Function of the Ah Receptor and its ligands in the nervous system – TOXAhBRAIN

Environmental pollution represents a growing threat for industrial and third world countries. It can lead to a disruption of ecosystem balance and has been partly associated with several major human diseases including asthma, diabetes or cancer. Environmental pollutants include numerous chemical families (arylamides, aromatic hydrocarbons, dioxins…). organisms have developed a few pleiotropic “sensors” (xenobiotic receptors), which detect and activate enzymatic and transport machineries allowing the elimination of xenobiotics (Tompkins and Wallace, 2007). One of the most important xenobiotic “sensor” is the Aryl hydrocarbon Receptor (AhR) (Barouki et al., 2007); dioxins, polycyclic aromatic hydrocarbons (PAH) and other environmental pollutants bind and trigger this ligand-activated transcription factor which increases the expression of several xenobiotic metabolism enzymes (XME). The role of the AhR in this adaptative response (typically, one xenobiotic activates its own metabolism) is well characterized in mammals (Wilson and Safe, 1998). However, recent studies suggest that this transcription factor regulates alternative signaling pathways independently of exposure to pollutants; invertebrates express AhR orthologs which do not bind xenobiotics (AhR-1 in Caenorhabditis elegans and Spineless in Drosophila melanogaster) in a specific group of neurons (Crews and Brenman, 2006; Huang et al., 2004; Powell-Coffman et al., 1998; Qin and Powell-Coffman, 2004; Qin et al., 2006). Analysis of ahr-1 mutants shows that, in C. elegans, the receptor promotes social feeding (Qin et al., 2006). The observed defects suggest that, in nematodes, AhR-1 is a central regulator of the neural circuit involved in aggregation behavior. While mammalian studies of AhR have mainly focused on its role as a regulator of XMEs, they have largely underestimated its potential endogenous functions, especially in the central and peripheral nervous system. The expression and function of the mammalian protein AhR in the nervous system is largely unknown. Moreover, several AhR ligands are suspected to be neurotoxic but the associated cellular mechanisms are not fully characterized (Gassmann et al., 2010; Kim and Yang, 2005; Latchney et al., 2010; Williamson et al., 2005). We speculate that the protein could also be critical for neural mammalian development. The present project aims 1) to characterize the expression of the AhR (mRNA and protein) in both central and peripheral nervous system and identify its endogenous neural functions using rodent models (wild-type vs knock-out mice) setting up behavioral and neurobehavioral tests, 2) to study the implication of the AhR in the myelination process in the mammalian nervous system, 3) to characterize the consequences of exposure to different AhR ligands on these behaviors. Parts 1-2 and 3 are related because disruption of endogenous functions may constitute one of the toxicity mechanisms of AhR ligand xenobiotics. This ANR program integrates both basic and applied research and is focused on the effects of neurotoxic pollutants in mammalian models. It constitutes a functional mechanistic approach that extends our recent work describing the identification of AhR targets in the mammalian central nervous system (preliminary data).