Discuss dioxins is via food, especially meat

Discuss both the structure of the aryl hydrocarbonreceptor and its role in chloracneDioxins,the most potent of which is 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), forma group of persistent organic pollutants present in the environment.

Theyaccumulate in the food chain, especially in the animal fat, and more than 90%of human exposure to dioxins is via food, especially meat and dairy products. Thearyl hydrocarbon receptor (AhR) is a ligand-activated transcription factorfound in the cytosol/nucleus and controls the expression of a diverse set ofgenes. TCDD is almost exclusively mediated through this receptor. However, thekey alterations in gene expression that mediate toxicity are poorly understood.This essay will first discuss the structure of AhR receptor and then explainits role in chloracne. Structure of AhRTheAhR and the AhR nuclear translocator (ARNT) belong to the family of basic helix-loop-helix-PER-ARNT-SIM(bhlh- PAS) domain containing transcription factors. ARNT shares homology with drosophilaproteins PER and SIM.

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The PAS-ARNT-SIM domain contains PAS-A and PAS-B regionsof ~130 amino acids each, further, the ligand-binding region is in the PAS-Bdomain (Wu et al. 2013). ARNT 1 is ubiquitously present whereas ARNT isexpressed in the brain and kidney. TheBhlh component is a well-characterised DNA binding protein motif composed oftwo a-helices connected by an intrinsically unstructured loop. They have theability to heterodimerise with the members of class I bHLH-PAS group e.g.hypoxia inducible factors (Hif-1a/ Hif-2a) and the single-minded proteins(SIM1/SIM2) to regulate a transcriptional response to xenobiotic.

Onthe other hand, AhR is a cytosolic signal sensor, which is guided into thenucleus upon binding of planar aromatic hydrocarbons e.g. TCDD. Further, TCDDmediates its toxicity through AhR activation (Poland et al. 1976). Atransactivation domain (TAD) involved in the recruitment of othertranscriptional co-activators.Structurallythe AhR and ARNT are very similar as demonstrated by the diagrams below: bHLHdimerization dna binding                            PAS secondary dimerization                                                                                              Transactivation   AhR                                                                                                           Xenobiotic response                         15aa          ARNT 1&2                                                                                         General partner factor TCDD Todate, the pathogenesis of Chloracne remains incompletely understood. However,most of the effects of TCDD in humans and animal models seems to be mediated bythe AhR signalling pathway.

Itis a planar halogenated aromatic hydrocarbon with high affinity for AhR;furthermore, it is highly lipophilic and shows low basal rates metabolically. Chloracneis both human and TCDD specific, it contains acne vulgaris like lesionsincluding open and closed comedones and cysts, and however unlike acne vulgaristhe lesions are sterile and non-inflammatory. Chloracne consists ofabnormalities in keratinocyte differentiation in the follicle, causing thickenedand compacted stratum corneum, which leads to follicular plugging andcharacteristic comedones.

AhR was previously found to be expressed andactivated in human keratinocytes and skin fibroblasts as well as in humansebaceous glands. In the skin lesions of chloracne patients exposed to dioxin,there was an activation and upregulation of p- epidermal growth factor receptorEGFR (EGFR), pmitogen-activated protein kinase, and CK17 in all chloracnetissues but not in the controls. Furthermore, an increase in the dioxinindependent transcriptional activity of the AhR has recently been demonstratedin a drosophila model to be also responsible for the in vivo dioxin toxicity(Ju et al,. 2011).Furthermore,Acne affects young adolescents whereas chloracne can affect any age group,anatomical localisation in the former is in the face, but the latter has awider variation of targets including the ears and the groin for example. Inacne, sebum production is increased, inflammation is common, limited comedonesand the sebaceous gland is hypertrophic. Conversely, in chloracne the sebumproduction is decreased, inflammation is rare, increased blackheads, andatrophy of the sebaceous gland is seen. Thereare animal models that exhibit chloracne-like disease (for example, thehairless mouse model (Panteleyev et al.

, 1997), but because of differences inthe hair follicle (the main site of TCDD induced changes causing chloracne)between human and animal, extrapolation from the animal models to human diseaseis difficult. Chloracne is characterised by hyperplasia of the epidermis,keratinisation of the pilsebaceous unit, hyperplasia/metaplasia of thesebaceous gland.Inits activated state the AhR resides in the cytoplasm in a complex with itschaperone proteins; the AhR interacting protein (AIP) and heat-shock protein(hsp90). This complex has multiple functions involving keeping the AhRlocalised in the cytoplasm and repressing conformational changes that occurduring activation. AIP/XAP2 is an immunophillin like protein that is part ofthe AhR-hsp90 complex binding to both AhR and hsp90 in the absence of ligand(Bell and Poland, 2000). AIP binding to the AhR inhibits nuclear translocationby inhibiting importin ? recognition of the NLS (Petrulis et al.

, 2003) andligand binding therefore breaks the XAP2-hsp90-AhR complex down which isthought to be required for AhR-hsp90 stability, ultimately the conformationalchange exposes the N-terminal of NLS, thus initiating nuclear import. Inthe nucleus, hsp90 is exchanged for partner ARNT; which dimerises with the AhRthrough aforementioned Bhlh and PAS domains to form a functional DNA bindingcomplex. Although the stage at which XAP2 and p23 are displaced is vague.  Yeasthybridisation and biochemical analysis have been used to demonstrate AhRinteraction with AIP2. Further, transient transfection studies demonstrate a~two-fold increase in XRE driven reporter gene activity upon AIP2 co-expressionwith the AhR, correlating with a ~two- fold increase in AhR protein levels. Tothis end, AIP2 decreases ubiquitinated forms of the AhR in transientoverexpression experiments. Treatment of AhR/chaperone complex in-vitro withgeldanamycin destabilises this complex such that p23 and XAP2 are lost from thecomplex. Thus supporting the idea that XAP2 is essential for the stability ofthe AhR/hsp90/p23 complex, preventing transient unmasking of the N-terminalnuclear localisation sequence within the AhR diminishing ligand independentnuclear accumulation.

Additionally, the presence of XAP2 in the latent chaperonecomplex protects the AhR from proteasome-mediated degradation, an observationindicative of a stable AhR–chaperone complex. SinceXAP2 interacts with both hsp90 and the AhR. it is likely that XAP2 acts as astabilising factor and the presence of XAP2 in this complex may denote a subsetof mature AhR–chaperone complexes. Recent evidence from Hepa-1 cells confirmsthat XAP2 functions to prevent nucleocytoplasmic shuttling, but that itsdepletion has no effect on ligand induced signalling in these cells (Pollenz etal. 2006).  Downstreammolecular targets of AhR signalling are versatile for example the drugmetabolising enzymes e.

g. CYP1A1 and CYP1A2, IL-Ib, Tgf’s, C-myc, EGFRs andBlimp1. Among the aforementioned targets of AhR, c-Myc and Blimp-1 supposedlyplay an important role in modulating directional differentiation of epidermalprogenitor cells and be a potential important target linkage between specificTCDD-induced skin pathology and the stem-cell differentiation changes in theskin.Activationof c-Myc favours differentiation along the lineages of the interfollicularepidermis and sebaceous gland, and it results in the appearance of groups ofdifferentiated sebocytes within the interfollicular epidermis. Inactivationof c-Myc results in hypoplasia of the sebaceous glands. Loss of Blimp1 resultsin the elevation of c-Myc expression and hyperplasia of the sebaceous glands.

45Taken together, TCCD/AhR/ARNT/Blimp1 and CYP1A1/c-Myc pathways may very likelybe the proposed signalling pathways of TCDD on skin stem cell progenitors, leadingto TCDD-induced abnormal differentiation of sebaceous gland. Treatment and conclusionKnowledgeand application of treatments are limited since the direct/combined mechanismsof TCDD toxicity remains unknown and tried methods have proved unsuccessful(Yip et al. 1993) although perhaps in the future, manipulation of AhRsignalling could be employed. Current options include self-resolution over timeand surgical removal of the comedones. Recently, a synthetic dietary fat substitute ‘Olestra’ has shown to havethe ability to bind to chloracnegens and accelerate their faecal excretion andindeed Geusau et al (1999) have showed that combining olestra and caloricrestriction causes a 30-fold increase in in rate of excretion of a labelledcompound, this may be a prospective therapeutic method in the future.

Inconclusion, much progress has been made regarding the biochemistry andfunctional role of AhR signalling in relation to dioxin toxicity however, a firmmechanism is yet to be elucidated, conversely, there may not be one singlepathological mechanism and rather AhR signalling is a multi-model system thatworks together to induce chloracne. 


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