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Adverse health effects of environmental chemical agents through non-genotoxic mechanisms
  1. Frank Henkler,
  2. Andreas Luch
  1. German Federal Institute for Risk Assessment, Department of Product Safety, Berlin, Germany
  1. Correspondence to Dr Andreas Luch, German Federal Institute for Risk Assessment, Department of Product Safety, Thielallee 88-92, 14195 Berlin, Germany; andreas.luch{at}bfr.bund.de

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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-mediated effects

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 …

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