92-87-5HFACYLZERDEVSX-UHFFFAOYSA-NHFACYLZERDEVSX-UHFFFAOYSA-N
C.I. Azoic Diazo Component 1124-(4-Aminophenyl)aniline
[1,1'-Biphenyl]-4,4'-diamine
(1,1'-Biphenyl)-4,4'-diamine
4,4'-Bianiline
4,4'-Biphenyldiamine
4,4'-Diamino-1,1'-biphenyl
4,4'-Diaminobiphenyl
4,4'-Diaminodiphenyl
4,4'-Diphenylenediamine
4'-Amino-[1,1'-biphenyl]-4-ylamine
bencidina
Benzidin
C.I. Azoic Diazo Component 112
Fast Corinth Base B
NSC 146476
p,p'-Bianiline
p,p'-Diaminobiphenyl
p-Diaminodiphenyl
UN 1885
DTXSID2020137262-12-4NFBOHOGPQUYFRF-UHFFFAOYSA-NNFBOHOGPQUYFRF-UHFFFAOYSA-N
Dibenzo-p-dioxinDibenzo[b,e][1,4]dioxin
Dibenzo[1,4]dioxin
dibenzo-p-dioxina
dibenzo-p-dioxinne
Diphenylene dioxide
Oxanthrene
Phenodioxin
DTXSID8020410118-74-1CKAPSXZOOQJIBF-UHFFFAOYSA-NCKAPSXZOOQJIBF-UHFFFAOYSA-N
Hexachlorobenzene(HCB
Benzene, hexachloro-
Anticarie
Benzene, 1,2,3,4,5,6-hexachloro-
Benzenehexachloride
Bunt-cure
Bunt-no-more
Co-op Hexa
Hexachlorbenzol
hexaclorobenceno
Julin's carbon chloride
No Bunt
No Bunt Liquid
NSC 9243
Pentachlorophenyl chloride
Perchlorobenzene
Sanocide
Snieciotox
UN 2729
Zaprawa nasienna sneciotox
1,2,3,4,5,6-Hexachloro-benzene
DTXSID2020682PR:000003858aryl hydrocarbon receptorGO:0004874aryl hydrocarbon receptor activity1increasedBenzidine2016-11-29T18:42:262016-11-29T18:42:26Dibenzo-p-dioxin2016-11-29T18:42:272016-11-29T18:42:27Polychlorinated biphenyl2016-11-29T18:42:272016-11-29T18:42:27Polychlorinated dibenzofurans2016-11-29T18:42:272016-11-29T18:42:27Hexachlorobenzene2016-11-29T18:42:272016-11-29T18:42:27Polycyclic aromatic hydrocarbons (PAHs)2017-02-09T15:43:002017-02-09T15:43:007955zebra danioWCS_9031Gallus gallus143350Pagrus major7904Acipenser transmontanus41871Acipenser fulvescensWCS_8022rainbow trout8030Salmo salarWCS_8355Xenopus laevis8296Ambystoma mexicanumWCS_9054Phasianus colchicusWCS_93934Coturnix japonica10090mouse10116ratWCS_9606human34823Microgadus tomcod9606Homo sapiensWCS_9606humansActivation, AhRActivation, AhRMolecular<h3>The AHR Receptor</h3>
<p>The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that belongs to the basic helix-loop-helix Per-ARNT-Sim (bHLH-PAS) superfamily and consists of three domains: the DNA-binding domain (DBD), ligand binding domain (LBD) and transactivation domain (TAD)<sup><a href="#cite_note-Okey2007-1">[1]</a></sup>. Other members of this superfamily include the AHR nuclear translocator (ARNT), which acts as a dimerization partner of the AHR <sup><a href="#cite_note-Hoffman1991-2">[2]</a></sup><sup><a href="#cite_note-Poland1976-3">[3]</a></sup>; Per, a circadian transcription factor; and Sim, the “single-minded” protein involved in neuronal development <sup><a href="#cite_note-Gu2000-4">[4]</a></sup><sup><a href="#cite_note-Kewley2004-5">[5]</a></sup>. This group of proteins shares a highly conserved PAS domain and is involved in the detection of and adaptation to environmental change<sup><a href="#cite_note-Gu2000-4">[4]</a></sup>.</p>
<p>Investigations of invertebrates possessing early homologs of the AhR suggest that the AhR evolutionarily functioned in regulation of the cell cycle, cellular proliferation and differentiation, and cell-to-cell communications (Hahn et al 2002). However, critical functions in angiogenesis, regulation of the immune system, neuronal processes, metabolism, development of the heart and other organ systems, and detoxification have emerged sometime in early vertebrate evolution (Duncan et al., 1998; Emmons et al., 1999; Lahvis and Bradfield, 1998).</p>
<h3>The molecular Initiating Event</h3>
<div>
<div><a class="image" href="/wiki/index.php/File:AHR_mechanism.jpeg"><img alt="" class="thumbimage" src="/wiki/images/thumb/6/6e/AHR_mechanism.jpeg/450px-AHR_mechanism.jpeg" style="height:331px; width:450px" /></a>
<div>Figure 1: The molecular mechanism of activation of gene expression by AHR.</div>
<div> </div>
</div>
</div>
<p>The molecular mechanism for AHR-mediated activation of gene expression is presented in Figure 1. In its unliganded form, the AHR is part of a cytosolic complex containing heat shock protein 90 (HSP90), the HSP90 co-chaperone p23 and AHR-interacting protein (AIP)<sup><a href="#cite_note-Fujii2010-6">[6]</a></sup>. Upon ligand binding, the AHR migrates to the nucleus where it dissociates from the cytosolic complex and forms a heterodimer with ARNT<sup><a href="#cite_note-Mimura2003-7">[7]</a></sup>. The AHR-ARNT complex then binds to a xenobiotic response element (XRE) found in the promoter of an AHR-regulated gene and recruits co-regulators such as CREB binding protein/p300, steroid receptor co-activator (SRC) 1, SRC-2, SRC-3 and nuclear receptor interacting protein 1, leading to induction or repression of gene expression<sup><a href="#cite_note-Fujii2010-6">[6]</a></sup>. Expression levels of several genes, including phase I (e.g. cytochrome P450 (CYP) 1A, CYP1B, CYP2A) and phase II enzymes (e.g. uridine diphosphate glucuronosyl transferase (UDP-GT), glutathione S-transferases (GSTs)), as well as genes involved in cell proliferation (transforming growth factor-beta, interleukin-1 beta), cell cycle regulation (p27, jun-B) and apoptosis (Bax), are regulated through this mechanism <sup><a href="#cite_note-Fujii2010-6">[6]</a></sup><sup><a href="#cite_note-Giesy2006-8">[8]</a></sup><sup><a href="#cite_note-Mimura2003-7">[7]</a></sup><sup><a href="#cite_note-Safe1994-9">[9]</a></sup>.</p>
<h3>AHR Isoforms</h3>
<ul>
<li>Over time the AhR has undergone gene duplication and diversification in vertebrates, which has resulted in multiple clades of AhR, namely AhR1, AhR2, and AhR3 (Hahn 2002).</li>
<li>Fishes and birds express AhR1s and AhR2s, while mammals express a single AhR that is homologous to the AhR1 (Hahn 2002; Hahn et al 2006).</li>
<li>The AhR3 is poorly understood and known only from some cartilaginous fishes (Hahn 2002).</li>
<li>Little is known about diversity of AhRs in reptiles and amphibians (Hahn et al 2002).</li>
<li>In some taxa, subsequent genome duplication events have further led to multiple isoforms of AhRs in some species, with up to four isoforms of the AhR (α, β, δ, γ) having been identified in Atlantic salmon (<em>Salmo salar</em>) (Hansson et al 2004).</li>
<li>Although homologs of the AhR have been identified in some invertebrates, compared to vertebrates these AhRs have differences in binding of ligands in the species investigated to date (Hahn 2002; Hahn et al 1994).</li>
</ul>
<p> </p>
<p>Roles of isoforms in birds:</p>
<p>Two AHR isoforms (AHR1 and AHR2) have been identified in the black-footed albatross (<em>Phoebastria nigripes</em>), great cormorant (<em>Phalacrocorax carbo</em>) and domestic chicken (<em>Gallus gallus domesticus</em>)<sup><a href="#cite_note-Yasui2007-10">[10]</a></sup>. AHR1 mRNA levels were similar in the kidney, heart, lung, spleen, brain, gonad and intestine from the great cormorant but were lower in muscle and pancreas. AHR2 expression was mainly observed in the liver, but was also detected in gonad, brain and intestine. AHR1 levels represented a greater proportion (80%) of total AHR levels than AHR2 in the cormorant liver<sup><a href="#cite_note-Yasui2007-10">[10]</a></sup>, and while both AHR isoforms bound to TCDD, AHR2 was less effective at inducing TCDD-dependent transactivation compared to AHR1 in black-footed albatross, great cormorant and domestic chicken<sup><a href="#cite_note-Lee2009-11">[11]</a></sup><sup><a href="#cite_note-Yasui2007-10">[10]</a></sup>.</p>
<ul>
<li>AhR1 and AhR2 both bind and are activated by TCDD <em>in vitro</em> (Yasui et al 2007).</li>
<li>AhR1 has greater binding affinity and sensitivity to activation by TCDD relative to AhR2 (Yasui et al 2007).</li>
<li>AhR1 is believed to mediate toxicities of DLCs, while AhR2 has no known role in toxicities (Farmahin et al 2012; Farmahin et al 2013; Manning et al 2012).</li>
</ul>
<p>Roles of isoforms in fishes:</p>
<ul>
<li>AhR1 and AhR2 both bind and are activated by TCDD <em>in vitro</em> (Bak et al 2013; Doering et al 2014; 2015; Karchner et al 1999; 2005).</li>
<li>AhR1 has greater sensitivity to activation by TCDD than AhR2 in red seabream (<em>Pagrus major</em>), white sturgeon (<em>Acipenser transmontanus</em>), and lake sturgeon (<em>Acipenser fulvescens</em>) (Bak et al 2013; Doering et al 2014; 2015)</li>
<li>AhR2 has greater binding affinity or activation by TCDD than AhR1 in zebrafish (<em>Danio rerio</em>) and mummichog (<em>Fundulus heteroclitus</em>) (Karchner et al 1999; 2005).</li>
<li>AhR2 is believed to mediate toxicities in fishes, while AhR1 has no known role in toxicities. Specifically, knockdown of AhR2 protects against toxicities of dioxin-like compounds (DLCs) and polycyclic aromatic hydrocarbons (PAHs) in zebrafish (<em>Danio rerio</em>) and mummichog (<em>Fundulus heteroclitus</em>), while knockdown of AhR1 offers no protection (Clark et al 2010; Prasch et al 2003; Van Tiem & Di Giulio 2011).</li>
</ul>
<p>Roles of isoforms in amphibians and reptiles:</p>
<ul>
<li>Less is known about AhRs of amphibians or reptiles.</li>
<li>AhR1 is believed to mediate toxicities in amphibians (Hahn 2002; Lavine et al 2005; Oka et al 2016; Shoots et al 2015). However, all AhRs of amphibians that have been investigated have very low affinity for TCDD (Hahn 2002; Lavine et al 2005; Oka et al 2016; Shoots et al 2015).</li>
<li>Both AhR1s and AhR2 of American alligator (<em>Alligator mississippiensis</em>) are activated by agonists with comparable sensitivities (Oka et al 2016). AhRs of no other reptiles have been investigated.</li>
</ul>
<p><em>Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible? </em></p>
<h3>Transactivation Reporter Gene Assays (recommended approach)</h3>
<h4>Transient transfection transactivation</h4>
<p>Transient transfection transactivation is the most common method for evaluating nuclear receptor activation<sup><a href="#cite_note-Raucy2010-12">[12]</a></sup>. Full-length AHR cDNAs are cloned into an expression vector along with a reporter gene construct (chimeric luciferase, P-lactamase or CAT reporter vectors containing the appropriate response elements for the gene of interest). There are a number of commercially available cell lines that can serve as recipients for these vectors (CV-1, HuH7, FLC-7, LS174T, LS180 MCF-7, HEC1, LLC-PK1, HEK293, HepG2, and Caco-2 cells)<sup><a href="#cite_note-Raucy2010-12">[12]</a></sup>. The greatest advantage of using transfected cells, rather than primary cell cultures, is the assurance that the nuclear receptor of interest is responsible for the observed induction. This would not be possible in a primary cell culture due to the co-regulation of different receptors for the same target genes. This model makes it easy to compare the responsiveness of the AHR across multiple species under the same conditions simply by switching out the AHR clone. One disadvantage to the transient transfection assay is the inherent variability associated with transfection efficiency, leading to a movement towards the use of stable cell lines containing the nuclear receptor and reporter gene linked to the appropriate response elements<sup><a href="#cite_note-Raucy2010-12">[12]</a></sup>.</p>
<h5>Luciferase reporter gene (LRG) assay</h5>
<p>The described luciferase reporter gene (LRG) assays have been used to investigate activation of AhRs of:</p>
<ul>
<li>Humans (<em>Homo sapiens</em>) (Abnet et al 1999) </li>
<li>Species of birds, namely chicken (<em>Gallus gallus</em>), ring-necked pheasant (<em>Phasianus colchicus</em>), Japanese quail (<em>Coturnix japonica</em>), and common tern (<em>Sterna hirundo</em>) (Farmahin et al 2012; Manning et al 2013), Mutant AhR1s with ligand binding domains resembling those of at least 86 avian species have also been investigated (Farmahin et al 2013). AhR2s of birds have only been investigated in black-footed albatross (<em>Phoebastria nigripes</em>) and common cormorant (<em>Phalacrocorax carbo</em>) (Yasio et al 2007).</li>
<li>American alligator (<em>Alligator mississippiensis</em>) is the only reptile for which AhR activation has been investigated (Oka et al 2016), AhR1A, AhR1B, and AhR2 of American alligator were assayed (Oka et al 2016).</li>
<li>AhR1 of two amphibians have been investigated, namely African clawed frog (<em>Xenopus laevis</em>) and salamander (<em>Ambystoma mexicanum</em>) (Lavine et al 2005; Shoots et al 2015; Ohi et al 2003),</li>
<li>AhR1s and AhR2s of several species of fish have been investigated, namely Atlantic salmon (<em>Salmo salar</em>), Atlantic tomcod (<em>Microgadus tomcod</em>), white sturgeon (<em>Acipenser transmontanus</em>), rainbow trout (<em>Onchorhynchys mykiss</em>), red seabream (<em>Pagrus major</em>), lake sturgeon (<em>Acipenser fulvescens</em>), and zebrafish (<em>Danio rerio</em>) (Andreasen et al 2002; Abnet et al 1999; Bak et al 2013; Doering et al 2014; 2015; Evans et al 2005; Hansson & Hahn 2008; Karchner et al 1999; Tanguay et al 1999; Wirgin et al 2011).</li>
</ul>
<p>For demonstrative purposes, a luciferase reporter gene assay used to measure AHR1-mediated transactivation for avian species is described here. However, comparable assays are utilized for investigating AHR1s and AHR2s of all taxa. A monkey kidney cell line (Cos-7) that has low endogenous AHR1 expression was transfected with the appropriate avian AHR1 clone, cormorant ARNT1, a CYP1A5 firefly luciferase reporter construct and a <em>Renilla</em> luciferase vector to control for transfection efficiency. After seeding, the cells were exposed to DLC and luciferase activity was measured using a luminometer. Luminescence, which is proportional to the extent of AHR activation, is expressed as the ratio of firefly luciferase units to <em>Renilla</em> luciferase units <sup><a href="#cite_note-Farmahin2012-13">[13]</a></sup>. This particular assay was modified from its original version to increase throughput efficiency; (a) cells were seeded in 96-well plates rather than Petri dishes or 48- well plates, (b) DLCs were added directly to the wells without changing the cell culture medium, and (c) the same 96-well plates were used to measure luminescence without lysing the cells and transferring to another plate. Similar reporter gene assays have been used to measure AHR1 activation in domestic and wild species of birds, including the chicken, ring-necked pheasant (Phasianus colchicus), Japanese quail (Coturnix japonica), great cormorant, black-footed albatross and peregrine falcon (Falco peregrinus).<sup><a href="#cite_note-Farmahin2013b-14">[14]</a></sup><sup><a href="#cite_note-Farmahin2012-13">[13]</a></sup><sup><a href="#cite_note-Fujisawa2012-15">[15]</a></sup><sup><a href="#cite_note-Lee2009-11">[11]</a></sup><sup><a href="#cite_note-Manning2012-16">[16]</a></sup><sup><a href="#cite_note-Mol2012-17">[17]</a></sup></p>
<h4>Transactivation in stable cell lines</h4>
<p>Stable cell lines have been developed and purified to the extent that each cell contains both the nuclear receptor and appropriate reporter vector, eliminating the variability associated with transfection <sup><a href="#cite_note-Raucy2010-12">[12]</a></sup>. A stable human cell line containing a luciferase reporter driven by multiple dioxin response elements has been developed that is useful in identifying AhR agonists and antagonists<sup><a href="#cite_note-Yueh2005-18">[18]</a></sup>. An added benefit of this model is the potential to multiplex 3 assays in a single well: receptor activation, cell viability and enzyme activity<sup><a href="#cite_note-Raucy2010-12">[12]</a></sup>. Such assays are used extensively in drug discovery due to their high throughput efficiency, and may serve just as useful for risk assessment purposes.</p>
<h3>Ligand-Binding Assays</h3>
<p>Ligand binding assays measure the ability of a test compound to compete with a labeled, high-affinity reference ligand for the LBD of a nuclear receptor. It is important to note that ligand binding does not necessitate receptor activation and therefore cannot distinguish between agonists and antagonists; however, binding affinities of AHR ligands are highly correlated with chemical potencies<sup><a href="#cite_note-Poland1982-19">[19]</a></sup> and can explain differences in species sensitivities to DLCs<sup><a href="#cite_note-Hesterman2000-20">[20]</a></sup><sup><a href="#cite_note-Farmahin2014-21">[21]</a></sup><sup><a href="#cite_note-Karchner2006-22">[22]</a></sup>; they are therefore worth mentioning. Binding affinity and efficacy have been used to develop structure-activity relationships for AHR disruption<sup><a href="#cite_note-Hesterman2000-20">[20]</a></sup><sup><a href="#cite_note-Lee2015-23">[23]</a></sup> that are potentially useful in risk-assessment. There has been tremendous progress in the development of ligand-binding assays for nuclear receptors that use homogenous assay formats (no wash steps) allowing for the detection of low-affinity ligands, many of which do not require a radiolabel and are amenable to high throughput screening<sup><a href="#cite_note-Jones2003-24">[24]</a></sup><sup><a href="#cite_note-Raucy2010-12">[12]</a></sup>. This author however was unable to find specific examples of such assays in the context of AHR binding and therefore some classic radioligand assays are described instead.</p>
<h4>Hydroxyapatite (HAP) binding assay</h4>
<p>The HAP binding assay makes use of an <em>in vitro</em> transcription/translation method to synthesize the AHR protein, which is then incubated with radiolabeled TDCPP and a HAP pellet. The occupied protein adsorbs to the HAP and the radioactivity is measured to determine saturation binding. An additional ligand can also be included in the mixture in order to determine its binding affinity relative to TCDD (competitive binding)<sup><a href="#cite_note-Gasiewicz1982-25">[25]</a></sup><sup><a href="#cite_note-Karchner2006-22">[22]</a></sup>. This assay is simple, repeatable and reproducible; however, it is insensitive to weak ligand-receptor interactions<sup><a href="#cite_note-Karchner2006-22">[22]</a></sup><sup><a href="#cite_note-Farmahin2014-21">[21]</a></sup><sup><a href="#cite_note-Nakai1995-26">[26]</a></sup>.</p>
<h4>Whole cell filtration binding assay</h4>
<p>Dold and Greenlee<sup><a href="#cite_note-Dold1990-27">[27]</a></sup> developed a method to detect specific binding of TCDD to whole mammalian cells in culture and was later modified by Farmahin et al.<sup><a href="#cite_note-Farmahin2014-21">[21]</a></sup> for avian species. The cultured cells are incubated with radiolabeled TCDD with or without the presence of a competing ligand and filtered. The occupied protein adsorbs onto the filter and the radioactivity is measured to determine saturation binging and/or competitive binding. This assay is able to detect weak ligand-receptor interactions that are below the detection limit of the HAP assay<sup><a href="#cite_note-Farmahin2014-21">[21]</a></sup>.</p>
<h3>Protein-DNA Interaction Assays</h3>
<p>The active AHR complexed with ARNT can be measured using protein-DNA interaction assays. Two methods are described in detail by Perez-Romero and Imperiale<sup><a href="#cite_note-Perez2007-28">[28]</a></sup>. Chromatin immunoprecipitation measures the interaction of proteins with specific genomic regions <em>in vivo</em>. It involves the treatment of cells with formaldehyde to crosslink neighboring protein-protein and protein-DNA molecules. Nuclear fractions are isolated, the genomic DNA is sheared, and nuclear lysates are used in immunoprecipitations with an antibody against the protein of interest. After reversal of the crosslinking, the associated DNA fragments are sequenced. Enrichment of specific DNA sequences represents regions on the genome that the protein of interest is associated with <em>in vivo</em>. Electrophoretic mobility shift assay (EMSA) provides a rapid method to study DNA-binding protein interactions in vitro. This relies on the fact that complexes of protein and DNA migrate through a nondenaturing polyacrylamide gel more slowly than free DNA fragments. The protein-DNA complex components are then identified with appropriate antibodies. The EMSA assay was found to be consistent with the LRG assay in chicken hepatoma cells dosed with dioxin-like compounds<sup><a href="#cite_note-Heid2001-29">[29]</a></sup>.</p>
<h3>In silico Approaches</h3>
<p>In silico homology modeling of the ligand binding domain of the AHR in combination with molecular docking simulations can provide valuable insight into the transactivation-potential of a diverse array of AHR ligands. Such models have been developed for multiple AHR isoforms and ligands (high/low affinity, endogenous and synthetic, agonists and antagonists), and can accurately predict ligand potency based on their structure and physicochemical properties (Bonati et al 2017; Hirano et al 2015; Sovadinova et al 2006).</p>
<p>The AHR structure has been shown to contribute to differences in species sensitivity to DLCs in several animal models. In 1976, a 10-fold difference was reported between two strains of mice (non-responsive DBA/2 mouse, and responsive C57BL/6 14 mouse) in CYP1A induction, lethality and teratogenicity following TCDD exposure<sup><a href="#cite_note-Poland1976-3">[3]</a></sup>. This difference in dioxin sensitivity was later attributed to a single nucleotide polymorphism at position 375 (the equivalent position of amino acid residue 380 in chicken) in the AHR LBD<sup><a href="#cite_note-Ema1994-30">[30]</a></sup><sup><a href="#cite_note-Poland1982-19">[19]</a></sup><sup><a href="#cite_note-Poland1994-31">[31]</a></sup>. Several other studies reported the importance of this amino acid in birds and mammals<sup><a href="#cite_note-Backlund2004-32">[32]</a></sup><sup><a href="#cite_note-Ema1994-30">[30]</a></sup><sup><a href="#cite_note-Karchner2006-22">[22]</a></sup><sup><a href="#cite_note-Murray2005-33">[33]</a></sup><sup><a href="#cite_note-Pandini2007-34">[34]</a></sup><sup><a href="#cite_note-Pandini2009-35">[35]</a></sup><sup><a href="#cite_note-Poland1994-31">[31]</a></sup><sup><a href="#cite_note-Ramadoss2004-36">[36]</a></sup>. It has also been shown that the amino acid at position 319 (equivalent to 324 in chicken) plays an important role in ligand-binding affinity to the AHR and transactivation ability of the AHR, due to its involvement in LBD cavity volume and its steric effect<sup><a href="#cite_note-Pandini2009-35">[35]</a></sup>. Mutation at position 319 in the mouse eliminated AHR DNA binding<sup><a href="#cite_note-Pandini2009-35">[35]</a></sup>.</p>
<p>The first study that attempted to elucidate the role of avian AHR1 domains and key amino acids within avian AHR1 in avian differential sensitivity was performed by Karchner <em>et al.</em><sup><a href="#cite_note-Karchner2006-22">[22]</a></sup>. Using chimeric AHR1 constructs combining three AHR1 domains (DBD, LBD and TAD) from the chicken (highly sensitive to DLC toxicity) and common tern (resistant to DLC toxicity), Karchner and colleagues<sup><a href="#cite_note-Karchner2006-22">[22]</a></sup>, showed that amino acid differences within the LBD were responsible for differences in TCDD sensitivity between the chicken and common tern. More specifically, the amino acid residues found at positions 324 and 380 in the AHR1 LBD were associated with differences in TCDD binding affinity and transactivation between the chicken (Ile324_Ser380) and common tern (Val324_Ala380) receptors<sup><a href="#cite_note-Karchner2006-22">[22]</a></sup>. Since the Karchner et al. (2006) study was conducted, the predicted AHR1 LBD amino acid sequences were been obtained for over 85 species of birds and 6 amino acid residues differed among species<sup><a href="#cite_note-Farmahin2013b-14">[14]</a></sup><sup><a href="#cite_note-Head2008-37">[37]</a></sup> . However, only the amino acids at positions 324 and 380 in the AHR1 LBD were associated with differences in DLC toxicity in ovo and AHR1-mediated gene expression in vitro<sup><a href="#cite_note-Farmahin2013b-14">[14]</a></sup><sup><a href="#cite_note-Head2008-37">[37]</a></sup><sup><a href="#cite_note-Manning2012-16">[16]</a></sup>. These results indicate that avian species can be divided into one of three AHR1 types based on the amino acids found at positions 324 and 380 of the AHR1 LBD: type 1 (Ile324_Ser380), type 2 (Ile324_Ala380) and type 3 (Val324_Ala380)<sup><a href="#cite_note-Farmahin2013b-14">[14]</a></sup><sup><a href="#cite_note-Head2008-37">[37]</a></sup><sup><a href="#cite_note-Manning2012-16">[16]</a></sup>.</p>
<ul>
<li>Little is known about differences in binding affinity of AhRs and how this relates to sensitivity in non-avian taxa.</li>
<li>Low binding affinity for DLCs of AhR1s of African clawed frog (<em>Xenopus laevis</em>) and axolotl (<em>Ambystoma mexicanum</em>) has been suggested as a mechanism for tolerance of these amphibians to DLCs (Lavine et al 2005; Shoots et al 2015).</li>
<li>Among reptiles, only AhRs of American alligator (<em>Alligator mississippiensis</em>) have been investigated and little is known about the sensitivity of American alligator or other reptiles to DLCs (Oka et al 2016).</li>
<li>Among fishes, great differences in sensitivity to DLCs are known both for AhRs and for embryos among species that have been tested (Doering et al 2013; 2014).</li>
<li>Differences in binding affinity of the AhR2 have been demonstrated to explain differences in sensitivity to DLCs between sensitive and tolerant populations of Atlantic Tomcod (<em>Microgadus tomcod</em>) (Wirgin et al 2011).
<ul>
<li>This was attributed to the rapid evolution of populations in highly contaminated areas of the Hudson River, resulting in a 6-base pair deletion in the AHR sequence (outside the LBD) and reduced ligand binding affinity, due to reduces AHR protein stability.</li>
</ul>
</li>
<li>Information is not yet available regarding whether differences in binding affinity of AhRs of fishes are predictive of differences in sensitivity of embryos, juveniles, or adults (Doering et al 2013).</li>
</ul>
<p><span style="font-size:12pt"><span style="font-family:"Times New Roman",serif">The AhR is a very conserved and ancient protein (95) and the AhR is present in human and mice (96–98). </span></span><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">The AhR is present in human physiology and pathology. T</span></span><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">he AhR is highly expressed at several important physiological barriers such as the placenta, lung, gastrointestinal system, and liver in human (Wakx, Marinelli, Watanabe). In these tissues, the AhR is involved in both detoxication processes involving xenobiotic metabolizing enzymes such as cytochromes P450, and in immune functions translating chemical signals into immune defence pathways (Marinelli, Stobbe). Moreover, it has a regulatory role in human dendritic cells and myelination (Kado, Shackleford).</span></span> <span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">The lung constitutes another barrier exposed to components of air pollution such as particles and hydrocarbons (air pollution, cigarette smoke). The AhR detects such hydrocarbons and protects the pulmonary cells from their deleterious effects through metabolization.</span></span> <span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">The regulatory effect on blood cells of the AhR, balancing different related cell types, can be extended to the megakaryocytes and their precursors; indeed, StemRegenin 1 (SR1), an antagonist of the AhR increases the human population of CD34+CD41low cells, a fraction of very efficient precursors of proplatelets (Bock).</span></span> <span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">The occurrence of a nystagmus has been subsequently diagnosed in humans bearing a AhR mutation (Borovok).</span></span></span></span></p>
<p><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">In human cancer, the AhR has either a pro or con tumor effect depending on the tissue, the ligand, and the duration of the activation (Zudaire, Chang, Litzenburg, Gramatzki, Lin, Wang). In human breast cancer, the AhR is thoughts to be responsible of its progression (Goode, Kanno, Optiz, Novikov, Hall, </span></span><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Subramaniam, Barhoover</span></span><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">). </span></span><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">In human mammary benign cells, Brooks et al. noted that a high level of AhR was associated with a modified cell cycle (with a 50% increase in population doubling time in cells expressing the AhR by more than 3-fold) and EMT including increased cell migration. Narasimnhan et al. found that suppression of the AhR pathway had a pro-tumorigenic effect in vitro (EMT, tumor migration) in triple negative breast cancer.</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Many endogenous and exogenous ligands are present for the AhR in human (Optiz, Adachi, Schroeder, </span></span><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Rothhammer</span></span><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">). </span></span><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Indoles, such as indole-3-carbinol or one of its secondary metabolites, 3-3'- Diindolylmethane, are degradation products found in cruciferous vegetables and characterized as AhR ligands (Ema, Kall, Miller) they are also inducers of the human and rat CYP1A1 (Optiz). FICZ is the most potent AhR ligand known to date: it has a stronger affinity than TCDD for the human AhR (TCDD Kd=0.48 nM/FICZ Kd=0.07 nM) (Coumoul).</span></span></span></span></p>
<p> </p>
<p> </p>
HighUnspecificHighEmbryoHighDevelopmentHighAll life stagesHighHighHighHighHighHighHighHighHighHighHighHighHighHighHighNot Specified<ol>
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<li>↑ <sup><a href="#cite_ref-Manning2012_16-0">16.0</a></sup> <sup><a href="#cite_ref-Manning2012_16-1">16.1</a></sup> <sup><a href="#cite_ref-Manning2012_16-2">16.2</a></sup> Manning, G. E., Farmahin, R., Crump, D., Jones, S. P., Klein, J., Konstantinov, A., Potter, D., and Kennedy, S. W. (2012). A luciferase reporter gene assay and aryl hydrocarbon receptor 1 genotype predict the embryolethality of polychlorinated biphenyls in avian species. Toxicol.Appl.Pharmacol. 263, 390-399.</li>
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<li>↑ <sup><a href="#cite_ref-Hesterman2000_20-0">20.0</a></sup> <sup><a href="#cite_ref-Hesterman2000_20-1">20.1</a></sup> Hestermann, E. V., Stegeman, J. J., and Hahn, M. E. (2000). Relative contributions of affinity and intrinsic efficacy to aryl hydrocarbon receptor ligand potency. <em>Toxicol. Appl. Pharmacol </em> <strong>168</strong> (2), 160-172.</li>
<li>↑ <sup><a href="#cite_ref-Farmahin2014_21-0">21.0</a></sup> <sup><a href="#cite_ref-Farmahin2014_21-1">21.1</a></sup> <sup><a href="#cite_ref-Farmahin2014_21-2">21.2</a></sup> <sup><a href="#cite_ref-Farmahin2014_21-3">21.3</a></sup> <sup><a href="#cite_ref-Farmahin2014_21-4">21.4</a></sup> Farmahin, R., Jones, S. P., Crump, D., Hahn, M. E., Giesy, J. P., Zwiernik, M. J., Bursian, S. J., and Kennedy, S. W. (2014). Species-specific relative AHR1 binding affinities of 2,3,4,7,8-pentachlorodibenzofuran explain avian species differences in its relative potency. <em>Comp Biochem. Physiol C. Toxicol. Pharmacol.</em> <strong>161C</strong>, 21-25.</li>
<li>↑ <sup><a href="#cite_ref-Karchner2006_22-0">22.0</a></sup> <sup><a href="#cite_ref-Karchner2006_22-1">22.1</a></sup> <sup><a href="#cite_ref-Karchner2006_22-2">22.2</a></sup> <sup><a href="#cite_ref-Karchner2006_22-3">22.3</a></sup> <sup><a href="#cite_ref-Karchner2006_22-4">22.4</a></sup> <sup><a href="#cite_ref-Karchner2006_22-5">22.5</a></sup> <sup><a href="#cite_ref-Karchner2006_22-6">22.6</a></sup> Karchner, S. I., Franks, D. G., Kennedy, S. W., and Hahn, M. E. (2006). The molecular basis for differential dioxin sensitivity in birds: Role of the aryl hydrocarbon receptor. <em>Proc. Natl. Acad. Sci. U. S. A</em> <strong>103</strong> (16), 6252-6257.</li>
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<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, et al. 2011. An endogenous tumour promoting ligand of the human aryl hydrocarbon receptor. Nature. 478(7368):197–203</span></span></span></span></p>
<p style="text-align:justify"> </p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Novikov O, Wang Z, Stanford EA, Parks AJ, Ramirez-Cardenas A, et al. 2016. An Aryl Hydrocarbon Receptor-Mediated Amplification Loop That Enforces Cell Migration in ER-/PR-/Her2- Human Breast Cancer Cells. Mol Pharmacol. 90(5):674–88</span></span></span></span></p>
<p style="text-align:justify"> </p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Litzenburger UM, Opitz CA, Sahm F, Rauschenbach KJ, Trump S, et al. 2014. Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR. Oncotarget. 5(4):1038–51</span></span></span></span></p>
<p style="text-align:justify"> </p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Hall JM, Barhoover MA, Kazmin D, McDonnell DP, Greenlee WF, Thomas RS. 2010. Activation of the aryl-hydrocarbon receptor inhibits invasive and metastatic features of human breast cancer cells and promotes breast cancer cell differentiation. Mol Endocrinol. 24(2):359–69</span></span></span></span></p>
<p style="text-align:justify"> </p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Gramatzki D, Pantazis G, Schittenhelm J, Tabatabai G, K.hle C, et al. 2009. </span></span><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Aryl hydrocarbon receptor inhibition downregulates the TGF-beta/Smad pathway in human glioblastoma cells. Oncogene. 28(28):2593–2605</span></span></span></span></p>
<p style="text-align:justify"> </p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Subramaniam V, Ace O, Prud’homme GJ, Jothy S. 2011. Tranilast treatment decreases cell growth, migration and inhibits colony formation of human breast cancer cells. Exp Mol Pathol. 90(1):116–22</span></span></span></span></p>
<p style="text-align:justify"> </p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Rothhammer V, Borucki DM, Kenison JE, Hewson P, Wang Z, et al. 2018. Detection of aryl hydrocarbon receptor agonists in human samples. Sci Rep. 8(1):4970</span></span></span></span></p>
<p style="text-align:justify"> </p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Lin P, Chang H, Tsai W-T, Wu M-H, Liao Y-S, et al. 2003. </span></span><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Overexpression of aryl hydrocarbon receptor in human lung carcinomas. Toxicol Pathol. 31(1):22–30</span></span></span></span></p>
<p style="text-align:justify"> </p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Barhoover MA, Hall JM, Greenlee WF, Thomas RS. 2010. Aryl hydrocarbon receptor regulates cell cycle progression in human breast cancer cells via a functional interaction with cyclin-dependent kinase 4. Mol Pharmacol. 77(2):195–201</span></span></span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"> </span></span></p>
<p style="text-align:justify"><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Wang K, Li Y, Jiang Y-Z, Dai C-F, Patankar MS, et al. 2013. </span></span><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">An endogenous aryl hydrocarbon receptor ligand inhibits proliferation and migration of human ovarian cancer cells. Cancer Lett. 340(1):63–71</span></span></span></span></p>
<p style="text-align:justify"> </p>
<p><span style="font-size:12pt"><span style="font-family:Aptos,sans-serif"><span style="font-size:10.0pt"><span style="font-family:"Times New Roman",serif">Borovok N, Weiss C, Sharkia R, Reichenstein M, Wissinger B, et al. 2020. Gene and Protein Expression in Subjects With a Nystagmus-Associated AHR Mutation. Front Genet. 11:582796</span></span></span></span></p>
2016-11-29T18:41:222024-02-28T05:12:53Altered gene expression, NF-kB dependent Interleukin-6 pathwayAltered expression of IL-6 pathway-dependent genesMolecular2021-08-19T01:14:242021-08-19T07:30:37Induction, Epithelial Mesenchymal TransitionEMTCellular<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Process:transition of epithelial cells to mesenchymal Object: epithelial cells </span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"> Action:increased</span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Process:transition of epithelial cells to mesenchymal Object: epithelial cells </span></span></p>
<p><span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"> Action:increased</span></span></p>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="color:black">Biological state</span></strong></span></span></p>
<p> </p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">An epithelial-mesenchymal transition (EMT) is a biologic process in which epithelial cells are polarized, interact through their basal surface with basement membrane, and undergo biochemical changes to assume a mesenchymal cell phenotype. </span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">This phenotypic transformation has various characters such as enhanced migratory capacity, high invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components (Kalluri, R., and Neilson, E.G. 2003). The completion of an EMT is signalled by the degradation of the underlying basement membrane and the formation of a mesenchymal cell that can migrate away from the epithelial layer in which it originated.</span></span></span></p>
<p> </p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black"> EMT has a number of distinct molecular processes like activation of transcription factors, expression of specific cell surface proteins, reorganization and expression of cytoskeletal proteins, production of ECM-degrading enzymes, and changes in the expression of specific microRNAs. These factors are used as biomarkers to demonstrate the passage of a cell through an EMT. </span></span></span></p>
<p> </p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="color:black">Biological compartment </span></strong></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Cellular</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><strong><span style="color:black">Role in General Biology:</span></strong></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">Excessive proliferation of epithelial cells and angiogenesis mark the initiation and early growth of primary epithelial cancers. (Hanahan, D., and Weinberg, R.A. 2000). The subsequent acquisition of invasiveness, initially manifest by invasion through the basement membrane, is thought to herald the onset of the last stages of the multi-step process that leads eventually to metastatic dissemination, with life-threatening consequences. There has been an intense research going on in the genetic controls and biochemical mechanisms underlying the acquisition of the invasive phenotype and the subsequent systemic spread of the cancer cell. Activation of an EMT program has been proposed as the critical mechanism for the acquisition of malignant phenotypes by epithelial cancer cells (Thiery, J.P. 2002).</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black"> Pre-clinical experiments such as mice models and cell culture experiments has demonstrated that carcinoma cells can acquire a mesenchymal phenotype and express mesenchymal markers such as </span><span style="color:black">α</span><span style="color:black">-SMA, FSP1, vimentin, and desmin (Yang, J., and Weinberg, R.A. 2008). These cells are seen at the invasive front of primary tumors and are considered to be the cells that eventually enter into subsequent steps of the invasion-metastasis cascade, i.e., intravasation, transport through the circulation, extravasation, formation of micro metastases, and ultimately colonization (the growth of small colonies into macroscopic metastases) (Thiery, J.P. 2002, Fidler, I.J., and Poste, G. 2008, Brabletz, T., et al. 2001).</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">An apparent paradox comes from the observation that the EMT-derived migratory cancer cells typically establish secondary colonies at distant sites that resemble, at the histopathological level, the primary tumor from which they arose; accordingly, they no longer exhibit the mesenchymal phenotypes ascribed to metastasizing carcinoma cells. Reconciling this behaviour with the proposed role of EMT as a facilitator of metastatic dissemination requires the additional notion that metastasizing cancer cells must shed their mesenchymal phenotype via a MET during the course of secondary tumor formation (Zeisberg, M et al 2005). The tendency of disseminated cancer cells to undergo EMT likely reflects the local microenvironments that they encounter after extravasation into the parenchyma of a distant organ, quite possibly the absence of the heterotypic signals they experienced in the primary tumor that were responsible for inducing the EMT in the first place (Thiery, J.P. 2002, Jechlinger, M et al 2002, Bissell, M.J et al 2002). These evidences indicate that induction of an EMT is likely to be a centrally important mechanism for the progression of carcinomas to a metastatic stage and implicates MET during the subsequent colonization process. However, many steps of this mechanistic model still require direct experimental validation. It remains unclear at present whether these phenomena and molecular mechanisms relate to and explain the metastatic dissemination of non-epithelial cancer cells.</span></span></span></p>
<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="color:black">The entire spectrum of signaling agents that contribute to EMTs of carcinoma cells remains unclear. One theory suggests that the genetic and epigenetic alterations undergone by cancer cells during the course of primary tumor formation render them especially responsive to EMT-inducing heterotypic signals originating in the tumor-associated stroma. Oncogenes induce senescence, and recent studies suggest that cancer cell EMTs may also play a role in preventing senescence induced by oncogenes, thereby facilitating subsequent aggressive dissemination (Smit, M.A., and Peeper, D.S. 2008, Ansieau, S., et al. 2008, Weinberg, R.A. 2008). In the case of many carcinomas, EMT-inducing signals emanating from the tumor-associated stroma, notably HGF, EGF, PDGF, and TGF-</span><span style="color:black">β</span><span style="color:black">, appear to be responsible for the induction or functional activation in cancer cells of a series of EMT-inducing transcription factors, notably Snail, Slug, zinc finger E-box binding homeobox 1 (ZEB1), Twist, Goosecoid, and FOXC2 (Thiery, J.P. 2002, Jechlinger, M et al 2002, Shi, Y., and Massague, J. 2003, Niessen, K., et al. 2008, Medici, D et al 2008, Kokudo, T., et al. 2008). Once expressed and activated, each of these transcription factors can act pleiotropically to choreograph the complex EMT program, more often than not with the help of other members of this cohort of transcription factors. The actual implementation by these cells of their EMT program depends on a series of intracellular signaling networks involving, among other signal- transducing proteins, ERK, MAPK, PI3K, Akt, Smads, RhoB, </span><span style="color:black">β</span><span style="color:black">-catenin, lymphoid enhancer binding factor (LEF), Ras, and c-Fos as well as cell surface proteins such as </span><span style="color:black">β</span><span style="color:black">4 integrins, </span><span style="color:black">α</span><span style="color:black">5</span><span style="color:black">β</span><span style="color:black">1 integrin, and </span><span style="color:black">α</span><span style="color:black">V</span><span style="color:black">β</span><span style="color:black">6 integrin (Tse, J.C., and Kalluri, R. 2007). Activation of EMT programs is also facilitated by the disruption of cell-cell adherens junctions and the cell-ECM adhesions mediated by integrins (Yang, J., and Weinberg, R.A. 2008, Weinberg, R.A. 2008, Gupta, P.B et al 2005, Yang, J et al 2006, Mani, S.A., et al. 2007, Mani, S.A., et al. 2008, Hartwell, K.A., et al. 2006, Taki, M et al 2006)..</span></span></span></p>
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<p>Loss of <a href="https://en.wikipedia.org/wiki/E-cadherin">E-cadherin</a> and cell polarity is considered to be a fundamental event in epithelial-mesenchymal transition. The simultaneous expression of epithelial (e.g. E-cadherin) and mesenchymal markers (e.g. N-cadherin and vimentin) within the airway epithelium are indicative for ongoing transition (Borthwick et al. 2009, 2010).</p>
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<p style="text-align:justify"> </p>
</td>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Method/ measurement referenc</span></span></p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Reliability</span></span></p>
<p style="text-align:justify"> </p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Strength of evidence</span></span></p>
<p style="text-align:justify"> </p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Assay fit for purpose</span></span></p>
<p style="text-align:justify"> </p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Repeatability/ reproducibility</span></span></p>
<p style="text-align:justify"> </p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Direct measure</span></span></p>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Human cell line</span></span></p>
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<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:155px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">qRT-PCR,cell viability assay,</span></span></p>
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Western blotting,EdU incorporation assay</span></span></p>
</td>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">+</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Strong</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:67px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
</td>
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<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Human</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:155px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">IHC,micro array,qPCR, SNP array</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:73px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">+</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:68px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Moderate</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:63px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:102px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes</span></span></p>
</td>
<td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:67px">
<p style="text-align:justify"><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Yes </span></span></p>
</td>
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<p><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif">Regulation of miRNA expression by DNA replication,damage and repair responses,transcription and translation has been proved in animals like mice,canine and cell line experiments.</span></span></p>
Not SpecifiedUnspecificNot SpecifiedNot Otherwise SpecifiedHigh<p>Borthwick, L. A., Parker, S. M., Brougham, K. A., Johnson, G. E., Gorowiec, M. R., Ward, C., … Fisher, A. J. (2009). Epithelial to mesenchymal transition (EMT) and airway remodelling after human lung transplantation. <em>Thorax</em>, <em>64</em>(9), 770–777. <a href="https://doi.org/10.1136/thx.2008.104133"><u>https://doi.org/10.1136/thx.2008.104133</u></a></p>
<p>Borthwick, L. A., McIlroy, E. I., Gorowiec, M. R., Brodlie, M., Johnson, G. E., Ward, C., … Fisher, A. J. (2010). Inflammation and epithelial to mesenchymal transition in lung transplant recipients: Role in dysregulated epithelial wound repair. <em>American Journal of Transplantation</em>, <em>10</em>(3), 498–509. <a href="https://doi.org/10.1111/j.1600-6143.2009.02953.x"><u>https://doi.org/10.1111/j.1600-6143.2009.02953.x</u></a></p>
<p>Al Saleh, S., Al Mulla, F., & Luqmani, Y. A. (2011). Estrogen receptor silencing induces epithelial to mesenchymal transition in human breast cancer cells. PloS one, 6(6), e20610.</p>
<p>Bissell, M. J., Radisky, D. C., Rizki, A., Weaver, V. M., & Petersen, O. W. (2002). The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation, 70(9-10), 537-546.</p>
<p>Bouris, P., Skandalis, S. S., Piperigkou, Z., Afratis, N., Karamanou, K., Aletras, A. J., ... & Karamanos, N. K. (2015). Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells. Matrix Biology, 43, 42-60.</p>
<p> Brabletz, T., Jung, A., Reu, S., Porzner, M., Hlubek, F., Kunz-Schughart, L. A., ... & Kirchner, T. (2001). Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proceedings of the National Academy of Sciences, 98(18), 10356-10361.</p>
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<p>idler, I. J., & Poste, G. (2008). The “seed and soil” hypothesis revisited. The lancet oncology, 9(8), 808.</p>
<p>Gupta, P. B., Mani, S., Yang, J., Hartwell, K., & Weinberg, R. A. (2005, January). The evolving portrait of cancer metastasis. In Cold Spring Harbor symposia on quantitative biology (Vol. 70, pp. 291-297). Cold Spring Harbor Laboratory Press.</p>
<p>Hanahan, D., and Weinberg, R.A. (2000). The hall- marks of cancer. Cell. 100:57–70.</p>
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Lin, H. Y., Liang, Y. K., Dou, X. W., Chen, C. F., Wei, X. L., Zeng, D., ... & Zhang, G. J. (2018). Notch3 inhibits epithelial–mesenchymal transition in breast cancer via a novel mechanism, upregulation of GATA-3 expression. Oncogenesis, 7(8), 1-15.</p>
<p>Liu, Y., Liu, R., Fu, P., Du, F., Hong, Y., Yao, M., ... & Zheng, S. (2015). N1-Guanyl-1, 7-diaminoheptane sensitizes estrogen receptor negative breast cancer cells to doxorubicin by preventing epithelial-mesenchymal transition through inhibition of eukaryotic translation initiation factor 5A2 activation. Cellular Physiology and Biochemistry, 36(6), 2494-2503.</p>
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<p>Niessen, K., Fu, Y., Chang, L., Hoodless, P. A., McFadden, D., & Karsan, A. (2008). Slug is a direct Notch target required for initiation of cardiac cushion cellularization. The Journal of cell biology, 182(2), 315-325.</p>
<p>Shi, Y., & Massagué, J. (2003). Mechanisms of TGF-β signaling from cell membrane to the nucleus. cell, 113(6), 685-700.</p>
<p>Smit, M. A., & Peeper, D. S. (2008). Deregulating EMT and senescence: double impact by a single twist. Cancer cell, 14(1), 5-7.</p>
<p>Taki, M., Verschueren, K., Yokoyama, K., Nagayama, M., & Kamata, N. (2006). Involvement of Ets-1 transcription factor in inducing matrix metalloproteinase-2 expression by epithelial-mesenchymal transition in human squamous carcinoma cells. International journal of oncology, 28(2), 487-496.</p>
<p>Thiery, J. P. (2002). Epithelial–mesenchymal transitions in tumour progression. Nature reviews cancer, 2(6), 442-454.</p>
<p>Tse, J. C., & Kalluri, R. (2007). Mechanisms of metastasis: epithelial‐to‐mesenchymal transition and contribution of tumor microenvironment. Journal of cellular biochemistry, 101(4), 816-829.</p>
<p>Weinberg, R. A. (2008). Twisted epithelial–mesenchymal transition blocks senescence. Nature cell biology, 10(9), 1021-1023.</p>
<p>Wik, E., Ræder, M. B., Krakstad, C., Trovik, J., Birkeland, E., Hoivik, E. A., ... & Salvesen, H. B. (2013). Lack of estrogen receptor-α is associated with epithelial–mesenchymal transition and PI3K alterations in endometrial carcinoma. Clinical Cancer Research, 19(5), 1094-1105.</p>
<p>Yang, J., & Weinberg, R. A. (2008). Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Developmental cell, 14(6), 818-829.</p>
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<p>Ye, Y., Xiao, Y., Wang, W., Yearsley, K., Gao, J. X., Shetuni, B., & Barsky, S. H. (2010). ERα signaling through slug regulates E-cadherin and EMT. Oncogene, 29(10), 1451-1462.</p>
<p>Zeisberg, M., Shah, A. A., & Kalluri, R. (2005). Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. Journal of Biological Chemistry, 280(9), 8094-8100.</p>
<p>Zeng, Q., Zhang, P., Wu, Z., Xue, P., Lu, D., Ye, Z., ... & Yan, X. (2014). Quantitative proteomics reveals ER-α involvement in CD146-induced epithelial-mesenchymal transition in breast cancer cells. Journal of proteomics, 103, 153-169. <br />
</p>
<p> </p>
<ul>
<li><span style="font-size:11pt"><span style="font-family:Calibri,sans-serif"><span style="font-size:10.0pt"><span style="background-color:white"><span style="font-family:"Arial",sans-serif"><span style="color:#222222">Zeng, Q., Zhang, P., Wu, Z., Xue, P., Lu, D., Ye, Z., ... & Yan, X. (2014). Quantitative proteomics reveals ER-α involvement in CD146-induced epithelial-mesenchymal transition in breast cancer cells. <em>Journal of proteomics</em>, <em>103</em>, 153-169.</span></span></span></span> </span></span></li>
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2017-07-26T19:11:332023-08-27T07:39:03Increased, extracellular matrix depositionIncreased extracellular matrix depositionTissue<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">ECM is a macromolecular structure that provides physical support to tissues and is essential for organ function. The composition of ECM is tissue specific and consists mainly of fibrous proteins, glycoproteins, and proteoglycans. The ECM in lung is compartmentalised to basement membrane and the interstitial space. Fibroblasts found in the interstitial space are the main sources of ECM in lung (White, 2015). Altered composition of ECM is observed in several lung diseases of inflammatory origin in humans including chronic obstructive pulmonary disease, asthma and idiopathic lung fibrosis. The composition and architecture of the ECM determines 1) the open sites of attachment that are available to cells, 2) the mechanical properties of the ECM and 3) the mechanical loading (breathing) experienced by the cells. Thus, changes in the ECM composition during the exaggerated wound healing process determines if an organism commits to fibrotic process or completes the wound healing (<span style="color:red">Blaauboer et al., 2014</span>).</span></span></p>
<p><strong><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><em><span style="color:red">Evidence for its perturbation in the context of pulmonary fibrosis:</span></em></span></span></strong></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">In lung fibrosis, an exaggerated amount of ECM is distributed in the alveolar parenchyma in a non-heterogenous manner, leading to lower spirometry readings implying occlusion of alveolar regions and reduced gas exchange. Collagen 1 and Collagen III are suggested to be the main components of the ECM in the thickened alveolar septa in fibrosis with other constituents such as fibronectin, elastin and tenacin C (Zhang et al., 1994; Hinz, 2006; Kuhn & McDonald, 1991; Crabb et al., 2006; Bensadoun et al., 1996; Klingberg et al., 2012; McKleroy et al., 2013). It is suggested that ECM composition dramatically changes during the fibrotic process. The early fibrotic process is characterised by collagen III deposition and collagen 1 predominates the later stages of the fibrosis. Excessive collagen production by myofibroblasts is necessary for the development of fibrosis (scarred tissue), with established areas of scar formation containing almost exclusively Type I collagen (Bateman et al., 1981; McKleroy et al., 2013; Zhang et al., 1994). Studies have demonstrated that while total collagen increases in IPF, there is also a shift toward the less elastic type I collagen, which contributes to the stiffness of the scar tissue within the lung (Nimni, 1983; Rozin et al., 2005; McKleroy et al., 2013).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">The fibrotic ECM contains characteristic accumulation of fibroblasts and myofibroblasts, which are the major contributors of ECM synthesised. The proliferation of fibroblasts and their differentiation into myofibroblasts is, in turn, guided by the composition and structure of the ECM. For example, <span style="color:red">s</span>tudies have demonstrated that cytokines secreted in response to inflammation are capable of activating fibroblasts, and that these changes could cause alterations in the fibroblasts that lead to excessive proliferation and ECM deposition (Sivakumar et al., 2012; Wynn, 2011).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong><em><span style="color:red">qRT-PCR, Immunosorbant assays, and immunohistochemistry:</span></em></strong></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">The qRT-PCR, ELISA, and immunohistochemistry are routinely used to assess the levels of protein and mRNA levels. The various genes and proteins that are assessed include, collagen I, collagen III, elastin and tenacin C. Histological staining with stains such as Masson Trichrome, Picro-sirius red are used to identify the tissue/cellular distribution of collagen, which can be quantified using morphometric analysis both in vivo and in vitro. The assays are routinely used and are quantitative.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong><em>Sircol Collagen Assay for collagen quantification:</em></strong></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">The Serius dye has been used for many decades to detect collagen in histology samples. The Serius Red F3BA selectively binds to collagen and the signal can be read at 540 nm (Chen & Raghunath, 2009; Nikota et al., 2017).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong><em>Hydroxyproline assay:</em></strong></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Hydroxyproline is a non-proteinogenic amino acid formed by the prolyl-4-hydroxylase. Hydroxyproline is only found in collagen and thus, it serves as a direct measure of the amount of collagen present in cells or tissues. Colorimetric methods are readily available and have been extensively used to quantify collagen using this assay (Chen & Raghunath, 2009; Nikota et al., 2017).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><strong><em><span style="color:red">Ex vivo and in vitro models of ECM deposition:</span></em></strong></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><span style="color:red">No models currently exist which allow for in vitro assessment of ECM deposition. Using single, or co-cultures containing fibroblasts, the production of soluble ECM components can be assessed after exposure to a stressor of interest using either ELISA or qRT-PCR experiments as a proxy. </span></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">1. Bateman, E., Turner-Warwick, M. and Adelmann-Grill, B. (1981). Immunohistochemical study of collagen types in human foetal lung and fibrotic lung disease. Thorax, 36(9), pp.645-653.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">2. Bensadoun, E., Burke, A., Hogg, J. and Roberts, C. (1996). Proteoglycan deposition in pulmonary fibrosis. American Journal of Respiratory and Critical Care Medicine, 154(6), pp.1819-1828.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">3. Blaauboer M et al. Extracellular matrix proteins: A positive feedback loop in lung fibrosis. Matrix Biology, 2014, 34, 170-178</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">4. Chen, C. and Raghunath, M. (2009). Focus on collagen: in vitro systems to study fibrogenesis and antifibrosis _ state of the art. Fibrogenesis & Tissue Repair, 2(1).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">5. Crabb, R., Chau, E., Decoteau, D. and Hubel, A. (2006). Microstructural Characteristics of Extracellular Matrix Produced by Stromal Fibroblasts. Annals of Biomedical Engineering, 34(10), pp.1615-1627.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">6. HINZ, B. (2006). Masters and servants of the force: The role of matrix adhesions in myofibroblast force perception and transmission. European Journal of Cell Biology, 85(3-4), pp.175-181.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">7. Kuhn C, McDonald JA. The roles of the myofibroblast in idiopathic pulmonary fibrosis. Ultrastructural and immunohistochemical features of sites of active extracellular matrix synthesis. Am J Pathol. 1991;138(5):1257–1265.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">8. Klingberg, F., Hinz, B. and White, E. (2012). The myofibroblast matrix: implications for tissue repair and fibrosis. The Journal of Pathology, 229(2), pp.298-309.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">9. McKleroy, W., Lee, T. and Atabai, K. (2013). Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis. American Journal of Physiology-Lung Cellular and Molecular Physiology, 304(11), pp.L709-L721.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">10. Nikota, J., Banville, A., Goodwin, L., Wu, D., Williams, A., Yauk, C., Wallin, H., Vogel, U. and Halappanavar, S. (2017). Stat-6 signaling pathway and not Interleukin-1 mediates multi-walled carbon nanotube-induced lung fibrosis in mice: insights from an adverse outcome pathway framework. Particle and Fibre Toxicology, 14(1).</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">11. Nimni, M. (1983). Collagen: Structure, function, and metabolism in normal and fibrotic tissues. Seminars in Arthritis and Rheumatism, 13(1), pp.1-86.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">12. Rozin, G., Gomes, M., Parra, E., Kairalla, R., de Carvalho, C. and Capelozzi, V. (2005). Collagen and elastic system in the remodelling process of major types of idiopathic interstitial pneumonias (IIP). Histopathology, 46(4), pp.413-421.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">13. Sivakumar, P., Ntolios, P., Jenkins, G. and Laurent, G. (2012). Into the matrix. Current Opinion in Pulmonary Medicine, 18(5), pp.462-469.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">14. White, E. (2015). Lung Extracellular Matrix and Fibroblast Function. Annals of the American Thoracic Society, 12(Supplement 1), pp.S30- S33. </span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">15. Wynn, T. (2011). Integrating mechanisms of pulmonary fibrosis. The Journal of Experimental Medicine, 208(7), pp.1339-1350.</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">16. Zhang K, Rekhter MD, Gordon D, Phan SH. Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis. A combined immunohistochemical and in situ hybridization study. Am J Pathol. 1994;145(1):114–125</span></span></p>
2018-01-05T13:12:182022-01-25T16:26:23Lung fibrosisLung fibrosisOrgan<p>This consecutive KE resulting in the acquisition of the accumulation of excess fibrous connective tissue, the adverse outcome on pulmonary fibrosis. Scar formation, the accumulation of excess fibrous connective tissue (the process called fibrosis), leads to thickening of the walls, and causes reduced oxygen supply in the blood. As a consequence patients suffer from perpetual shortness of breath.</p>
2017-02-15T02:55:562017-12-26T02:10:27Aryl hydrocarbon receptor activation leading to lung fibrosis through IL-6 toxicity pathwayAHR activation leading to lung fibrosis via IL-6 tox path<p>Dianke Yu</p>
<p>Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China</p>
<p> </p>
<p> </p>
Under development: Not open for comment. Do not cite<p>The AHR can be activated by several structurally diverse chemicals, but binds preferentially to planar halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons. Dioxin-like compounds (DLCs), which include polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and certain polychlorinated biphenyls (PCBs), are among the most potent AHR ligands<sup><a href="#cite_note-Denison2011-38">[38]</a></sup>. Only a subset of PCDD, PCDF and PCB congeners has been shown to bind to the AHR and cause toxic effects to those elicited by TCDD. Until recently, TCDD was considered to be the most potent DLC in birds<sup><a href="#cite_note-Van1998-39">[39]</a></sup>; however, recent reports indicate that 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) is more potent than TCDD in some species of birds.<sup><a href="#cite_note-Cohen2011b-40">[40]</a></sup><sup><a href="#cite_note-Farmahin2012-13">[13]</a></sup><sup><a href="#cite_note-Farmahin2013a-41">[41]</a></sup><sup><a href="#cite_note-Farmahin2014-21">[21]</a></sup><sup><a href="#cite_note-Herve2010a-42">[42]</a></sup><sup><a href="#cite_note-Herve2010b-43">[43]</a></sup> When screened for their ability to induce aryl hydrocarbon hydroxylase (AHH) activity, dioxins with chlorine atoms at a minimum of three out of the four lateral ring positions, and with at least one non-chlorinated ring position are the most active<sup><a href="#cite_note-Poland1973-44">[44]</a></sup>. Of the dioxin-like PCBs, non-ortho congeners are the most toxicologically active, while mono-ortho PCBs are generally less potent<sup><a href="#cite_note-McFarland1989-45">[45]</a></sup><sup><a href="#cite_note-Safe1994-9">[9]</a></sup>. Chlorine substitution at ortho positions increases the energetic costs of assuming the coplanar conformation required for binding to the AHR <sup><a href="#cite_note-McFarland1989-45">[45]</a></sup>. Thus, a smaller proportion of mono-ortho PCB molecules are able to bind to the AHR and elicit toxic effects, resulting in reduced potency of these congeners. Other PCB congeners, such as di-ortho substituted PCBs, are very weak AHR agonists and do not likely contribute to dioxin-like effects <sup><a href="#cite_note-Safe1994-9">[9]</a></sup>.</p>
<ul>
<li>Contrary to studies of birds and mammals, even the most potent mono-ortho PCBs bind to AhRs of fishes with very low affinity, if at all (Abnet et al 1999; Doering et al 2014; 2015; Eisner et al 2016; Van den Berg et al 1998).</li>
</ul>
<p>The role of the AHR in mediating the toxic effects of planar hydrophobic contaminants has been well studied, however the endogenous role of the AHR is less clear <sup><a href="#cite_note-Okey2007-1">[1]</a></sup>. Some endogenous and natural substances, including prostaglandin PGG2 and the tryptophan derivatives indole-3-carbinol, 6-formylindolo[3,2-b]carbazole (FICZ) and kynurenic acid can bind to and activate the AHR. <sup><a href="#cite_note-Fujii2010-6">[6]</a></sup><sup><a href="#cite_note-Omie2011-46">[46]</a></sup><sup><a href="#cite_note-Swed2010-47">[47]</a></sup><sup><a href="#cite_note-Diani2011-48">[48]</a></sup><sup><a href="#cite_note-Wincent2012-49">[49]</a></sup> The AHR is thought to have important endogenous roles in reproduction, liver and heart development, cardiovascular function, immune function and cell cycle regulation <sup><a href="#cite_note-Baba2005-50">[50]</a></sup><sup><a href="#cite_note-Denison2011-38">[38]</a></sup><sup><a href="#cite_note-Fernandez1995-51">[51]</a></sup><sup><a href="#cite_note-Ichihara2007-52">[52]</a></sup><sup><a href="#cite_note-Lahvis2000-53">[53]</a></sup><sup><a href="#cite_note-Mimura1997-54">[54]</a></sup><sup><a href="#cite_note-Omie2011-46">[46]</a></sup><sup><a href="#cite_note-Schmidt1996-55">[55]</a></sup><sup><a href="#cite_note-Thack2002-56">[56]</a></sup><sup><a href="#cite_note-Zhang2010-57">[57]</a></sup> and activation of the AHR by DLCs may therefore adversely affect these processes.</p>
2021-08-14T01:25:232023-04-29T16:03:05