br Author contributions br Funding This

Author contributions
Funding This work was supported by the Czech Science Foundation, project no. 14-16220S. Additional support was provided by NIH R01CA117907 grant awarded to J.M.E.
Conflict of interest
Introduction The dioxin-like family includes polyhalogenated aromatic hydrocarbons such as polychlorinated dibenzodioxins (PCDD), polychlorinated dibenzofurans (PCDF) and polychlorinated biphenyls (PCB) (Fig. 1). PCDD and PCDF are by-products of organic synthesis and incineration procedures, whereas PCB were used as dielectric and coolant fluids in transformers, capacitors, and electric motors (Van den Berg et al., 1994, WHO, 2002). These persistent organic pollutants were associated to industrial accidents such as the BASF plant in Ludwigshafen in 1953 (Thiess et al., 1982) and the Icmesa factory in Seveso in 1976 (Assennato et al., 1989), to the toxic contaminant of the Agent Orange used by the U.S. army during the war of Vietnam in the 1960s (Steele et al., 1990), and more recently to the poisoning of the former Ukrainian President Victor Yushchenko in 2004 during his presidential campaign (Ryan, 2005, Saurat et al., 2012, Sorg et al., 2009). The aryl hydrocarbon receptor (AhR) is a member of the bHLH (basic Helix–Loop–Helix)—PAS (Per-ARNT-Sim) family of transcription factors that regulate various physiological and developmental processes (McIntosh et al., 2010, Moglich et al., 2009, Tian, 2009, Zudaire et al., 2008). Many human tissues including the lung, the liver, the kidney, the skin, the spleen and the placenta express AhR (Abel and Haarmann-Stemmann, 2010). The receptor is localised in the Fludarabine Phosphate and is activated by a variety of xenobiotic (exogenous) compounds diffusing through plasma membranes owing to their lipophilic properties. Following AhR activation, the signalling pathway leads to the modulation of genes involved in the metabolism of these lipophilic compounds (Abel and Haarmann-Stemmann, 2010, Guyot et al., 2013, Hahn, 2002). The notoriety of AhR is mostly due to the clinical manifestations following activation by a very potent agonist, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Poland and Knutson, 1982, Van den Berg et al., 1994). For this reason AhR is sometimes called “the dioxin receptor”, which is a quite restrictive point of view when considering the great variety of the physiological processes modulated by AhR. Indeed, besides the well known and misnomer chloracne syndrome (Saurat and Sorg, 2010), AhR activation induces a broad spectrum of biochemical and toxic effects, such as teratogenesis, modulation of the immune system and tumour promotion (Mimura and Fujii-Kuriyama, 2003, Quintana, 2013). Regarding the toxicity of dioxins, the relationships between AhR activation and toxicity has to be re-evaluated, as various compounds induce a similar toxic syndrome without activating AhR, and some natural AhR agonists (NAHRA) found in vegetables for instance do not induce chloracne (Connor et al., 2008, de Waard et al., 2008).
AhR signalling
AhR signalling assessment
Dioxin toxicity
Dioxins, AHR and chloracne The dioxin family usually includes PCDD, PCDF and PCB (Fig. 1), a family of polychlorinated aromatic hydrocarbons that activate AhR with various potencies, as measured by their respective TEF (Table 1). When AhR was shown to be the receptor for dioxins, it had seemed logical to consider that the biological effects of dioxins were mediated by the AhR signalling pathway. The current known AhR agonists are not confined to the dioxin-like family, and show an increasing diversity of molecular structures as new agonists are discovered (Fig. 5, Fig. 6). On the other hand certain AhR agonists do not induce the so-called chloracne syndrome (Fig. 6), whereas known chloracnegens do not activate AhR (Fig. 7). In other cases, people develop a chloracne-like syndrome although their blood level of TCDD is not above average and the causative agent is unknown. It is the case for instance for patients in Bologne (Northern Italy) who showed a typical chloracne syndrome, both clinically and histologically, although their blood TEQ values were under that of the general population (Passarini et al., 2010). More surprisingly, several natural compounds found in food may activate AhR. For instance, cruciferous vegetables contain glucosinolates such as glucobrassicin and gluocoraphanin, which are converted by the plant enzyme myrosinase to indole-3 carbinol and sulforaphane, respectively (Fig. 6). Not only do not these natural AhR agonists (NAHRA) seem to induce chloracne, but also they exert anticancer and antimicrobial properties in experimental models, and thus appear beneficial for human health (Connor et al., 2008, de Waard et al., 2008, Jeffery and Araya, 2009). Connor and coll. developed a sensitive bioassay to assess AhR signalling intensity and found in a clinical trial that global activation of AhR pathway by blood samples was ≈1000-fold higher than that due to only dioxin-like compounds; moreover, a diet enriched in indole-3-carbinol (a NAHRA) induced a 4-fold increase of the bioassay (Connor et al., 2008). This would mean that the true activation of AhR signalling pathway is much higher than previously thought, and thus the toxicity of dioxin-like compounds could not be fully explained by AhR activation, since natural non-toxic compounds found in food account for more than 99% of AhR activation. In this case another mechanism would explain the toxicity of polycyclic/polychlorinated aromatic hydrocarbons.