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首页> 外文期刊>Journal of applied toxicology >The adrenal cortex and steroidogenesis as cellular and molecular targets for toxicity: critical omissions from regulatory endocrine disrupter screening strategies for human health?
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The adrenal cortex and steroidogenesis as cellular and molecular targets for toxicity: critical omissions from regulatory endocrine disrupter screening strategies for human health?

机译：肾上腺皮质和类固醇生成作为毒性的细胞和分子靶标：人类健康的调节性内分泌干扰物筛选策略的关键遗漏？

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Current testing strategies to assess the endocrine disrupting properties of chemicals have omitted examination of the adrenal gland and do not adequately cover the process of steroidogenesis. Steroidogenesis is critical for adrenocortical function as well as that of the testes and ovaries, and presents multiple molecular targets for toxicity, ranging from general effects on all steroidogenic tissues (e.g. via StAR protein or CYP11A1 cholesterol side-chain cleavage) through to speci fi c targets affecting only adrenocortical function (e.g. CYP11beta/18 and glucocorticoid synthesis). Numerous chemicals of environmental relevance are now being shown to affect adrenocortical function both in vivo in aquatic species and in vitro in human cell lines, and given the vital role of the adrenal gland to human health and development, there is a strong case for including dedicated assessment techniques in screening batteries for endocrine-disrupting chemicals, not least to assist in general data interpretation (e.g. whether adrenal hypertrophy is due to stress or to a more sinister adrenocortical insuf fi ciency). Cell lines such as H295R (derived from a human adrenocortical adenocarcinoma) currently exist that will allow assessment of cortisol production and most of the major enzymes and functional proteins in the steroidogenic pathway (e.g. StAR; CYP11A1/scc; CYP11beta/18; CYP17; CYP19; CYP21; 3beta-hydroxysteroid dehydrogenase). Adequate assessment of adrenocortical function, as with any component of the integrated endocrine system, probably also will require the development of speci fi c in vivo methodology to include effects on hypothalamo-pituitary function. Finally, although there is currently no direct evidence that environmental exposure to endocrine-disrupting (oestrogenic) chemicals has actually caused adverse human health effects, lessons have been learned on their potential from the diethylstilboestrol case. Similar evidence exists from aminoglutethimide and etomidate on the lethal impact of unpredicted chemically induced adrenal insuf fi ciency in sensitive human subgroups, and it would seem prudent to incorporate relevant tests for adrenal function and steroidogenesis into current regulatory validation programmes. Published in 2003 by John Wiley & Sons, Ltd.
机译：当前评估化学品的内分泌干扰特性的测试策略已经省略了对肾上腺的检查，并且不能充分涵盖类固醇生成的过程。类固醇生成对肾上腺皮质以及睾丸和卵巢的功能至关重要，并呈现出多种毒性分子靶标，范围从对所有类固醇生成组织的一般影响（例如，通过StAR蛋白或CYP11A1胆固醇侧链裂解）一直到特异性仅影响肾上腺皮质功能的靶标（例如CYP11beta / 18和糖皮质激素的合成）。现在已经显示出许多与环境有关的化学物质会影响水生物种体内和人类细胞系体外的肾上腺皮质功能，并且鉴于肾上腺对于人类健康和发展的至关重要的作用，因此有专门的理由在筛选电池中是否存在破坏内分泌的化学物质方面的评估技术，尤其是有助于一般数据的解释（例如，肾上腺肥大是由于压力还是更险恶的肾上腺皮质功能不全所致）。目前存在诸如H295R（源自人类肾上腺皮质腺癌）的细胞系，该细胞系可以评估皮质醇的产生以及类固醇生成途径中的大多数主要酶和功能蛋白（例如StAR; CYP11A1 / scc; CYP11beta / 18; CYP17; CYP19 ; CYP21; 3beta-羟基类固醇脱氢酶）。与整合内分泌系统的任何组成部分一样，对肾上腺皮质功能的充分评估可能还需要开发特定的体内方法，以包括对下丘脑-垂体功能的影响。最后，尽管目前尚无直接证据表明环境暴露于破坏内分泌（雌激素）的化学物质实际上已对人类健康产生不利影响，但已从二乙基雌二醇事件中吸取了关于其潜力的经验教训。来自氨基谷氨酰胺和依托咪酯的相似证据也表明，未预测的化学诱导的肾上腺功能不全会对敏感的人类亚组造成致命影响，因此将有关肾上腺功能和类固醇生成的相关测试纳入当前的监管验证计划中似乎是审慎的做法。 John Wiley＆Sons，Ltd.于2003年出版。

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