胞瘤是由各种非遗传毒性药物诱导的，我们假设这些药物通过刺激嗜铬细胞增殖间接诱导病变。维生素D3，以前没有与肾上腺髓质增生性病变，是最有效的体内刺激嗜铬细胞增殖尚未确定。本研究利用维生素D3模型，前瞻性地测试促有丝分裂和局灶性增生性病变在肾上腺髓质之间的关系，并确定这些病变的发病机制的早期事件。Charles River Crl：CD BR大鼠经口插管给予0、5000、10，000或20，000 IU/kg/天的维生素D3玉米油溶液（5 ml/kg）。在治疗4、8、12或26周后，在使用微型泵用溴脱氧尿苷（BrdU）标记的最后一周后，处死大鼠。肾上腺切片进行BrdU和苯乙醇胺-N-甲基转移酶（PNMT）双重染色，以区分肾上腺素（E）和去甲肾上腺素（NE）细胞，或囊泡乙酰胆碱转运蛋白（VAchT），以确定胆碱能神经末梢。维生素D3在第4周引起BrdU标记增加4-5倍，到第26周减少至增加2倍。标记的E细胞的初始优势让位于标记的NE细胞的优势。到第26周，接受2个最高剂量维生素D3的17/19（89%）动物出现局灶性肾上腺髓质增生性病变，而对照组大鼠无病变。病变范围包括BrdU标记的“热点”，在H和E切片上不易观察到，增生性结节和嗜铬细胞瘤。病变通常是多中心的，双边的，周围的位置，几乎所有的PNMT阴性。病变没有胆碱能神经支配，这表明自主增殖。热点、增生结节和嗜铬细胞瘤似乎代表一个连续体而不是单独的实体。它们的发展可能涉及嗜铬细胞亚群对有丝分裂信号的选择性反应，受神经支配和皮质髓质相互作用的影响。已知许多诱导大鼠嗜铬细胞瘤的非遗传毒性化合物会影响钙稳态。这项研究的结果提供了进一步的证据，以支持这一假设，改变钙稳态是间接参与嗜铬细胞瘤的发病机制，通过对嗜铬细胞增殖的影响。
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.
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利血平持续刺激大鼠肾上腺嗜铬细胞增殖。
DOI：
10.1006/taap.1995.1231
发表时间：
1995
期刊：
Toxicology and applied pharmacology.
影响因子：
--
作者：
Tischler,AS;Ziar,J;Downing,JC;McClain,RM
通讯作者：
McClain,RM
影响因子：
10.4
作者：
Ames BN;Shigenaga MK;Gold LS
通讯作者：
Gold LS
急性刺激成年大鼠肾上腺髓质中的嗜铬细胞增殖。
DOI：
--
发表时间：
1988
期刊：
Laboratory investigation; a journal of technical methods and pathology
影响因子：
--
作者：
Tischler,AS;DeLellis,RA;Nunnemacher,G;Wolfe,HJ
通讯作者：
Wolfe,HJ
低消化碳水化合物（多元醇和乳糖）：大鼠肾上腺髓质增殖性病变的意义。
DOI：
--
发表时间：
1996
期刊：
Regulatory toxicology and pharmacology : RTP
影响因子：
--
作者：
Barry Lynch;A. Tischler;C. Capen;I. Munro;L. McGirr;R. Mcclain
通讯作者：
R. Mcclain
成人肾上腺髓质中嗜铬细胞增殖的药理刺激。
影响因子：
--
作者：
Tischler,AS;Ruzicka,LA;Donahue,SR;DeLellis,RA
通讯作者：
DeLellis,RA