92-87-5HFACYLZERDEVSX-UHFFFAOYSA-NHFACYLZERDEVSX-UHFFFAOYSA-N
Benzidine4-(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 receptorCL:0000066epithelial cellCL:0000077mesothelial cellUBERON:0002048lungGO:0004874aryl hydrocarbon receptor activityGO:0008283cell proliferationHP:0100526Neoplasm of the lungMP:0008014increased lung tumor incidence1increasedBenzidine2016-11-29T18:42:262016-11-29T18:42:26Dibenzo-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)2017-02-09T15:43:002017-02-09T15:43:00Ionizing Radiation<p>Ionizing radiation can vary in energy, dose, charge, and in the spatial distributions of energy transferred to other matter (linear energy transfer per unit length or LET) (ICRU 1970). At the same dose, low and high LET both generate energy deposition events, including many higher energy events (Goodhead and Nikjoo 1989). However, they differ in the spatial distribution and upper range of intensity of energy deposited. Lower LET such as gamma rays sparsely deposit many individual excitations or small clusters of excitations of low energy (Goodhead 1988). In contrast, high LET such as alpha particles have fewer tracks but readily transfer their energy to matter and therefore deposit their energy over a much smaller area (Goodhead 1994). Consequently, alpha and other high LET particles penetrate less deeply into tissue, interactions are densely focused on a narrow track, and individual energy depositions can be large (Goodhead 1988). These different energy deposition patterns can lead to differences in radiation effects including the pattern of DNA damage.</p>
<p>Exposure to ionizing radiation can come from natural and industrial sources. Space and terrestrial radiation includes a range of LET particles, while diagnostic radiation methods such as X-ray imaging, mammography and CT scans use low LET X-rays. Radiation therapy can use an external beam to direct radiation on a focused tissue area, or deposit solid or liquid radioactive materials in the body that release (mostly gamma) radiation internally. External radiotherapy typically uses X-rays but is moving towards higher LET charged particles such as protons and heavy ions (Durante, Orecchia et al. 2017).</p>
2019-05-03T12:36:362019-05-07T12:12:13High aspect ratio material2019-08-13T04:38:402019-08-13T04:38:407955zebra danioWCS_9031Gallus gallus143350Pagrus major7904Acipenser transmontanus41871Acipenser fulvescensWCS_8022rainbow trout8030Salmo salarWCS_8355Xenopus laevis8296Ambystoma mexicanumWCS_9054Phasianus colchicusWCS_93934Coturnix japonica10090mouse10116ratWCS_9606human34823Microgadus tomcod9606Homo sapiensWikiUser_17mammalsActivation, 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></p>
HighUnspecificHighEmbryoHighDevelopmentHighAll life stagesHighHighHighHighHighHighHighHighHighHighHighHighHighHighHighNot Specified<ol>
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<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>
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<li><a href="#cite_ref-Schmidt1996_55-0">↑</a> Schmidt, J. V., Su, G. H., Reddy, J. K., Simon, M. C., and Bradfield, C. A. (1996). Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. <em>Proc.Natl.Acad.Sci U.S.A</em> <strong>93</strong>, 6731-6736.</li>
<li><a href="#cite_ref-Thack2002_56-0">↑</a> Thackaberry, E. A., Gabaldon, D. M., Walker, M. K., and Smith, S. M. (2002). Aryl hydrocarbon receptor null mice develop cardiac hypertrophy and increased hypoxia-inducible factor-1alpha in the absence of cardiac hypoxia. <em>Cardiovasc.Toxicol.</em> <strong>2</strong>, 263-274.</li>
<li><a href="#cite_ref-Zhang2010_57-0">↑</a> Zhang, N., Agbor, L. N., Scott, J. A., Zalobowski, T., Elased, K. M., Trujillo, A., Duke, M. S., Wolf, V., Walsh, M. T., Born, J. L., Felton, L. A., Wang, J., Wang, W., Kanagy, N. L., and Walker, M. K. (2010). An activated renin-angiotensin system maintains normal blood pressure in aryl hydrocarbon receptor heterozygous mice but not in null mice. <em>Biochem.Pharmacol.</em> <strong>80</strong>, 197-2040.</li>
</ol>
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<p> </p>
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2016-11-29T18:41:222022-12-20T08:29:48Altered gene expression, NRF2 dependent antioxidant pathwayAltered expression of NRF2 pathway-dependent genesMolecular2021-08-17T02:18:452021-08-19T07:35:29Increase, Cell ProliferationIncrease, Cell ProliferationCellular<p><span style="color:#e74c3c">Throughout their life, cells replicate their organelles and genetic information before dividing to form two new daughter cells, in a process known as cellular proliferation. This replicative process is known as the cell cycle and is subdivided into various stages notably, G1, S, G2, and M in mammals. G1 and G2 are gap phases, separating mitosis and DNA synthesis. Differentiated cells typically remain in G1; however, quiescent cells reside in an optional phase just before G1, known as G0. </span></p>
<p><span style="color:#e74c3c">Progression through the cycle is dependent on sufficient nutrient availability to provide optimal nucleic acid, protein, and lipid levels, as well as sufficient cell mass. To this end, the cell cycle is mediated by three major checkpoints: the restriction (R) point, or G1/S checkpoint, controlling entry into S phase, the G2/M checkpoint, controlling entry into mitosis, and one more controlling entry into cytokinesis. If conditions are ideal for division, cells will pass the restriction point (G1/S) and begin the activation and expression of genes used for duplicating centrosomes and DNA, eventually leading to proliferation (Cuyàs et al., 2014). </span></p>
<p><span style="color:#e74c3c">Various protein complexes, known as cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs) regulate passage through each phase by activating and inhibiting specific processes (Lovicu et al., 2014). The CDKs are responsible for controlling progression through the cell cycle. They promote DNA synthesis and mitosis, and therefore cell division (Barnum & O’Connell, 2014). Furthermore, growth factors are required to stimulate cell division, but after passing through the restriction point at G1 they are no longer necessary (Lovicu et al., 2014).</span> </p>
<p>In the context of cancer, one hallmark is the sustained and uncontrolled cell proliferation (Hanahan et al., 2011, Portt et al., 2011). When cells obtain a growth advantage due to mutations in critical genes that regulate cell cycle progression, they may begin to proliferate excessively, resulting in hyperplasia and potentially leading to the development of a tumor. <span style="color:#e74c3c">This is often achieved through oncogene activation and inactivation of tumor suppressor genes</span> (Hanahan et al., 2011). Cell inactivation and the replacement of these cells can initiate clonal expansion (Heidenreich adn Paretzke et al., 2008). </p>
<p>Sustained atrophy/degeneration olfactory epithelium under the influence of a cytotoxic agent leads to adaptive tissue remodeling. Cell types unique to olfactory epithelium, e.g. olfactory neurons, sustentacular cells and Bowmans glands, are replaced by cell types comprising respiratory epithelium or squamous epithelium.</p>
<p>Two common methods of measuring cell proliferation in vivo are the use of Bromodeoxyuridine (5-bromo-2'-deoxyuridine, BrdU) labeling (Pera, 1977), and Ki67 immunostaining (Grogan, 1988). BrdU is a synthetic analogue of the nucleoside Thymidine. BrDu is incorporated into DNA synthesized during the S1 phase of cell replication and is stable for long periods. Labeling of dividing cells by BrdU is accomplished by infusion, bolus injection, or implantation of osmotic pumps containing BrdU for a period of time sufficient to generate measureable numbers of labeled cells. Tissue sections are stained immunhistochemically with antibodies for BrdU and labeled cells are counted as dividing cells. Ki67 is a cellular marker of replication not found in quiescent cells (Roche, 2015). Direct immunohistochemical staining of cells for protein Ki67 using antibodies is an alternative to the use of BrdU, with the benefit of not requiring a separate treatment (injection for pulse-labeling). Cells positive for Ki67 are counted as replicating cells. Replicating cell number is reported per unit tissue area or per cell nuclei (Bogdanffy, 1997). <span style="color:#e74c3c">Listed below are common methods for detecting the KE, however there may be other comparable methods that are not listed.</span></p>
<table border="1" cellpadding="1" cellspacing="1" style="height:298px; width:595px">
<tbody>
<tr>
<td style="background-color:#dddddd; text-align:center"><span style="color:#0000cd"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif"><strong>Assay Name</strong></span></span></span></td>
<td style="background-color:#dddddd; text-align:center"><span style="font-family:arial,helvetica,sans-serif"><span style="color:#0000cd"><span style="font-size:12px"><strong>References</strong></span></span></span></td>
<td style="background-color:#dddddd; text-align:center"><span style="color:#0000cd"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif"><strong>Description</strong></span></span></span></td>
<td style="background-color:#dddddd; text-align:center"><span style="font-family:arial,helvetica,sans-serif"><span style="font-size:12px"><span style="color:#0000cd"><strong>OECD Approved Assay</strong></span></span></span></td>
</tr>
<tr>
<td><span style="color:#0000cd"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">CyQuant Cell Proliferation Assay</span></span></span></td>
<td><span style="font-family:arial,helvetica,sans-serif"><span style="font-size:12px"><span style="color:#0000cd">Jones et al., 2001</span></span></span></td>
<td><span style="font-family:arial,helvetica,sans-serif"><span style="font-size:12px"><span style="color:#0000cd">DNA-binding dye is added to cell cultures, and the dye signal is measured directly to provide a cell count and thus an indication of cellular proliferation</span></span></span></td>
<td><span style="color:#0000cd">N/A</span></td>
</tr>
<tr>
<td><span style="color:#0000cd"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Nucleotide Analog Incorporation Assays (e.g. BrdU, EdU)</span></span></span></td>
<td><span style="color:#0000cd"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Romar et al., 2016, Roche; 2013</span></span></span></td>
<td><span style="font-family:arial,helvetica,sans-serif"><span style="font-size:12px"><span style="color:#0000cd">Nucleoside analogs are added to cells in culture or injected into animals and become incorporated into the DNA at different rates, depending on the level of cellular proliferation; Antibodies conjugated to a peroxidase or fluorescent tag are used for quantification of the incorporated nucleoside analogs using techniques such as ELISA, flow cytometry, or microscopy</span></span></span></td>
<td><span style="font-family:arial,helvetica,sans-serif"><span style="font-size:12px"><span style="color:#0000cd">Yes (No. 442B)</span></span></span></td>
</tr>
<tr>
<td><span style="color:#0000cd"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Cytoplasmic Proliferation Dye Assays</span></span></span></td>
<td><span style="color:#0000cd"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Quah & Parish, 2012</span></span></span></td>
<td><span style="font-family:arial,helvetica,sans-serif"><span style="font-size:12px"><span style="color:#0000cd">Cells are incubated with a cytoplasmic dye of a certain fluorescent intensity; Cell divisions decrease the intensity in such a way that the number of divisions can be calculated using flow cytometry measurements</span></span></span></td>
<td><span style="font-family:arial,helvetica,sans-serif"><span style="font-size:12px"><span style="color:#0000cd">N/A</span></span></span></td>
</tr>
<tr>
<td><span style="color:#0000cd"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Colourimetric Dye Assays</span></span></span></td>
<td><span style="color:#0000cd"><span style="font-size:12px"><span style="font-family:arial,helvetica,sans-serif">Vega-Avila & Pugsley, 2011; American Type Culture Collection</span></span></span></td>
<td><span style="font-family:arial,helvetica,sans-serif"><span style="font-size:12px"><span style="color:#0000cd">Cells are incubated with a dye that changes colour following metabolism; Colour change can be measured and extrapolated to cell number and thus provide an indication of cellular proliferation rates</span></span></span></td>
<td><span style="font-family:arial,helvetica,sans-serif"><span style="font-size:12px"><span style="color:#0000cd">N/A</span></span></span></td>
</tr>
</tbody>
</table>
<p> </p>
<p><span style="color:#27ae60"><strong> </strong></span>Cell proliferation is a central process supporting development, tissue homeostasis and carcinogenesis, each of which occur in all vertebrates. This key event has been observed nasal tissues of rats exposed to the chemical initiator vinyl acetate. <span style="font-family:arial,helvetica,sans-serif"><span style="color:#0000cd">In general, cell proliferation is necessary in the biological development and reproduction of most organisms. This KE is thus relevant and applicable to all multicellular cell types, tissue types, and taxa.</span></span></p>
<p><span style="color:#e74c3c"><strong>Life stage applicability: </strong>This key event is not life stage specific (Fujimichi and Hamada, 2014; Barnard et al., 2022). </span></p>
<p><span style="color:#e74c3c"><strong>Sex applicability:</strong> This key event is not sex specific (Markiewicz et al., 2015). </span></p>
<p><span style="color:#e74c3c"><strong>Evidence for perturbation by a stressor:</strong> There is a large body of evidence supporting the effectiveness of ionizing radiation, UV, and mechanical wounding as stressors for increased cell proliferation. These stressors can be subdivided into X-rays (van Sallmann, 1951; Ramsell and Berry, 1966; Richards, 1966; Riley et al., 1988; Riley et al., 1989; Kleiman et al., 2007; Pendergrass et al., 2010; Fujimichi and Hamada, 2014, Markiewicz et al., 2015; Bahia et al., 2018), 60Co γ-rays (Hanna and O’Brien, 1963; Barnard et al., 2022; McCarron et al., 2021), 137Cs γ-rays (Andley and Spector, 2005), neutrons (Richards, 1966; Riley et al., 1988; Riley et al., 1989), 40Ar (Worgul et al., 1986), 56Fe (Riley et al., 1989), UVB (Söderberg et al., 1986; Andley et al., 1994; Cheng et al., 2019), UVC (Trenton and Courtois, 1981), and mechanical wounding (Riley et al., 1989).</span></p>
HighUnspecificHighAll life stagesHighHighHigh<p><span style="color:#e74c3c">Andley, U. P. et al. (1994), “Modulation of lens epithelial cell proliferation by enhanced prostaglandin synthesis after UVB exposure”, Investigative Ophthalmology & Visual Science, Vol. 35/2, Rockville, pp. 374-381 </span></p>
<p><span style="color:#e74c3c">Andley, U. and A. Spector (2005), “Peroxide resistance in human and mouse lens epithelial cell lines is related to long-term changes in cell biology and architecture”, Free Radical Biology & Medicine, Vol. 39/6, Elsevier B.V, United States, https://doi.org/10.1016/j.freeradbiomed.2005.04.028 </span></p>
<p><span style="color:#e74c3c">Bahia, S. et al. (2018), “Oxidative and nitrative stress-related changes in human lens epithelial cells following exposure to X-rays”, International journal of radiation biology, Vol. 94/4, England, </span><a href="https://doi.org/10.1080/09553002.2018.1439194" rel="noreferrer noopener" target="_blank"><span style="color:#e74c3c">https://doi.org/10.1080/09553002.2018.1439194</span></a><span style="color:#e74c3c"> </span></p>
<p><span style="color:#e74c3c">Barnard, S. et al. (2022), “Lens Epithelial Cell Proliferation in Response to Ionizing Radiation.”, Radiation Research, Vol. 197/1, Radiation Research Society, United States, </span><a href="https://doi.org/10.1667/RADE-20-00294.1" rel="noreferrer noopener" target="_blank"><span style="color:#e74c3c">https://doi.org/10.1667/RADE-20-00294.1</span></a><span style="color:#e74c3c"> </span></p>
<p><span style="color:#e74c3c">Barnum, K. and M. O’Connell (2014), “Cell cycle regulation by checkpoints”, in Cell cycle control, Springer, New York, http://doi.org/ 10.1007/978-1-4939-0888-2 </span></p>
<p><span style="color:mediumblue; font-family:arial,sans-serif; font-size:9pt">Bogdanffy. et al. (1997). “FOUR-WEEK INHALATION CELL PROLIFERATION STUDY OF THE EFFECTS OF VINYL ACETATE ON RAT NASAL EPITHELIUM”, Inhalation Toxicology, Taylor & Francis. 9: 331-350.</span></p>
<p> </p>
<p><span style="color:#e74c3c">Cheng, T. et al. (2019), “lncRNA H19 contributes to oxidative damage repair in the early age-related cataract by regulating miR-29a/TDG axis”, Journal of cellular and molecular medicine, Vol. 23/9, Wiley Subscription Services, Inc. England, https://doi.org/10.1111/jcmm.14489 </span></p>
<p><span style="color:#e74c3c">Cuyàs, E. et al. (2014), “Cell cycle regulation by the nutrient-sensing mammalian target of rapamycin (mTOR) pathway”, in Cell cycle control, Springer, New York, http://dx.doi.org/ 10.1007/978-1-4939-0888-2 </span></p>
<p><span style="color:#e74c3c">Fujimichi, Y. and N. Hamada (2014), “Ionizing irradiation not only inactivates clonogenic potential in primary normal human diploid lens epithelial cells but also stimulates cell proliferation in a subset of this population”, PloS one, Vol. 9/5, e98154, Public Library of Science, United States, </span><a href="https://doi.org/10.1371/journal.pone.0098154" rel="noreferrer noopener" target="_blank"><span style="color:#e74c3c">https://doi.org/10.1371/journal.pone.0098154</span></a><span style="color:#e74c3c"> </span></p>
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<p> </p>
2016-11-29T18:41:272023-04-24T11:08:07Lung cancerLung cancerOrgan<p><span style="font-family:times new roman,serif; font-size:12.0pt">Lung cancer is one of the most prevalent cancer in the world. This cancer occur mainly at the level of bronchial cells and affect more rarely at the level of alveoli. Lung cancer affects more men rather than women because of tabacco consumption (trend is reversing). This disease is at the first place on terms of mortality due to the late detection (Cancer League, WHO).</span></p>
<p>Lung cancer can be measured in human by analysis of the sputum cytology, the chest X-ray and all the techniques usually used in this medical field.</p>
<p>In animal experiments, the OECD guidelines n°451 provide the procedure for the study of carcinogenesis development.</p>
<p><span style="font-family:times new roman,serif; font-size:12.0pt">Lung cancer can occur in mammals, male or female, generally in adults</span></p>
Not SpecifiedUnspecificNot SpecifiedAdultNot Specified2019-07-03T11:51:272019-08-13T05:34:23Aryl hydrocarbon receptor activation leading to lung cancer through sustained NRF2 toxicity pathwayAHR leading to lung cancer via NRF2 tox path<p>Dianke Yu</p>
<p>Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China</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>
2021-08-14T02:01:322023-04-29T13:02:20