Harvey Philip W, Everett David J
Covance Laboratories Ltd, Otley Road, Harrogate, North Yorkshire HG3 1PY, UK.
J Appl Toxicol. 2003 Mar-Apr;23(2):81-7. doi: 10.1002/jat.896.
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 specific 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 insufficiency). 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 specific 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 insufficiency in sensitive human subgroups, and it would seem prudent to incorporate relevant tests for adrenal function and steroidogenesis into current regulatory validation programmes.
当前用于评估化学物质内分泌干扰特性的测试策略忽略了对肾上腺的检查，并且没有充分涵盖类固醇生成过程。类固醇生成对于肾上腺皮质功能以及睾丸和卵巢的功能至关重要，并且呈现出多个毒性分子靶点，范围从对所有类固醇生成组织的一般影响（例如通过类固醇生成急性调节蛋白或细胞色素P450 11A1胆固醇侧链裂解酶）到仅影响肾上腺皮质功能的特定靶点（例如细胞色素P450 11β/18和糖皮质激素合成）。现在有大量与环境相关的化学物质被证明在水生物种的体内以及人类细胞系的体外都会影响肾上腺皮质功能，鉴于肾上腺对人类健康和发育的重要作用，在用于筛选内分泌干扰化学物质的检测组合中纳入专门的评估技术很有必要，这尤其有助于进行一般数据解释（例如肾上腺肥大是由于应激还是更严重的肾上腺皮质功能不全）。目前存在如H295R（源自人肾上腺皮质腺癌）这样的细胞系，可用于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（例如类固醇生成急性调节蛋白；细胞色素P450 11A1/胆固醇侧链裂解酶；细胞色素P450 11β/18；细胞色素P450 17；芳香化酶；细胞色素P450 21；3β-羟基类固醇脱氢酶）。与综合内分泌系统的任何组成部分一样，对肾上腺皮质功能进行充分评估可能还需要开发特定的体内方法，以纳入对下丘脑-垂体功能的影响。最后，尽管目前没有直接证据表明环境中接触内分泌干扰（雌激素）化学物质实际上已对人类健康造成不良影响，但己烯雌酚事件让我们吸取了有关其潜在影响的教训。氨基导眠能和依托咪酯也有类似证据表明，在敏感的人类亚组中，意外的化学诱导肾上腺功能不全具有致命影响，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似乎是谨慎之举。
