Adverse health effects of environmental chemical agents through non-genotoxic mechanisms
Adverse health effects of environmental chemical agents through non-genotoxic mechanisms
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环境化学制剂通过非遗传毒性机制对健康产生不利影响
DOI：
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发表时间：
2010
影响因子：
6.3
通讯作者：
A. Luch
中科院分区：
文献类型：
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作者：
F. Henkler;A. Luch
在过去的一个世纪里，西半球的工业化导致了成千上万种不同化学品和复杂制剂的大量生产，并将它们释放到环境中。这些化合物可以分为有意合成和释放的化合物和从各种工业过程中产生的副产品。这些化学物质中的一个亚组在环境生物降解方面是持久的，因此在环境中存活很长时间，有可能成为食物链中的污染物。有意生产的化合物包括杀菌剂、杀虫剂、阻燃剂、增塑剂、防腐剂和食品、化妆品和消费品中使用的添加剂。许多这些化合物现在被怀疑或已经被证明能够通过模仿或抵消内源性受体配体来调节涉及生理信号级联的细胞受体反应。除了典型的激素受体——比如那些控制细胞对雌激素、雄激素、黄体酮、糖皮质激素、矿物皮质激素和甲状腺激素的生理水平的反应的受体——还有许多其他的，包括那些参与外来生物识别和反应的受体在毒理学方面，在后一种所谓的“异种传感器”中最重要的是芳烃受体（AHR），孕烷X受体和组成型雄烷受体。虽然妊娠X受体和构成型雄烷受体在配体结合中或多或少是混杂的，但某些内源性激动剂已被确定，AHR似乎是例外，因为尚未确定明确的生理配体
Over the past century, industrialisation in the western hemisphere led to the high-volume production of thousands of different chemicals and complex preparations and their release into the environment. These compounds can be separated into those that were synthesised and released intentionally and others that arose as by-products from various industrial processes. A subgroup among these chemicals are persistent in terms of environmental biodegradation and thus stay alive for a long time in the environment with the potential to emerge as contaminants in the food chain. Compounds produced on purpose include biocides, pesticides, flame retardants, plasticisers, preservatives and additives used in foods or cosmetics, and consumer products. Many of these compounds are now suspected or have already been demonstrated to be capable of modulating cellular receptor responses involved in physiological signal cascades by mimicking or counteracting endogenous receptor ligands. Besides typical hormone receptors—such as those that govern cellular responses to physiological levels of oestrogens, androgens, progesterone, glucocorticoids, mineralocorticoids and thyroid hormones—many others were characterised, including those involved in xenobiotic recognition and responses.1 In terms of toxicology, most important among the latter so-called ‘xenosensors’ are the arylhydrocarbon receptor (AHR), the pregnane X receptor and the constitutive androstane receptor. While the pregnane X receptor and the constitutive androstane receptor are more or less promiscuous in ligand binding, with certain endogenous agonists being identified, AHR seems exceptional, as no definite physiological ligands have yet been identified.2
AHR has been recognised for decades as a ligand-activated transcription factor that is—along with its nuclear translocator—responsible for the induction of drug metabolising enzymes such as cytochrome P450-dependent monooxygenases. Not until recently have other functions of this protein begun to be recognised, and it is now clear that AHR also functions in pathways beyond xenobiotic metabolising enzyme induction. Chemical impairment of these other pathways may help …