Europe PMC

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.

From Nucleus to Organs: Insights of Aryl Hydrocarbon Receptor Molecular Mechanisms.

Author information

Affiliations

  • 1. Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, 06006 Badajoz, Spain.
      Authors
    • Rejano-Gordillo CM 1
    • Marín-Díaz B 1
    • Ordiales-Talavero A 1
    • Merino JM 1
    • González-Rico FJ 1
    • Fernández-Salguero PM 1
    (6 authors)

ORCIDs linked to this article

International Journal of Molecular Sciences, 29 Nov 2022, 23(23):14919
https://doi.org/10.3390/ijms232314919 PMID: 36499247 PMCID: PMC9738205

Review

This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC

Abstract 

The aryl hydrocarbon receptor (AHR) is a markedly established regulator of a plethora of cellular and molecular processes. Its initial role in the detoxification of xenobiotic compounds has been partially overshadowed by its involvement in homeostatic and organ physiology processes. In fact, the discovery of its ability to bind specific target regulatory sequences has allowed for the understanding of how AHR modulates such processes. Thereby, AHR presents functions in transcriptional regulation, chromatin architecture modifications and participation in different key signaling pathways. Interestingly, such fields of influence end up affecting organ and tissue homeostasis, including regenerative response both to endogenous and exogenous stimuli. Therefore, from classical spheres such as canonical transcriptional regulation in embryonic development, cell migration, differentiation or tumor progression to modern approaches in epigenetics, senescence, immune system or microbiome, this review covers all aspects derived from the balance between regulation/deregulation of AHR and its physio-pathological consequences.

Free full text 

Logo of ijmsLink to Publisher's site
Int J Mol Sci. 2022 Dec; 23(23): 14919.
Published online 2022 Nov 29. https://doi.org/10.3390/ijms232314919
PMCID: PMC9738205
PMID: 36499247

From Nucleus to Organs: Insights of Aryl Hydrocarbon Receptor Molecular Mechanisms

Claudia M. Rejano-Gordillo,1,2 Beatriz Marín-Díaz,1,2 Ana Ordiales-Talavero,1,2 Jaime M. Merino,1,2 Francisco J. González-Rico,1,2,* and Pedro M. Fernández-Salguero1,2,*
Jose Javier Lopez, Academic Editor, Carlos Gutierrez-Merino, Academic Editor, and José Manuel González Ros, Academic Editor
Author information Article notes Copyright and License information Disclaimer

Abstract

The aryl hydrocarbon receptor (AHR) is a markedly established regulator of a plethora of cellular and molecular processes. Its initial role in the detoxification of xenobiotic compounds has been partially overshadowed by its involvement in homeostatic and organ physiology processes. In fact, the discovery of its ability to bind specific target regulatory sequences has allowed for the understanding of how AHR modulates such processes. Thereby, AHR presents functions in transcriptional regulation, chromatin architecture modifications and participation in different key signaling pathways. Interestingly, such fields of influence end up affecting organ and tissue homeostasis, including regenerative response both to endogenous and exogenous stimuli. Therefore, from classical spheres such as canonical transcriptional regulation in embryonic development, cell migration, differentiation or tumor progression to modern approaches in epigenetics, senescence, immune system or microbiome, this review covers all aspects derived from the balance between regulation/deregulation of AHR and its physio-pathological consequences.

Keywords: aryl hydrocarbon receptor, epigenetics, signaling pathways, organ homeostasis

1. Introduction

Intensive and uninterrupted research on aryl hydrocarbon receptor (AHR) emerged in the 1970–1980s (Figure 1). Initially, AHR was discovered in the cytoplasm of mouse liver cells. It was defined as a protein involved in the detoxification of xenobiotics due to its involvement in the induction of detoxifying enzymes such as cytochrome P450 CYP1A1 [1,2]. During the following years, the basic molecular mechanism of action of the receptor was traced, the translocation to the nucleus of the receptor was described as being dependent on its binding to exogenous ligands (generally polycyclic aromatic hydrocarbons) [3] and its relationship with the protein ARNT (aryl hydrocarbon receptor nuclear translocator) was uncovered [4]. Afterwards, its purification, cloning and sequencing was carried out, which allowed it to be considered a member of the superfamily bHLH/PAS of transcription factors with sequences of the basic-Helix-Loop-Helix (bHLH) type of class VII [5,6], which also includes the PAS domain transcription regulators: Per (Period), ARNT and Sim (Single Minded). Finally, the production of mutant mice by gene knock-out techniques was achieved, confirming the toxicological role of the receptor: AHR-/- mice were resistant to the toxic and carcinogenic effects of xenobiotics such as dioxin TCDD (2,3,7,8-tetrachloro-dibenzo-p-dioxin) and Benzo[a]pyrene (BP) [7,8,9]. Those initial investigations based on AHR knock-out murine models revealed an unexpected molecular and physiological role for the receptor, with a strong implication in cell cycle, proliferation, apoptosis and carcinogenesis [10].

An external file that holds a picture, illustration, etc. Object name is ijms-23-14919-g001.jpg

Early timeline of AHR research.

Most of the studies on the transcriptional activity of AHR have focused on the activation mediated by the binding of exogenous ligands. Once translocated to the nucleus, it has the ability to bind to DNA [11,12,13] in consensus sequences called XREs or DREs (xenobiotic/dioxin response elements) in the promoter regions of its target genes, which contributes to increase or repress their transcription [14,15]. Consequently, the regulation of such transcriptional activity in the absence of xenobiotics is one of the most thrilling aspects of the functionality of this receptor.

2. Epigenetics and Chromatin: AHR-Driven Barriers

Non-coding regions represent about 98% of the human genome. The biological and evolutive argument behind this vast percentage contains regulatory elements that control gene expression such as promoters, enhancers, insulators, boundaries and post-transcriptional control elements. Together, all these regulatory elements allow the non-coding region of the genome to maintain the proper balance of gene expression that allows the cell an adaptive response to environmental and homeostatic stimuli [16]. In the last decade, this type of special regulation, far from the classic transcriptional regulation, has experienced a growing interest, with AHR presenting a pivotal role in the interaction of retrotransposons, chromatin spatial organization and epigenetic modifications [17].

2.1. Retrotransposons

The human genome comprises approximately 40% mobile elements that includes retrotransposons (retrotransposable elements, RTEs), DNA transposons and elements of retroviral origin, which potentially play a role in this whole mechanism. The transposons include short interspersed nuclear elements (SINE), long interspersed nuclear elements (LINE) and long terminal repeat (LTR) [18,19]. Several years have passed since these elements were molecularly and genetically described [20,21] until their functional implications in physiology and development were partially addressed [22]. Bioinformatic analysis confirmed that a high percentage of the binding sites for transcription factors established in the mammalian genomes resided in repetitive elements and, additionally, they were grouped in small regions forming similar structures to the cis elements that regulate genes, sharing a common expression pattern [23], allowing for a potential fast response to abrupt environmental changes. The group of SINEs includes the B1 and B2 elements from the mouse genome, named for their homology with double-stranded regions of the dsRNA-B nuclear pre-mRNAs [24], as well as their equivalent human Alu elements, which are named for the presence of a cleavage site for the AluI restriction enzyme [25,26]. Interestingly, both B1 and Alu elements present potential AHR binding sites [27,28]. In the mouse genome, the repetitive element B1 × 35S presents a functional XRE site for AHR binding within 35 bp from an E-box functional site for Slug/SNAI2 binding, resulting in the repression of several X35S-containing cis-reporter genes [27]. In fact, the transcription of this B1 × 35S element is dependent on an RNA polymerase switch triggered by AHR binding to the XRE site present on the retrotransposon itself, which includes the release of RNA Pol III and the recruitment of RNA Pol II [29]. On the other hand, in the human genome, bioinformatic analysis confirmed the presence of three B1 × 35S counterparts, with the Alu elements X45S, X36S and X14S having the XRE and SLUG/SNAI2 sequences separated by 45, 36 and 14 bp, respectively [28,30]. In these works, it has been described that, using an in vitro human differentiation model, AHR was able to bind to the Alu elements flanking stemness-relevant genes such as NANOG and OCT4, whose promoters harbor AHR and RNA Pol III binding sites. Furthermore, repression of such genes would likely imply processing of Alu-derived transcripts through the miRNA machinery involving a microprocessor (DGCR8 and DROSHA) and RISC (RNA induced silencing complex) [28], showing a regulation of carcinoma cell differentiation via AHR-regulated Alu retrotransposons. Together, these results suggest the existence of an AHR-driven control of gene expression through modulation of retrotransposons activity.

2.2. Chromatin Structural Organization

Chromatin fold/unfold balance provides a mechanism of control of gene expression through changes in the spatial organization of the chromosomes. This creates the possibility for long range interaction between distant regions, allowing the formation of topologically associated domains (TADs) for such purpose [31,32,33,34,35]. In fact, the position that regulatory elements occupy throughout the genome (promoters, repressor elements, enhancers and insulators, among others) is key to such regulation. Regarding this, it has been described that AHR is able to form a chromatin loop that encases the NANOG locus through the binding to its Alu flanking retrotransposons, controlling its ratio of expression/repression [30]. Interestingly, subsequent proteomic analysis revealed a complex network of proteins recruited by this Alu–AHR axis, which are implied in the conformation of such a loop. This group includes the chromatin assembly factor 1 subunit B (CHAF1B) and the protein arginine methyltransferase 1 (PRMT1). Additionally, the activation of AHR during early embryo differentiation alters such process through nucleosome remodeling and deacetylation complex (NuRD), controlling the pluripotency program during development [36]. Consequently, these interactions confirmed the connection between AHR-driven chromatin conformational changes and other epigenetic marks, such as histone methylation [30]. This interaction was hinted in previous works with the downregulation of AHR by its promoter hypermethylation in acute lymphoblastic leukemia. Suchlike molecular mechanism is driven through the unbinding of transcription factor Sp1 from AHR promoter, suggesting an epigenetic mechanism for the control of AHR expression in human tumor cells [37]. Moreover, the histone methylation pattern from me3H3K4, me3H3K9 and me3H3K27 marks was altered in the absence of AHR both in the human and mouse genome [29,30], reinforcing the importance of AHR in this regulation. Additionally, regarding the position of regulatory elements through the genome, the mouse retrotransposon B1 × 35S presented insulator activity both in vivo and in vitro, being able to repress gene expression depending on its physical position between the enhancer and the promoter [29]. Interestingly, the mutation of the AHR and Slug/Snai2 binding sites translated in a loss of insulator activity [27]. This retrotransposon enhancer blocking activity has emerged as a novel regulation of gene expression in recent years [38,39], being also very similar to the genomic control exerted by CCCTC-binding factor (CTCF) due to its insulator capacities [40,41]. In fact, CTCF is able to promote the formation of chromatin loops that modulate the accessibility of RNA polymerases and related proteins to gene regulatory regions, contributing to this chromatin barrier regulatory network [42,43,44]. Moreover, binding of CTCF also provides a physical anchor point for nucleosome positioning and chromatin remodeling [45]. The cooperation between CTCF and AHR initially addressed in mouse retrotransposon regulation [29] was later also confirmed in human Alu elements [30]. Thereby, the retrotransposons X45S and X14S showed a notably enhanced blocking activity, being AHR and CTCF co-recruited for the retrotransposon-propelled cell differentiation through NANOG locus silencing.

The novel findings reported in the molecular mechanisms underlying chromatin structural reorganization have been considered a milestone due to the non-canonical nature of its regulation. The implication of AHR in such processes remains a promising path to travel in the future of epigenetics.

3. AHR Signaling

Beyond the role of AHR in transcriptional regulation, its implication in multiple signaling pathways has built a field of study regarding its participation in the control and maintenance of different physiological and pathological processes [46]. The variety of responses resulting from AHR activation may be due to the different interactions of the receptor with other proteins or transcriptional cofactors [47]. Therefore, numerous proteins affecting AHR activity and vice versa have been described over the years, constituting a solid trend in cell signaling.

3.1. The Wnt/β-Catenin Pathway

The importance of this pathway resides in its participation in the correct development of most organs [48,49,50]. It has been described that Wnt-mediated signaling needs to be in balance in order to obtain a proper development program, as both downregulation and over-signaling of Wnt can lead to several defects [51,52,53], including lung, breast and skin cancer [54].

Despite AHR and Wnt signaling have been long studied independently, numerous evidence of crosstalk between the two pathways have emerged in recent years [55]. Interestingly, it has been described that AHR and Wnt/β-catenin cooperate in the induction of AHR transcriptional targets, such as Cyp1a1 and Cyp1b1, with the persistent AHR activation triggering reduced levels of active β-catenin, affecting the phenotype of hepatic progenitor cells and leading them towards other more differentiated types [56]. Furthermore, AHR agonists such as indole-3-carbinol (I3C), 3,3′-diindolylmethane (DIM) and indirubin-3′-monoxime were able to downregulate CTNNB1(β-catenin) expression [57,58,59].

Subsequently, AHR was identified as an inhibitor of the canonical Wnt signaling pathway in mouse intestine, being able to suppress intestinal carcinogenesis by degradation of β-catenin [60], with activated AHR expression also downregulating CTNNB1 expression in human colon cancer cell lines [55]. In the human breast cancer cell line, constitutive expression of AHR by introduction of a mutation was able to negatively regulate CTNNB1 [55]. Furthermore, in mouse liver, elevated levels of β-catenin were detected in AHR -/- preweaning mice [61]. This alteration could be possible due to AHR being part of the repressive complex that binds to CTNNB1, promoting its ubiquitination and subsequent degradation [55,60], since both proteins co-immunoprecipitated under basal conditions in adult liver [61]. AHR ligands also decrease ABC levels and generate further alterations in the Wnt pathway, such as Dvl dephosphorylation [56]. On the other hand, TCDD-induced reduction of the canonical Wnt pathway has been associated with a decrease in R-Spondin2 (Rspo2) and R-Spondin3 (Rspo3) activators [62]. However, in zebrafish, AHR activation by TCDD was shown to upregulate canonical Wnt signaling by overexpression of R-Spondin1 (Rspo1) [63]. Such Rspo1 signaling is mediated by the co-receptor LRP6 (low-density lipoprotein receptor-related protein 6), which is required for TCDD to upregulate the Wnt pathway and inhibit regeneration in zebrafish. This is consistent with data indicating that the role of AHR is cell type, tissue, organ and animal model dependent [64,65,66].

3.2. The PI3K/AKT Pathway

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway is one of the key regulators of cell proliferation, cell cycle and apoptosis [67]. Moreover, its over activation and de-regulation is a common feature in human malignancies, making it an ideal candidate for drug-based cancer therapies [68].

The importance of AHR in such processes is notorious, presenting a relevant series of interactions with the pathway. Hence, AHR has been found to reduce apoptosis in a mouse hepatoma cell line due to increased AKT activation [69]. However, a recent in vivo study evidenced that there was more AKT activity in AHR -/- mouse liver, thus p-AKT target GSK3β is more efficiently phosphorylated in the liver of such knockout animals [61]. In fact, GSK3β constitutes a link between the Wnt-β-Catenin and PI3K/AKT pathways, being able to inhibit itself in the absence of AHR and ensuring the maintenance of cellular homeostasis. Furthermore, PI3K also was found to have a connection with the Ras pathway via regulation of the activation of mitogen-activated kinases (MAPKs), presenting a sustained PI3K-dependent ERK1/2 activation in AHR -/- mice liver [61,70].

AHR has also been reported to control AKT phosphorylation under basal conditions without the necessity to respond to growth factors, cigarette smoke extract (CSE) or AHR ligands. Due to the finding that in the absence of AHR there is differential phosphorylation of several proteins such as fibrillin and fibronectin, it is speculated that the increased phosphorylation of AKT in AHR-/-MLF (mouse lung fibroblast) could be associated with extracellular matrix (ECM) deregulation [71]. This apparent discordance between the results of different studies suggests that AHR regulation of basal AKT activity may be cell-type specific and/or reflect differences between primary and cancer cells, a well-known feature of AHR [17].

3.3. Interaction with TGF-β Signaling

Transforming growth factors β (TGF-β) are cytokines that have an important role in proliferation, development, homeostasis and tumorigenesis [72,73]. It is known that TGF-β can be activated by mechanisms involving proteolytic cleavage of latent TGF-β binding protein (LTBP-1) and the release of thrombospondin-1 (TSP-1) [72,74]. Once activated, it binds to its membrane receptors, initiating the signaling pathway [75]. Due to the processes that present TGF-β participation, its crosstalk with AHR has been widely studied. Regarding this, in a mouse fibrosis liver model, AHR-/- mice showed higher levels of LTBP-1 protein, co-localizing with TGF-β1 and collagen accumulation. This LTBP-1 could be responsible for TGF-β activation through alterations of the proteases PA/plasmin, elastase and TSP-1 (Thrombospondin 1), all of them affected by the presence or absence of AHR [75]. In fact, in mouse liver and mouse embryonic fibroblasts (MEFs) from AHR-/- mice, a higher level of total and active TGF-β versus the AHR+/+ ones was reported, leading to a reduced proliferation rate and increased apoptosis [14,75,76]. Furthermore, the AHR knockout mice also presented a better skin wound healing process than the wild type ones, which could be a consequence of the higher cell migration pattern triggered by the over-activation of TGF-β pathway [77,78].

Interestingly, the interaction between AHR and TGF-β seems to be tissue-dependent. In fact, while AHR is able to repress TGF-β signaling in brain tumors [79], TGF-β is also needed for the maintenance of proper AHR expression levels in lymphocytes [80]. Moreover, the tandem TGF-β/Smad can dissociate the AHR/ARNT complex through the inhibition of CYP1A1-mediated metabolic activation of polycyclic aromatic hydrocarbons (PAHs), resulting in cell protection against carcinogenesis [81].

3.4. NF-κβ and p65

The modulation exerted by AHR in the inflammatory response via the nuclear factor kappa enhancer of activated B-cell light chains (NF-κβ) has been widely studied. The acute inflammatory response in macrophages is mediated by the recognition of microbial products by toll-like receptors (TLRs), and its activity is controlled by NF-κβ and RelA/p65 [82]. It has been shown that the RelB subunit of NF-κβ is physically associated with AHR in U937 macrophage cell line, whereas in TCDD-treated Hepa1c1c7 cells it was seen that the physical association involved AHR and RelA/p65 [83,84]. In fact, it has been revealed the ability of AHR to suppress NF-κβ/p65 signaling pathway in intestinal epithelium [85]. Interestingly, a similar pattern was found in a model of inflammatory response in lung, where AHR presented a negative regulatory capacity of such response through direct modulation of NF-κβ signaling [86]. Additionally, this association of AHR with RelA has been found to activate NF-κβ activity in order to upregulate interleukin-6 (IL-6) expression [87]. Consequently, there is thus a crosstalk between the NF-κβ and AHR pathways, in such a way AHR activation favors RelA/p65 protein degradation by ubiquitin–proteasome system (UPS) and lysosomes, resulting in decreased levels of proinflammatory cytokines in mouse macrophages [88]. In fact, such crosstalk between AHR and NF-κβ pathways could contribute to a variety of AHR responses during the different types and stages of chronic kidney disease (CKD) [89].

Therefore, the interaction between AHR, RelA, RelB and NF-κβ signaling pathways continues to be an interesting field of study since it was only initially unveiled [90].

3.5. Other Protein Interactions

Additionally, there are multiple proteins which has been described to affect AHR activity and vice versa. Their main interactions are highlighted in the Table 1.

Table 1

List of other AHR-interacting proteins.

FactorFunctional ConsequenceReference
SRC-1, NCoA2, p300/CBP, p/CIPCoactivators with HAT activity that interact with AHR and/or ARNT to facilitate transcriptional activation[91]
SHPInhibits transcriptional activity of the AHR/ARNT complex[92]
Brg-1Histone-modifying factor dependent on ATPase activity and activator of transcription mediated by AHR/ARNT[93]
Med220, CDK8Subunits of the mediator complex involved in AHR/ARNT transcriptional activation[94]
ERαFunctional interactor with AHR in gene regulation[95]
RBDirect interaction between Rb and AHR is required for maximal induction of Cyp1a1, suggesting a role of coactivator for RB[96]
Mybbp1aAssociates with AHR and favors transactivation[97]
Nedd8Interacts with AHR increasing its nuclear accumulation and transcriptional activity[98]
p16, p21AHR transcriptionally regulates the expression of senescence-related genes[99]
VEGF, HGFAHR modulation of angiogenesis through a mechanism that requires VEGF activation in the endothelium[100]
FGFIncreased fibroblast growth factor (FGF) levels with AHR overexpression.[99]
Per2 y Bmal1Circadian rhythms-mediated interaction with AHR. Exposure to TCDD alters their expression pattern.[101]
Cav-1AHR modulation of Caveolin-1 in cell migration[102]

4. AHR Physiological Functions

The initial approach on AHR research has been developed from a toxicological point of view due to the abusive use of xenobiotic compounds and their detrimental effect on human health in the last decades. However, numerous experimental evidences, mainly derived from the study of AHR knock-out mice, have revealed its physiological role, since its absence causes hepatic, reproductive, cardiac and immunological alterations [103]. In addition, several facts support the functional relevance of AHR in cell physiology: (i) its presence on the evolutionary scale long before that of polycyclic aromatic compounds in the atmosphere, (ii) its constitutive expression in most cell types, and (iii) its degree of conservation among various groups of both aquatic and terrestrial vertebrates [104].

Its physiological role may also be justified due to the evidence that different molecules generated during cellular homeostasis can activate its function [105]. This molecular sensor can integrate a wide variety of endogenous and exogenous signals, and the effects of its activation are specific according to binding ligand, cell type, tissue or organ. For this reason, the role of AHR may be so divergent and widespread depending on its physiological context (Figure 2).

An external file that holds a picture, illustration, etc. Object name is ijms-23-14919-g002.jpg

Implication of AHR in organ homeostasis regulation.

4.1. Embryo

It has been described how AHR shows different levels of expression in mammalian tissues, with an ubiquitous presence in most of these organisms [106], even from the embryonic development [107]. In fact, AHR has a main role in early embryogenesis, as AHR-null mice embryos show delayed expression of trophectoderm differentiation markers [108], cardiac hypertrophy markers with cardiac enlargement [109], and a zebrafish line with an AHR2 mutation which presents jaw, gill and fin malformations in adult fish [110]. Furthermore, its gestational overactivation leads to altered developmental trajectories, triggering pathological processes in multiple organs and tissues such as lung in rats [111], cleft palate in mice [112], hydronephrosis in mice kidneys [113], prostate and urinary tract dysfunction in mice [114,115,116] and heart and craniofacial malformations in zebrafish [117,118].

4.2. Liver

One of the best-characterized phenotypes that provides the most support for the role of AHR in cellular homeostasis is the appearance of marked liver pathology after gene inactivation of the receptor in mice. Thereby, different liver characteristics have been described, including reduced size [119], collagen accumulation resulting in hepatic fibrosis [120], exacerbated proliferation of blood vessels [103] and lack of resolution of the portosystemic connection in adult mice [121]. Recently, the involvement of AHR in the control of hepatic energy and lipid metabolism and its relationship with metabolites from gut microbiome has been discovered [122,123,124,125]. Furthermore, AHR also regulates PI3K, ERK, and Wnt/β-Catenin signaling pathways, which are responsible for proliferation, differentiation and metabolism in the hepatic polyploidization process during liver maturation [61]. This fact is supported by previous studies that show that AHR prevents mitotic progression and induces differentiation, as well as preventing pluripotency in different cell types [28,30,126,127,128]. Moreover, several groups of genes involved in cell differentiation and development are regulated directly by AHR in the absence of an exogenous ligand [129,130].

Additionally, AHR is strongly related to liver stem/progenitor cells [131], with AHR-/- mice showing a more undifferentiated and pluripotent liver phenotype. This absence of AHR increases the susceptibility to hepatocarcinoma development after diethylnitrosamine (DEN) treatment, but also leading to a higher regenerative capacity [132,133]. Therefore, AHR has a direct implication on both processes, since its absence exacerbates cellular senescence markers and increases liver progenitor cells in age-induced hepatocarcinoma [99]. Furthermore, its exogenous modulation by TCDD inhibits hepatic regeneration in mice after partial hepatectomy of the liver [134,135], while hexachlorobenzene (HCB) induces its expression in preneoplastic foci both on rat liver and HepG2 human hepatocarcinoma cell line [136].

4.3. Gut

AHR integrates environmental, dietary, microbial and metabolic signals in a ligand- and cell-specific manner. Interestingly, AHR has been found to be regulated by some metabolites from microbiome activity such as short-chain fatty acids and ketone bodies, which can influence host metabolic pathways [137]. In fact, the altered and reduced production of AHR ligands by the commensal flora due to the smoking, antibiotics, oral contraceptives and nonsteroidal anti-inflammatory drugs, have been described to influence inflammatory bowel diseases (IBD) [138,139,140]. Consequently, AHR has started to be considered as a potential target in treatments for the control of intestinal inflammation [141,142,143]. However, its activation has been also reported to lead to proinflammatory effects in the gut [144].

Moreover, AHR signaling plays a main role in the regulation of the proliferation of intestinal stem cells controlling Wnt/β-catenin, EGFR-MAPK/ERK and Notch pathways [145]. However, AHR expression appears to be deregulated in patients with colon cancer according to the cancer genome atlas (TCGA) database (https://xenabrowser.net/, accessed on 25 January 2021), although its endogenous activation by ligands from the diet such as Indole-3-acetic acid (IAA) or β-naphthoflavone (βNF) prevents colon tumorigenesis [146]. The AHR modulation by other ligands has paramount effect in gut because its exogenous activation by 6-Formylindolo [3,2-b]carbazole (FICZ) favors the differentiation of goblet cells enhancing the production of the mucus [144]. Moreover, tryptophan catabolites are responsible for the high production of interleukin 22, providing protection against pathogens [147,148], and in tolerogenic responses in the gastrointestinal tract both in mice and in zebrafish [149]. For these reasons, a correct balance of AHR signaling in this system is needed to maintain a proper physiological homeostasis.

4.4. Immune System

The products of tryptophan metabolism derived from bacterial activity mentioned in the previous section affect the activity of different types of immune cells through the activation of AHR [150]. A large body of evidence support a prominent role for AHR in the tolerogenic phenotype and progression of inflammatory and autoimmune diseases. There is an increase in tolerogenic regulatory T cells dependent on the degradation of tryptophan by the enzyme Indoleamine-pyrrole 2,3-dioxygenase (IDO1) and retinoid acid [151,152,153,154] and Lactobacillus reuteri (tryptophanase bacterium) stimulates AHR activity and suppresses proinflammatory activities [155,156]. In addition, certain CD4+CD25+Foxp3+ Treg subsets express higher levels of both AHR and Cyp1a1 [157,158]. In fact, AHR-/- models or its inhibition have shown less Treg differentiation [157,159,160,161]. Besides, AHR is connected and works together with CD39, a tolerogenic protein expressed in Treg cells, in the production of IL10 and differentiation of Tr1 cells [162,163,164]. AHR could modulate the gene expression of proinflammatory cytokines, since AHR binding sites have been identified in the promoters of these genes [165,166,167,168], and its activation by TCDD can reverse the demethylation of IL-17 promoters [160]. Moreover, various models of inflammatory and autoimmune diseases have revealed that activation of AHR in vivo by TCDD suppresses allergic responses and immune lung diseases as well as multiple sclerosis and diabetes [150].

4.5. Central Nervous System

AHR ligands impact neuronal proliferation, differentiation, and survival and consequently learning skills and memory [169]. It has been found that AHR modifies its gene expression temporally and spatially in the CNS of mice [170]. In addition, AHR is expressed by astrocytes, endothelial cells from the blood–brain barrier and glial cells, regulating CNS integrity and survival [171,172,173]. However, it should be noted that the activation of AHR by various ligands such as TCDD or 3,3′-Diindolylmethane (DIM) can cause neurodegeneration by triggering apoptotic events [174,175,176].

The importance of the “gut-brain axis” has begun to emerge and AHR plays a key role in this connection because microbial ligands have been detected in the brain in physiological conditions [177] and AHR activation by them controls CNS cell function [178,179]. In the experimental autoimmune encephalomyelitis (EAE) model, ITE (2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester) [180,181], I3S (indoxyl-3-sulphate) [182] and TA (tryptamine) [183] induce tolerogenic responses with attenuating neuroinflammation. The reduced level of these agonists is related to neural pathological processes as multiple sclerosis (MS) [182,184,185]. Additionally, the anti-inflammatory effect of AHR ligand Laquinimod, has emerged as a potential clinical treatment for both MS and Huntington disease [186,187].

4.6. Skin

The dioxin receptor modulates cell plasticity and migration, and its stimulation by xenobiotics results in severe lesions in the skin as contact hypersensitivity, dermatitis and chloracne. TCDD, the most potent AHR ligand known in humans with a wide range of pathogenic effects, is produced by ultraviolet radiation in the skin [188]. However, it has been described how ligand FICZ improves the skin barrier functions by reducing the local inflammation through involvement of OVO-like proteins [189]. In that context, AHR activation by TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) causes chloracne by a mechanism involving stem cells and keratinocytes, modifying gene expression of several genes encoding growth- and differentiation-regulating proteins and its chronic activation produces epidermal hyperplasia and sustained inflammation [190,191]. Furthermore, retinoic acid co-treatment with TCDD aggravates severity of skin lesions in hairless mice via induction of inflammatory response [192]. In line with this, Tapinarof, an AHR agonist derived from bacteria, has recently been reported to have beneficial clinical effects for the treatment of skin inflammation [193]. In contrast, pharmacological inhibition of AHR in human skin equivalents impaired terminal differentiation, epidermal stratification and stratum corneum formation [194]. AHR-/- mice have a patent altered skin homeostasis, regeneration, and hair cycling due to defects in the number and/or functionality of epidermal stem cells (EpdSCs) [195]. Additionally, AHR deficiency in the skin favors bacterial infection with difficulties in controlling stable skin microflora [196,197], while this lack of AHR also protects against UVB-induced cutaneous squamous cell carcinomas [198] or skin tumorigenesis caused by Benzo[a]pyrene [9].

4.7. Lung

AHR is considered as a modulator of lung inflammation, function and homeostasis. Most of lung cells show AHR expression, such us macrophages, club cells, alveolar type II cells and endothelial cells [199,200,201]. In particular, AHR participates in barrier function metabolizing components of pollution and other toxic compounds, which can damage lungs. In this way, deficient AHR murine models has been reported to have increased lung inflammation and damage upon exposure to tobacco smoke, lipopolysaccharide and hyperoxia [202,203,204]. Conversely, AHR activation by TCDD has been shown to control secretion of cytokines and infiltration of neutrophils and macrophages which can attenuate inflammation in rodent model of asthma [205] or model of acute hyperoxic lung injury [206]. However, receptor activation by air pollutants and cigarette smoke induce inflammation, contributing to the pathogenesis of chronic obstructive pulmonary disease [207,208,209]. However, lung regeneration has been improved in AHR-/- mice through the expansion of undifferentiated Clara and basal cells and of epithelial cells expressing pluripotency markers Nanog and Oct4 [210].

Regarding non-small-cell lung carcinoma (NSCLC), AHR is considered both a promoter and inhibitor. AHR promotes tumor development by sustaining cell stemness through Jak/Stat3 [211], detoxifying effects of benzo[a]pyrene [212] and regulating CYP1B1 enzyme [213,214]. In the opposite way, AHR represses lung tumors by reducing epithelial-to-mesenchymal transition and invasiveness [215], activation of TGFβ-Smad2 pathway, suppressing lung metastasis [216] and attenuating the oncogenic potential of K-RasG12D [108].

In fact, the involvement of the receptor in the SARS-CoV-2 infection triggered the AHR signaling in lung epithelial cells, leading to the overexpression of mucins and limiting host anti-viral responses mediated by IFN-I and NF-κβ, promoting viral replication [217,218]. Moreover, gene expression data available in gene expression omnibus (GEO) public repository have revealed the activation of AHR signaling following infection by M-CoV, SARS-CoV-1, HCoV-229E, MERS-CoV and SARS-CoV-2 viruses [217].

5. Final Thoughts

Since its discovery, AHR has been earning new functions and interactions over the years. As we have addressed in this review, its participation at molecular level involves changes and modifications in the genome structure, epigenetic patterns, regulation of gene expression and signaling pathways, all of them leading to an irrevocable control of tissue/organ physiology and homeostasis. This widespread participation has placed AHR at the core of cell migration, proliferation, pluripotency, tumorigenesis and regenerative processes. Such tendency raises AHR to an almost never-ending source of research in the upcoming years at molecular biology and biomedicine fields.

Funding Statement

This work was supported by grants to P.M.F-S. from the Spanish Ministry of Economy and Competitiveness (SAF2017-82597-R, PID2020-114846RB-I00) financed by MCIN/AEI/10.13039/501100011033 and from the Junta de Extremadura (GR21117 and IB20014). F.J.G.-R. was supported by the Junta de Extremadura and Programa Talento AECC (Asociación Española Contra el Cáncer). C.M.R.-G. and A.O.-T. were predoctoral fellows of the Ministry of Science and Innovation. B.M.-D. was under contract by the Ministry of Science and Innovation. All Spanish funding is co-sponsored by the European Union FEDER “Una manera de hacer Europa” program.

Author Contributions

C.M.R.-G., B.M.-D., A.O.-T., J.M.M., F.J.G.-R. and P.M.F.-S. contributed to the design and discussion of the review and writing of the manuscript; F.J.G.-R. and P.M.F.-S. coordinated the study and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare that the review was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Footnotes

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

1. Okey A.B., Bondy G.P., Mason M.E., Kahl G.F., Eisen H.J., Guenthner T.M., Nebert D.W. Regulatory gene product of the Ah locus. Characterization of the cytosolic inducer-receptor complex and evidence for its nuclear translocation. J. Biol. Chem. 1979;254:11636–11648. 10.1016/S0021-9258(19)86532-8. [Abstract] [CrossRef] [Google Scholar]
2. Poland A., Knutson J.C. 2,3,7,8-tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: Examination of the mechanism of toxicity. Annu. Rev. Pharmacol. Toxicol. 1982;22:517–554. 10.1146/annurev.pa.22.040182.002505. [Abstract] [CrossRef] [Google Scholar]
3. Greenlee W.F., Poland A. Nuclear uptake of 2,3,7,8-tetrachlorodibenzo-p-dioxin in C57BL/6J and DBA/2J mice. Role of the hepatic cytosol receptor protein. J. Biol. Chem. 1979;254:9814–9821. 10.1016/S0021-9258(19)83589-5. [Abstract] [CrossRef] [Google Scholar]
4. Reyes H., Reisz-Porszasz S., Hankinson O. Identification of the Ah Receptor Nuclear Translocator Protein (Arnt) as a Component of the DNA Binding Form of the Ah Receptor. Science. 1992;256:1193–1195. 10.1126/science.256.5060.1193. [Abstract] [CrossRef] [Google Scholar]
5. Bradfield C.A., Glover E., Poland A. Purification and N-terminal amino acid sequence of the Ah receptor from the C57BL/6J mouse. Mol. Pharmacol. 1991;39:13–19. [Abstract] [Google Scholar]
6. Burbach K.M., Poland A., Bradfield C.A. Cloning of the Ah-receptor cDNA reveals a distinctive ligand-activated transcription factor. Proc. Natl. Acad. Sci. USA. 1992;89:8185–8189. 10.1073/pnas.89.17.8185. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
7. Fernandez-Salguero P.M., Hilbert D.M., Rudikoff S., Ward J.M., Gonzalez F.J. Aryl-hydrocarbon receptor-deficient mice are resistant to 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced toxicity. Toxicol. Appl. Pharmacol. 1996;140:173–179. 10.1006/taap.1996.0210. [Abstract] [CrossRef] [Google Scholar]
8. Mimura J., Yamashita K., Nakamura K., Morita M., Takagi T.N., Nakao K., Ema M., Sogawa K., Yasuda M., Katsuki M., et al. Loss of teratogenic response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in mice lacking the Ah (dioxin) receptor. Genes Cells. 1997;2:645–654. 10.1046/j.1365-2443.1997.1490345.x. [Abstract] [CrossRef] [Google Scholar]
9. Shimizu Y., Nakatsuru Y., Ichinose M., Takahashi Y., Kume H., Mimura J., Fujii-Kuriyama Y., Ishikawa T. Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. USA. 2000;97:779–782. 10.1073/pnas.97.2.779. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
10. Marlowe J.L., Puga A. Aryl hydrocarbon receptor, cell cycle regulation, toxicity, and tumorigenesis. J. Cell. Biochem. 2005;96:1174–1184. 10.1002/jcb.20656. [Abstract] [CrossRef] [Google Scholar]
11. Kazlauskas A., Poellinger L., Pongratz I. Evidence That the Co-chaperone p23 Regulates Ligand Responsiveness of the Dioxin (Aryl Hydrocarbon) Receptor. J. Biol. Chem. 1999;274:13519–13524. 10.1074/jbc.274.19.13519. [Abstract] [CrossRef] [Google Scholar]
12. Kazlauskas A., Sundström S., Poellinger L., Pongratz I. The hsp90 chaperone complex regulates intracellular localization of the dioxin receptor. Mol. Cell. Biol. 2001;21:2594–2607. 10.1128/MCB.21.7.2594-2607.2001. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
13. Lees M.J., Whitelaw M.L. Multiple Roles of Ligand in Transforming the Dioxin Receptor to an Active Basic Helix-Loop-Helix/PAS Transcription Factor Complex with the Nuclear Protein Arnt. Mol. Cell. Biol. 1999;19:5811–5822. 10.1128/MCB.19.8.5811. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
14. Gomez-Duran A., Ballestar E., Carvajal-Gonzalez J.M., Marlowe J.L., Puga A., Esteller M., Fernandez-Salguero P.M. Recruitment of CREB1 and Histone Deacetylase 2 (HDAC2) to the Mouse Ltbp-1 Promoter Regulates its Constitutive Expression in a Dioxin Receptor-dependent Manner. J. Mol. Biol. 2008;380:1–16. 10.1016/j.jmb.2008.04.056. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
15. Niermann T., Schmutz S., Erne P., Resink T. Aryl hydrocarbon receptor ligands repress T-cadherin expression in vascular smooth muscle cells. Biochem. Biophys. Res. Commun. 2003;300:943–949. 10.1016/S0006-291X(02)02970-4. [Abstract] [CrossRef] [Google Scholar]
16. Ule J. Alu elements: At the crossroads between disease and evolution. Pt 6Biochem. Soc. Trans. 2013;41:1532–1535. 10.1042/BST20130157. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
17. Rejano-Gordillo C., Ordiales-Talavero A., Nacarino-Palma A., Merino J.M., González-Rico F.J., Fernández-Salguero P.M. Aryl Hydrocarbon Receptor: From Homeostasis to Tumor Progression. Front. Cell Dev. Biol. 2022;10:884004. 10.3389/fcell.2022.884004. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
18. Batzer M.A., Deininger P.L. Alu repeats and human genomic diversity. Nat. Rev. Genet. 2002;3:370–379. 10.1038/nrg798. [Abstract] [CrossRef] [Google Scholar]
19. Deininger P.L., Moran J.V., Batzer M.A., Kazazian H.H. Mobile elements and mammalian genome evolution. Curr. Opin. Genet. Dev. 2003;13:651–658. 10.1016/j.gde.2003.10.013. [Abstract] [CrossRef] [Google Scholar]
20. Vasicek T.J., Zeng L., Guan X.J., Zhang T., Costantini F., Tilghman S.M. Two dominant mutations in the mouse fused gene are the result of transposon insertions. Genetics. 1997;147:777–786. 10.1093/genetics/147.2.777. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
21. Kondo-Iida E., Kobayashi K., Watanabe M., Sasaki J., Kumagai T., Koide H., Saito K., Osawa M., Nakamura Y., Toda T. Novel mutations and genotype-phenotype relationships in 107 families with Fukuyama-type congenital muscular dystrophy (FCMD) Hum. Mol. Genet. 1999;8:2303–2309. 10.1093/hmg/8.12.2303. [Abstract] [CrossRef] [Google Scholar]
22. Gogvadze E., Buzdin A. Retroelements and their impact on genome evolution and functioning. Cell. Mol. Life Sci. 2009;66:3727–3742. 10.1007/s00018-009-0107-2. [Abstract] [CrossRef] [Google Scholar]
23. Polak P., Domany E. Alu elements contain many binding sites for transcription factors and may play a role in regulation of developmental processes. BMC Genom. 2006;7:133. 10.1186/1471-2164-7-133. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
24. Kramerov D.A., Grigoryan A.A., Ryskov A.P., Georgiev G.P. Long double-stranded sequences (dsRNA-B) of nuclear pre-mRNA consist of a few highly abundant classes of sequences: Evidence from DNA cloning experiments. Nucleic Acids Res. 1979;6:697–713. 10.1093/nar/6.2.697. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
25. Rubin C.M., Houck C.M., Deininger P.L., Friedmann T., Schmid C.W. Partial nucleotide sequence of the 300-nucleotide interspersed repeated human DNA sequences. Nature. 1980;284:372–374. 10.1038/284372a0. [Abstract] [CrossRef] [Google Scholar]
26. Deininger P.L., Jolly D.J., Rubin C.M., Friedmann T., Schmid C.W. Base sequence studies of 300 nucleotide renatured repeated human DNA clones. J. Mol. Biol. 1981;151:17–33. 10.1016/0022-2836(81)90219-9. [Abstract] [CrossRef] [Google Scholar]
27. Roman A.C., Benitez D.A., Carvajal-Gonzalez J.M., Fernandez-Salguero P.M. Genome-wide B1 retrotransposon binds the transcription factors dioxin receptor and Slug and regulates gene expression in vivo. Proc. Natl. Acad. Sci. USA. 2008;105:1632–1637. 10.1073/pnas.0708366105. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
28. Morales-Hernández A., González-Rico F.J., Román A.C., Rico-Leo E., Alvarez-Barrientos A., Sánchez L., Macia Á., Heras S.R., García-Pérez J.L., Merino J.M., et al. Alu retrotransposons promote differentiation of human carcinoma cells through the aryl hydrocarbon receptor. Nucleic Acids Res. 2016;44:4665–4683. 10.1093/nar/gkw095. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
29. Román A.C., González-Rico F.J., Moltó E., Hernando H., Neto A., Vicente-Garcia C., Ballestar E., Gómez-Skarmeta J.L., Vavrova-Anderson J., White R.J., et al. Dioxin receptor and SLUG transcription factors regulate the insulator activity of B1 SINE retrotransposons via an RNA polymerase switch. Genome Res. 2011;21:422–432. 10.1101/gr.111203.110. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
30. González-Rico F.J., Vicente-García C., Fernández A., Muñoz-Santos D., Montoliu L., Morales-Hernández A., Merino J.M., Román A.-C., Fernández-Salguero P.M. Alu retrotransposons modulate Nanog expression through dynamic changes in regional chromatin conformation via aryl hydrocarbon receptor. Epigenetics Chromatin. 2020;13:15. 10.1186/s13072-020-00336-w. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
31. Fraser J., Ferrai C., Chiariello A., Schueler M., Rito T., Laudanno G., Barbieri M., Moore B., Kraemer D., Aitken S., et al. Hierarchical folding and reorganization of chromosomes are linked to transcriptional changes in cellular differentiation. Mol. Syst. Biol. 2015;11:852. 10.15252/msb.20156492. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
32. Narendra V., Bulajić M., Dekker J., Mazzoni E.O., Reinberg D. CTCF-mediated topological boundaries during development foster appropriate gene regulation. Genes Dev. 2016;30:2657–2662. 10.1101/gad.288324.116. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
33. Bonev B., Mendelson Cohen N., Szabo Q., Fritsch L., Papadopoulos G.L., Lubling Y., Xu X., Lv X., Hugnot J.-P., Tanay A., et al. Multiscale 3D Genome Rewiring during Mouse Neural Development. Cell. 2017;171:557–572.e24. 10.1016/j.cell.2017.09.043. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
34. Poterlowicz K., Yarker J.L., Malashchuk I., Lajoie B.R., Mardaryev A.N., Gdula M.R., Sharov A.A., Kohwi-Shigematsu T., Botchkarev V.A., Fessing M.Y. 5C analysis of the Epidermal Differentiation Complex locus reveals distinct chromatin interaction networks between gene-rich and gene-poor TADs in skin epithelial cells. PLOS Genet. 2017;13:e1006966. 10.1371/journal.pgen.1006966. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
35. Niskanen H., Tuszynska I., Zaborowski R., Heinäniemi M., Ylä-Herttuala S., Wilczynski B., Kaikkonen M.U. Endothelial cell differentiation is encompassed by changes in long range interactions between inactive chromatin regions. Nucleic Acids Res. 2018;46:1724–1740. 10.1093/nar/gkx1214. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
36. Gialitakis M., Tolaini M., Li Y., Pardo M., Yu L., Toribio A., Choudhary J.S., Niakan K., Papayannopoulos V., Stockinger B. Activation of the Aryl Hydrocarbon Receptor Interferes with Early Embryonic Development. Stem Cell Rep. 2017;9:1377–1386. 10.1016/j.stemcr.2017.09.025. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
37. Mulero-Navarro S., Carvajal-Gonzalez J.M., Herranz M., Ballestar E., Fraga M.F., Ropero S., Esteller M., Fernandez-Salguero P.M. The dioxin receptor is silenced by promoter hypermethylation in human acute lymphoblastic leukemia through inhibition of Sp1 binding. Carcinogenesis. 2006;27:1099–1104. 10.1093/carcin/bgi344. [Abstract] [CrossRef] [Google Scholar]
38. Nabirochkin S., Ossokina M., Heidmann T. A Nuclear Matrix/Scaffold Attachment Region Co-localizes with the Gypsy Retrotransposon Insulator Sequence. J. Biol. Chem. 1998;273:2473–2479. 10.1074/jbc.273.4.2473. [Abstract] [CrossRef] [Google Scholar]
39. Glinsky G.V. Contribution of transposable elements and distal enhancers to evolution of human-specific features of interphase chromatin architecture in embryonic stem cells. Chromosome Res. 2018;26:61–84. 10.1007/s10577-018-9571-6. [Abstract] [CrossRef] [Google Scholar]
40. Román A.C., González-Rico F.J., Fernández-Salguero P.M. B1-SINE retrotransposons: Establishing genomic insulatory networks. Mob. Genet. Elem. 2011;1:66–70. 10.4161/mge.1.1.15455. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
41. Schmidt D., Schwalie P.C., Wilson M.D., Ballester B., Gonçalves A., Kutter C., Brown G.D., Marshall A., Flicek P., Odom D.T. Waves of retrotransposon expansion remodel genome organization and CTCF binding in multiple mammalian lineages. Cell. 2012;148:335–348. 10.1016/j.cell.2011.11.058. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
42. Phillips J.E., Corces V.G. CTCF: Master weaver of the genome. Cell. 2009;137:1194–1211. 10.1016/j.cell.2009.06.001. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
43. Wendt K.S., Yoshida K., Itoh T., Bando M., Koch B., Schirghuber E., Tsutsumi S., Nagae G., Ishihara K., Mishiro T., et al. Cohesin mediates transcriptional insulation by CCCTC-binding factor. Nature. 2008;451:796–801. 10.1038/nature06634. [Abstract] [CrossRef] [Google Scholar]
44. Parelho V., Hadjur S., Spivakov M., Leleu M., Sauer S., Gregson H.C., Jarmuz A., Canzonetta C., Webster Z., Nesterova T., et al. Cohesins functionally associate with CTCF on mammalian chromosome arms. [(accessed on 7 January 2022)];Cell. 2008 132:422–433. 10.1016/j.cell.2008.01.011. Available online: https://pubmed.ncbi.nlm.nih.gov/18237772/ [Abstract] [CrossRef] [Google Scholar]
45. Fu Y., Sinha M., Peterson C.L., Weng Z. The Insulator Binding Protein CTCF Positions 20 Nucleosomes around Its Binding Sites across the Human Genome. PLoS Genet. 2008;4:e1000138. 10.1371/journal.pgen.1000138. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
46. Larigot L., Juricek L., Dairou J., Coumoul X. AhR signaling pathways and regulatory functions. Biochim. Open. 2018;7:1–9. 10.1016/j.biopen.2018.05.001. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
47. Denison M.S., Soshilov A.A., He G., DeGroot D.E., Zhao B. Exactly the same but different: Promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. Toxicol. Sci. 2011;124:1–22. 10.1093/toxsci/kfr218. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
48. Lo Celso C., Prowse D.M., Watt F.M. Transient activation of beta-catenin signalling in adult mouse epidermis is sufficient to induce new hair follicles but continuous activation is required to maintain hair follicle tumours. Development. 2004;131:1787–1799. 10.1242/dev.01052. [Abstract] [CrossRef] [Google Scholar]
49. Faraldo M.M., Taddei-De La Hosseraye I., Teulière J., Deugnier M.-A., Moumen M., Thiery J.-P., Glukhova M.A. Mammary gland development: Role of basal myoepithelial cells. J. Soc. Biol. 2006;200:193–198. 10.1051/jbio:2006021. [Abstract] [CrossRef] [Google Scholar]
50. Liu F., Chu E.Y., Watt B., Zhang Y., Gallant N.M., Andl T., Yang S.H., Lu M.-M., Piccolo S., Schmidt-Ullrich R., et al. Wnt/beta-catenin signaling directs multiple stages of tooth morphogenesis. Dev. Biol. 2008;313:210–224. 10.1016/j.ydbio.2007.10.016. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
51. van Amerongen R., Berns A. Knockout mouse models to study Wnt signal transduction. Trends Genet. 2006;22:678–689. 10.1016/j.tig.2006.10.001. [Abstract] [CrossRef] [Google Scholar]
52. Grigoryan T., Wend P., Klaus A., Birchmeier W. Deciphering the function of canonical Wnt signals in development and disease: Conditional loss- and gain-of-function mutations of β-catenin in mice. Genes Dev. 2008;22:2308–2341. 10.1101/gad.1686208. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
53. Rudloff S., Kemler R. Differential requirements for β-catenin during mouse development. Dev. Camb. Engl. 2012;139:3711–3721. 10.1242/dev.085597. [Abstract] [CrossRef] [Google Scholar]
54. Polakis P. Wnt signaling in cancer. Cold Spring Harb. Perspect. Biol. 2012;4:a008052. 10.1101/cshperspect.a008052. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
55. Schneider A.J., Branam A.M., Peterson R.E. Intersection of AHR and Wnt signaling in development, health, and disease. Int. J. Mol. Sci. 2014;15:17852–17885. 10.3390/ijms151017852. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
56. Procházková J., Kabátková M., Bryja V., Umannová L., Bernatík O., Kozubík A., Machala M., Vondrácek J. The interplay of the aryl hydrocarbon receptor and β-catenin alters both AhR-dependent transcription and Wnt/β-catenin signaling in liver progenitors. Toxicol. Sci. 2011;122:349–360. 10.1093/toxsci/kfr129. [Abstract] [CrossRef] [Google Scholar]
57. Bjeldanes L.F., Kim J.Y., Grose K.R., Bartholomew J.C., Bradfield C.A. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: Comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc. Natl. Acad. Sci. USA. 1991;88:9543–9547. 10.1073/pnas.88.21.9543. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
58. Peter Guengerich F., Martin M.V., McCormick W.A., Nguyen L.P., Glover E., Bradfield C.A. Aryl hydrocarbon receptor response to indigoids in vitro and in vivo. Arch. Biochem. Biophys. 2004;423:309–316. 10.1016/j.abb.2004.01.002. [Abstract] [CrossRef] [Google Scholar]
59. Jeong Y.-M., Li H., Kim S.Y., Yun H.-Y., Baek K.J., Kwon N.S., Myung S.C., Kim D.-S. Indole-3-carbinol inhibits prostate cancer cell migration via degradation of beta-catenin. Oncol. Res. 2011;19:237–243. 10.3727/096504011X12970940207922. [Abstract] [CrossRef] [Google Scholar]
60. Kawajiri K., Kobayashi Y., Ohtake F., Ikuta T., Matsushima Y., Mimura J., Pettersson S., Pollenz R.S., Sakaki T., Hirokawa T., et al. Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in ApcMin/+ mice with natural ligands. Proc. Natl. Acad. Sci. USA. 2009;106:13481–13486. 10.1073/pnas.0902132106. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
61. Moreno-Marín N., Merino J.M., Alvarez-Barrientos A., Patel D.P., Takahashi S., González-Sancho J.M., Gandolfo P., Rios R.M., Muñoz A., Gonzalez F.J., et al. Aryl Hydrocarbon Receptor Promotes Liver Polyploidization and Inhibits PI3K, ERK, and Wnt/β-Catenin Signaling. iScience. 2018;4:44–63. 10.1016/j.isci.2018.05.006. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
62. Branam A.M., Davis N.M., Moore R.W., Schneider A.J., Vezina C.M., Peterson R.E. TCDD inhibition of canonical Wnt signaling disrupts prostatic bud formation in mouse urogenital sinus. Toxicol. Sci. 2013;133:42–53. 10.1093/toxsci/kft027. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
63. Mathew L.K., Sengupta S.S., Ladu J., Andreasen E.A., Tanguay R.L. Crosstalk between AHR and Wnt signaling through R-Spondin1 impairs tissue regeneration in zebrafish. FASEB J. 2008;22:3087–3096. 10.1096/fj.08-109009. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
64. Abdelrahim M., Smith R., Safe S. Aryl hydrocarbon receptor gene silencing with small inhibitory RNA differentially modulates Ah-responsiveness in MCF-7 and HepG2 cancer cells. Mol. Pharmacol. 2003;63:1373–1381. 10.1124/mol.63.6.1373. [Abstract] [CrossRef] [Google Scholar]
65. Pohjanvirta R., Miettinen H., Sankari S., Hegde N., Lindén J. Unexpected gender difference in sensitivity to the acute toxicity of dioxin in mice. Toxicol. Appl. Pharmacol. 2012;262:167–176. 10.1016/j.taap.2012.04.032. [Abstract] [CrossRef] [Google Scholar]
66. Sun L. Recent advances in the development of AHR antagonists in immuno-oncology. RSC Med. Chem. 2021;12:902–914. 10.1039/D1MD00015B. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
67. Rodon J., Dienstmann R., Serra V., Tabernero J. Development of PI3K inhibitors: Lessons learned from early clinical trials. Nat. Rev. Clin. Oncol. 2013;10:143–153. 10.1038/nrclinonc.2013.10. [Abstract] [CrossRef] [Google Scholar]
68. Shi X., Wang J., Lei Y., Cong C., Tan D., Zhou X. Research progress on the PI3K/AKT signaling pathway in gynecological cancer (Review) Mol. Med. Rep. 2019;19:4529–4535. 10.3892/mmr.2019.10121. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
69. Wu R., Zhang L., Hoagland M.S., Swanson H.I. Lack of the aryl hydrocarbon receptor leads to impaired activation of AKT/protein kinase B and enhanced sensitivity to apoptosis induced via the intrinsic pathway. J. Pharmacol. Exp. Ther. 2007;320:448–457. 10.1124/jpet.106.111773. [Abstract] [CrossRef] [Google Scholar]
70. Buscà R., Pouysségur J., Lenormand P. ERK1 and ERK2 Map Kinases: Specific Roles or Functional Redundancy? Front. Cell Dev. Biol. 2016;4:53. 10.3389/fcell.2016.00053. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
71. Shi F., Aloufi N., Traboulsi H., Trempe J.-F., Eidelman D.H., Baglole C.J. Endogenous regulation of the Akt pathway by the aryl hydrocarbon receptor (AhR) in lung fibroblasts. Sci. Rep. 2021;11:23189. 10.1038/s41598-021-02339-3. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
72. Koli K., Saharinen J., Hyytiäinen M., Penttinen C., Keski-Oja J. Latency, activation, and binding proteins of TGF-beta. Microsc. Res. Tech. 2001;52:354–362. 10.1002/1097-0029(20010215)52:4<354::AID-JEMT1020>3.0.CO;2-G. [Abstract] [CrossRef] [Google Scholar]
73. Rifkin D.B. Latent transforming growth factor-beta (TGF-beta) binding proteins: Orchestrators of TGF-beta availability. J. Biol. Chem. 2005;280:7409–7412. 10.1074/jbc.R400029200. [Abstract] [CrossRef] [Google Scholar]
74. Lawrence D.A. Latent-TGF-beta: An overview. Mol. Cell. Biochem. 2001;219:163–170. 10.1023/A:1010819716023. [Abstract] [CrossRef] [Google Scholar]
75. Gomez-Duran A., Mulero-Navarro S., Chang X., Fernandez-Salguero P.M. LTBP-1 blockade in dioxin receptor-null mouse embryo fibroblasts decreases TGF-beta activity: Role of extracellular proteases plasmin and elastase. J. Cell. Biochem. 2006;97:380–392. 10.1002/jcb.20637. [Abstract] [CrossRef] [Google Scholar]
76. Corchero J., Martín-Partido G., Dallas S.L., Fernández-Salguero P.M. Liver portal fibrosis in dioxin receptor-null mice that overexpress the latent transforming growth factor-beta-binding protein-1. Int. J. Exp. Pathol. 2004;85:295–302. 10.1111/j.0959-9673.2004.00397.x. [Abstract] [CrossRef] [Google Scholar]
77. Carvajal-Gonzalez J.M., Mulero-Navarro S., Roman A.C., Sauzeau V., Merino J.M., Bustelo X.R., Fernandez-Salguero P.M. The dioxin receptor regulates the constitutive expression of the vav3 proto-oncogene and modulates cell shape and adhesion. Mol. Biol. Cell. 2009;20:1715–1727. 10.1091/mbc.e08-05-0451. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
78. Carvajal-Gonzalez J.M., Roman A.C., Cerezo-Guisado M.I., Rico-Leo E.M., Martin-Partido G., Fernandez-Salguero P.M. Loss of dioxin-receptor expression accelerates wound healing in vivo by a mechanism involving TGFbeta. Pt 11J. Cell Sci. 2009;122:1823–1833. 10.1242/jcs.047274. [Abstract] [CrossRef] [Google Scholar]
79. Sarić N., Selby M., Ramaswamy V., Kool M., Stockinger B., Hogstrand C., Williamson D., Marino S., Taylor M.D., Clifford S.C., et al. The AHR pathway represses TGFβ-SMAD3 signalling and has a potent tumour suppressive role in SHH medulloblastoma. Sci. Rep. 2020;10:148. 10.1038/s41598-019-56876-z. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
80. de Lima K.A., Donate P.B., Talbot J., Davoli-Ferreira M., Peres R.S., Cunha T.M., Alves-Filho J.C., Cunha F.Q. TGFβ1 signaling sustains aryl hydrocarbon receptor (AHR) expression and restrains the pathogenic potential of TH17 cells by an AHR-independent mechanism. Cell Death Dis. 2018;9:1130. 10.1038/s41419-018-1107-7. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
81. Nakano N., Sakata N., Katsu Y., Nochise D., Sato E., Takahashi Y., Yamaguchi S., Haga Y., Ikeno S., Motizuki M., et al. Dissociation of the AhR/ARNT complex by TGF-β/Smad signaling represses CYP1A1 gene expression and inhibits benze[a]pyrene-mediated cytotoxicity. J. Biol. Chem. 2020;295:9033–9051. 10.1074/jbc.RA120.013596. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
82. Fitzgerald K.A., Rowe D.C., Barnes B.J., Caffrey D.R., Visintin A., Latz E., Monks B., Pitha P.M., Golenbock D.T. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J. Exp. Med. 2003;198:1043–1055. 10.1084/jem.20031023. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
83. Tian Y., Ke S., Denison M.S., Rabson A.B., Gallo M.A. Ah Receptor and NF-κB Interactions, a Potential Mechanism for Dioxin Toxicity. J. Biol. Chem. 1999;274:510–515. 10.1074/jbc.274.1.510. [Abstract] [CrossRef] [Google Scholar]
84. Tian Y., Rabson A.B., Gallo M.A. Ah receptor and NF-kappaB interactions: Mechanisms and physiological implications. Chem. Biol. Interact. 2002;141:97–115. 10.1016/S0009-2797(02)00068-6. [Abstract] [CrossRef] [Google Scholar]
85. Yu M., Wang Q., Ma Y., Li L., Yu K., Zhang Z., Chen G., Li X., Xiao W., Xu P., et al. Aryl Hydrocarbon Receptor Activation Modulates Intestinal Epithelial Barrier Function by Maintaining Tight Junction Integrity. Int. J. Biol. Sci. 2018;14:69–77. 10.7150/ijbs.22259. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
86. Vázquez-Gómez G., Karasová M., Tylichová Z., Kabátková M., Hampl A., Matthews J., Neča J., Ciganek M., Machala M., Vondráček J. Aryl Hydrocarbon Receptor (AhR) Limits the Inflammatory Responses in Human Lung Adenocarcinoma A549 Cells via Interference with NF-κB Signaling. Cells. 2022;11:707. 10.3390/cells11040707. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
87. Chen P.-H., Chang H., Chang J.T., Lin P. Aryl hydrocarbon receptor in association with RelA modulates IL-6 expression in non-smoking lung cancer. Oncogene. 2012;31:2555–2565. 10.1038/onc.2011.438. [Abstract] [CrossRef] [Google Scholar]
88. Domínguez-Acosta O., Vega L., Estrada-Muñiz E., Rodríguez M.S., Gonzalez F.J., Elizondo G. Activation of aryl hydrocarbon receptor regulates the LPS/IFNγ-induced inflammatory response by inducing ubiquitin-proteosomal and lysosomal degradation of RelA/p65. Biochem. Pharmacol. 2018;155:141–149. 10.1016/j.bcp.2018.06.016. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
89. Curran C.S., Kopp J.B. Aryl Hydrocarbon Receptor Mechanisms Affecting Chronic Kidney Disease. Front. Pharmacol. 2022;13:782199. 10.3389/fphar.2022.782199. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
90. Vogel C.F.A., Sciullo E., Li W., Wong P., Lazennec G., Matsumura F. RelB, a new partner of aryl hydrocarbon receptor-mediated transcription. Mol. Endocrinol. 2007;21:2941–2955. 10.1210/me.2007-0211. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
91. Beischlag T.V., Wang S., Rose D.W., Torchia J., Reisz-Porszasz S., Muhammad K., Nelson W.E., Probst M.R., Rosenfeld M.G., Hankinson O. Recruitment of the NCoA/SRC-1/p160 family of transcriptional coactivators by the aryl hydrocarbon receptor/aryl hydrocarbon receptor nuclear translocator complex. Mol. Cell. Biol. 2002;22:4319–4333. 10.1128/MCB.22.12.4319-4333.2002. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
92. Klinge C.M., Jernigan S.C., Risinger K.E., Lee J.E., Tyulmenkov V.V., Falkner K.C., Prough R.A. Short heterodimer partner (SHP) orphan nuclear receptor inhibits the transcriptional activity of aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT) Arch. Biochem. Biophys. 2001;390:64–70. 10.1006/abbi.2001.2366. [Abstract] [CrossRef] [Google Scholar]
93. Wang S., Hankinson O. Functional involvement of the Brahma/SWI2-related gene 1 protein in cytochrome P4501A1 transcription mediated by the aryl hydrocarbon receptor complex. J. Biol. Chem. 2002;277:11821–11827. 10.1074/jbc.M110122200. [Abstract] [CrossRef] [Google Scholar]
94. Wang S., Ge K., Roeder R.G., Hankinson O. Role of Mediator in Transcriptional Activation by the Aryl Hydrocarbon Receptor. J. Biol. Chem. 2004;279:13593–13600. 10.1074/jbc.M312274200. [Abstract] [CrossRef] [Google Scholar]
95. Matthews J., Gustafsson J.-Å. Estrogen receptor and aryl hydrocarbon receptor signaling pathways. Nucl. Recept. Signal. 2006;4:e016. 10.1621/nrs.04016. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
96. Marlowe J.L., Knudsen E.S., Schwemberger S., Puga A. The aryl hydrocarbon receptor displaces p300 from E2F-dependent promoters and represses S phase-specific gene expression. J. Biol. Chem. 2004;279:29013–29022. 10.1074/jbc.M404315200. [Abstract] [CrossRef] [Google Scholar]
97. Jones L.C., Okino S.T., Gonda T.J., Whitlock J.P.J. Myb-binding protein 1a augments AhR-dependent gene expression. J. Biol. Chem. 2002;277:22515–22519. 10.1074/jbc.M200740200. [Abstract] [CrossRef] [Google Scholar]
98. Antenos M., Casper R.F., Brown T.J. Interaction with Nedd8, a ubiquitin-like protein, enhances the transcriptional activity of the aryl hydrocarbon receptor. J. Biol. Chem. 2002;277:44028–44034. 10.1074/jbc.M202413200. [Abstract] [CrossRef] [Google Scholar]
99. Nacarino-Palma A., Rico-Leo E.M., Campisi J., Ramanathan A., González-Rico F.J., Rejano-Gordillo C.M., Ordiales-Talavero A., Merino J.M., Fernández-Salguero P.M. Aryl hydrocarbon receptor blocks aging-induced senescence in the liver and fibroblast cells. Aging. 2022;14:4281–4304. 10.18632/aging.204103. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
100. Roman A.C., Carvajal-Gonzalez J.M., Rico-Leo E.M., Fernandez-Salguero P.M. Dioxin receptor deficiency impairs angiogenesis by a mechanism involving VEGF-A depletion in the endothelium and transforming growth factor-beta overexpression in the stroma. J. Biol. Chem. 2009;284:25135–25148. 10.1074/jbc.M109.013292. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
101. Tischkau S.A., Jaeger C.D., Krager S.L. Circadian clock disruption in the mouse ovary in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol. Lett. 2011;201:116–122. 10.1016/j.toxlet.2010.12.013. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
102. Rey-Barroso J., Alvarez-Barrientos A., Rico-Leo E., Contador-Troca M., Carvajal-Gonzalez J.M., Echarri A., Del Pozo M.A., Fernandez-Salguero P.M. The Dioxin receptor modulates Caveolin-1 mobilization during directional migration: Role of cholesterol. Cell Commun. Signal. 2014;12:57. 10.1186/s12964-014-0057-7. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
103. Fernandez-Salguero P.M., Ward J.M., Sundberg J.P., Gonzalez F.J. Lesions of Aryl-hydrocarbon Receptor–deficient Mice. Vet. Pathol. 1997;34:605–614. 10.1177/030098589703400609. [Abstract] [CrossRef] [Google Scholar]
104. Hahn M.E., Karchner S.I., Shapiro M.A., Perera S.A. Molecular evolution of two vertebrate aryl hydrocarbon (dioxin) receptors (AHR1 and AHR2) and the PAS family. Proc. Natl. Acad. Sci. USA. 1997;94:13743–13748. 10.1073/pnas.94.25.13743. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
105. Chang C.Y., Puga A. Constitutive activation of the aromatic hydrocarbon receptor. Mol. Cell. Biol. 1998;18:525–535. 10.1128/MCB.18.1.525. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
106. Harper P.A., Riddick D.S., Okey A.B. Regulating the regulator: Factors that control levels and activity of the aryl hydrocarbon receptor. Biochem. Pharmacol. 2006;72:267–279. 10.1016/j.bcp.2006.01.007. [Abstract] [CrossRef] [Google Scholar]
107. Zablon H.A., Ko C.-I., Puga A. Converging Roles of the Aryl Hydrocarbon Receptor in Early Embryonic Development, Maintenance of Stemness, and Tissue Repair. Toxicol. Sci. 2021;182:1–9. 10.1093/toxsci/kfab050. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
108. Nacarino-Palma A., González-Rico F.J., Rejano-Gordillo C.M., Ordiales-Talavero A., Merino J.M., Fernández-Salguero P.M. The aryl hydrocarbon receptor promotes differentiation during mouse preimplantational embryo development. Stem Cell Rep. 2021;16:2351–2363. 10.1016/j.stemcr.2021.08.002. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
109. Thackaberry E.A., Bedrick E.J., Goens M.B., Danielson L., Lund A.K., Gabaldon D., Smith S.M., Walker M.K. Insulin regulation in AhR-null mice: Embryonic cardiac enlargement, neonatal macrosomia, and altered insulin regulation and response in pregnant and aging AhR-null females. Toxicol. Sci. 2003;76:407–417. 10.1093/toxsci/kfg229. [Abstract] [CrossRef] [Google Scholar]
110. Goodale B.C., La Du J.K., Bisson W.H., Janszen D.B., Waters K.M., Tanguay R.L. AHR2 mutant reveals functional diversity of aryl hydrocarbon receptors in zebrafish. PLoS ONE. 2012;7:e29346. 10.1371/journal.pone.0029346. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
111. Kransler K.M., McGarrigle B.P., Olson J.R. Comparative developmental toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the hamster, rat and guinea pig. Toxicology. 2007;229:214–225. 10.1016/j.tox.2006.10.019. [Abstract] [CrossRef] [Google Scholar]
112. Takagi T.N., Matsui K.A., Yamashita K., Ohmori H., Yasuda M. Pathogenesis of cleft palate in mouse embryos exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Teratog. Carcinog. Mutagen. 2000;20:73–86. 10.1002/(SICI)1520-6866(2000)20:2<73::AID-TCM3>3.0.CO;2-M. [Abstract] [CrossRef] [Google Scholar]
113. Nishimura N., Matsumura F., Vogel C.F.A., Nishimura H., Yonemoto J., Yoshioka W., Tohyama C. Critical role of cyclooxygenase-2 activation in pathogenesis of hydronephrosis caused by lactational exposure of mice to dioxin. Toxicol. Appl. Pharmacol. 2008;231:374–383. 10.1016/j.taap.2008.05.012. [Abstract] [CrossRef] [Google Scholar]
114. Ko K., Theobald H.M., Peterson R.E. In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin in the C57BL/6J mouse prostate: Lobe-specific effects on branching morphogenesis. Toxicol. Sci. 2002;70:227–237. 10.1093/toxsci/70.2.227. [Abstract] [CrossRef] [Google Scholar]
115. Ricke W.A., Lee C.W., Clapper T.R., Schneider A.J., Moore R.W., Keil K.P., Abler L.L., Wynder J.L., López Alvarado A., Beaubrun I., et al. In Utero and Lactational TCDD Exposure Increases Susceptibility to Lower Urinary Tract Dysfunction in Adulthood. Toxicol. Sci. 2016;150:429–440. 10.1093/toxsci/kfw009. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
116. Vezina C.M., Lin T.-M., Peterson R.E. AHR signaling in prostate growth, morphogenesis, and disease. Biochem. Pharmacol. 2009;77:566–576. 10.1016/j.bcp.2008.09.039. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
117. Bugiak B.J., Weber L.P. Phenotypic anchoring of gene expression after developmental exposure to aryl hydrocarbon receptor ligands in zebrafish. Aquat. Toxicol. 2010;99:423–437. 10.1016/j.aquatox.2010.06.003. [Abstract] [CrossRef] [Google Scholar]
118. Burns F.R., Peterson R.E., Heideman W. Dioxin disrupts cranial cartilage and dermal bone development in zebrafish larvae. Aquat. Toxicol. 2015;164:52–60. 10.1016/j.aquatox.2015.04.005. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
119. Harstad E.B., Guite C.A., Thomae T.L., Bradfield C.A. Liver deformation in Ahr-null mice: Evidence for aberrant hepatic perfusion in early development. Mol. Pharmacol. 2006;69:1534–1541. 10.1124/mol.105.020107. [Abstract] [CrossRef] [Google Scholar]
120. Fernandez-Salguero P., Pineau T., Hilbert D.M., McPhail T., Lee S.S., Kimura S., Nebert D.W., Rudikoff S., Ward J.M., Gonzalez F.J. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science. 1995;268:722–726. 10.1126/science.7732381. [Abstract] [CrossRef] [Google Scholar]
121. Lahvis G.P., Lindell S.L., Thomas R.S., McCuskey R.S., Murphy C., Glover E., Bentz M., Southard J., Bradfield C.A. Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice. Proc. Natl. Acad. Sci. USA. 2000;97:10442–10447. 10.1073/pnas.190256997. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
122. Eti N.A., Flor S., Iqbal K., Scott R.L., Klenov V.E., Gibson-Corley K.N., Soares M.J., Ludewig G., Robertson L.W. PCB126 induced toxic actions on liver energy metabolism is mediated by AhR in rats. Toxicology. 2022;466:153054. 10.1016/j.tox.2021.153054. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
123. Jourova L., Anzenbacherova E., Dostal Z., Anzenbacher P., Briolotti P., Rigal E., Daujat-Chavanieu M., Gerbal-Chaloin S. Butyrate, a typical product of gut microbiome, affects function of the AhR gene, being a possible agent of crosstalk between gut microbiome, and hepatic drug metabolism. J. Nutr. Biochem. 2022;107:109042. 10.1016/j.jnutbio.2022.109042. [Abstract] [CrossRef] [Google Scholar]
124. Zhao W., Guo M., Feng J., Gu Z., Zhao J., Zhang H., Wang G., Chen W. Myristica fragrans Extract Regulates Gut Microbes and Metabolites to Attenuate Hepatic Inflammation and Lipid Metabolism Disorders via the AhR–FAS and NF-κB Signaling Pathways in Mice with Non-Alcoholic Fatty Liver Disease. Nutrients. 2022;14:1699. 10.3390/nu14091699. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
125. Sanmarco L.M., Chao C.-C., Wang Y.-C., Kenison J.E., Li Z., Rone J.M., Rejano-Gordillo C.M., Polonio C.M., Gutierrez-Vazquez C., Piester G., et al. Identification of environmental factors that promote intestinal inflammation. Nature. 2022;611:801–809. 10.1038/s41586-022-05308-6. [Abstract] [CrossRef] [Google Scholar]
126. Contador-Troca M., Alvarez-Barrientos A., Merino J.M., Morales-Hernández A., Rodríguez M.I., Rey-Barroso J., Barrasa E., Cerezo-Guisado M.I., Catalina-Fernández I., Sáenz-Santamaría J., et al. Dioxin receptor regulates aldehyde dehydrogenase to block melanoma tumorigenesis and metastasis. Mol. Cancer. 2015;14:148. 10.1186/s12943-015-0419-9. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
127. Esser C., Rannug A. The Aryl Hydrocarbon Receptor in Barrier Organ Physiology, Immunology, and Toxicology. Pharmacol. Rev. 2015;67:259–279. 10.1124/pr.114.009001. [Abstract] [CrossRef] [Google Scholar]
128. Ko C.-I., Fan Y., de Gannes M., Wang Q., Xia Y., Puga A. Repression of the Aryl Hydrocarbon Receptor Is Required to Maintain Mitotic Progression and Prevent Loss of Pluripotency of Embryonic Stem Cells. Stem Cells. 2016;34:2825–2839. 10.1002/stem.2456. [Abstract] [CrossRef] [Google Scholar]
129. Sartor M.A., Schnekenburger M., Marlowe J.L., Reichard J.F., Wang Y., Fan Y., Ma C., Karyala S., Halbleib D., Liu X., et al. Genomewide Analysis of Aryl Hydrocarbon Receptor Binding Targets Reveals an Extensive Array of Gene Clusters that Control Morphogenetic and Developmental Programs. Environ. Health Perspect. 2009;117:1139–1146. 10.1289/ehp.0800485. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
130. Rejano-Gordillo C.M., González-Rico F.J., Marín-Díaz B., Ordiales-Talavero A., Nacarino-Palma A., Román Á.C., Merino J.M., Fernández-Salguero P.M. Liver regeneration after partial hepatectomy is improved in the absence of aryl hydrocarbon receptor. Sci. Rep. 2022;12:15446. 10.1038/s41598-022-19733-0. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
131. Vondráček J., Machala M. Environmental Ligands of the Aryl Hydrocarbon Receptor and Their Effects in Models of Adult Liver Progenitor Cells. Stem Cells Int. 2016;2016:4326194. 10.1155/2016/4326194. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
132. Fan Y., Boivin G.P., Knudsen E.S., Nebert D.W., Xia Y., Puga A. The Aryl Hydrocarbon Receptor Functions as a Tumor Suppressor of Liver Carcinogenesis. Cancer Res. 2010;70:212–220. 10.1158/0008-5472.CAN-09-3090. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
133. Moreno-Marín N., Barrasa E., Morales-Hernández A., Paniagua B., Blanco-Fernández G., Merino J.M., Fernández-Salguero P.M. Dioxin Receptor Adjusts Liver Regeneration after Acute Toxic Injury and Protects Against Liver Carcinogenesis. Sci. Rep. 2017;7:10420. 10.1038/s41598-017-10984-w. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
134. Jackson D.P., Li H., Mitchell K.A., Joshi A.D., Elferink C.J. Ah Receptor–Mediated Suppression of Liver Regeneration through NC-XRE–Driven p21 Cip1 Expression. Mol. Pharmacol. 2014;85:533–541. 10.1124/mol.113.089730. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
135. Mitchell K.A., Lockhart C.A., Huang G., Elferink C.J. Sustained Aryl Hydrocarbon Receptor Activity Attenuates Liver Regeneration. Mol. Pharmacol. 2006;70:163–170. 10.1124/mol.106.023465. [Abstract] [CrossRef] [Google Scholar]
136. de Tomaso Portaz A.C., Caimi G.R., Sánchez M., Chiappini F., Randi A.S., Kleiman de Pisarev D.L., Alvarez L. Hexachlorobenzene induces cell proliferation, and aryl hydrocarbon receptor expression (AhR) in rat liver preneoplastic foci, and in the human hepatoma cell line HepG2. AhR is a mediator of ERK1/2 signaling, and cell cycle regulation in HCB-treated HepG2 cells. Toxicology. 2015;336:36–47. [Abstract] [Google Scholar]
137. Korecka A., Dona A., Lahiri S., Tett A.J., Al-Asmakh M., Braniste V., D’Arienzo R., Abbaspour A., Reichardt N., Fujii-Kuriyama Y., et al. Bidirectional communication between the Aryl hydrocarbon Receptor (AhR) and the microbiome tunes host metabolism. Npj Biofilms Microbiomes. 2016;2:16014. 10.1038/npjbiofilms.2016.14. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
138. Agus A., Planchais J., Sokol H. Gut Microbiota Regulation of Tryptophan Metabolism in Health and Disease. Cell Host Microbe. 2018;23:716–724. 10.1016/j.chom.2018.05.003. [Abstract] [CrossRef] [Google Scholar]
139. Lamas B., Richard M.L., Leducq V., Pham H.-P., Michel M.-L., Da Costa G., Bridonneau C., Jegou S., Hoffmann T.W., Natividad J.M., et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat. Med. 2016;22:598–605. 10.1038/nm.4102. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
140. Lamas B., Natividad J.M., Sokol H. Aryl hydrocarbon receptor and intestinal immunity. Mucosal Immunol. 2018;11:1024–1038. 10.1038/s41385-018-0019-2. [Abstract] [CrossRef] [Google Scholar]
141. Goettel J.A., Gandhi R., Kenison J.E., Yeste A., Murugaiyan G., Sambanthamoorthy S., Griffith A.E., Patel B., Shouval D.S., Weiner H.L., et al. AHR Activation Is Protective against Colitis Driven by T Cells in Humanized Mice. Cell Rep. 2016;17:1318–1329. 10.1016/j.celrep.2016.09.082. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
142. Pernomian L., Duarte-Silva M., de Barros Cardoso C.R. The Aryl Hydrocarbon Receptor (AHR) as a Potential Target for the Control of Intestinal Inflammation: Insights from an Immune and Bacteria Sensor Receptor. Clin. Rev. Allergy Immunol. 2020;59:382–390. 10.1007/s12016-020-08789-3. [Abstract] [CrossRef] [Google Scholar]
143. Schiering C., Wincent E., Metidji A., Iseppon A., Li Y., Potocnik A.J., Omenetti S., Henderson C.J., Wolf C.R., Nebert D.W., et al. Feedback control of AHR signalling regulates intestinal immunity. Nature. 2017;542:242–245. 10.1038/nature21080. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
144. Rannug A. How the AHR Became Important in Intestinal Homeostasis-A Diurnal FICZ/AHR/CYP1A1 Feedback Controls Both Immunity and Immunopathology. Int. J. Mol. Sci. 2020;21:5681. 10.3390/ijms21165681. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
145. Wisniewski P.J., Nagarkatti M., Nagarkatti P.S. Regulation of Intestinal Stem Cell Stemness by the Aryl Hydrocarbon Receptor and Its Ligands. Front. Immunol. 2021;12:638725. 10.3389/fimmu.2021.638725. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
146. Han H., Davidson L.A., Hensel M., Yoon G., Landrock K., Allred C., Jayaraman A., Ivanov I., Safe S.H., Chapkin R.S. Loss of aryl hydrocarbon receptor promotes colon tumorigenesis in ApcS580/+; KrasG12D/+ mice. Mol. Cancer Res. 2021;19:771–783. 10.1158/1541-7786.MCR-20-0789. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
147. Monteleone I., Rizzo A., Sarra M., Sica G., Sileri P., Biancone L., MacDonald T.T., Pallone F., Monteleone G. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology. 2011;141:237–248.e1. 10.1053/j.gastro.2011.04.007. [Abstract] [CrossRef] [Google Scholar]
148. Zelante T., Iannitti R.G., Cunha C., De Luca A., Giovannini G., Pieraccini G., Zecchi R., D’Angelo C., Massi-Benedetti C., Fallarino F., et al. Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22. Immunity. 2013;39:372–385. 10.1016/j.immuni.2013.08.003. [Abstract] [CrossRef] [Google Scholar]
149. Abron J.D., Singh N.P., Mishra M.K., Price R.L., Nagarkatti M., Nagarkatti P.S., Singh U.P. An endogenous aryl hydrocarbon receptor ligand, ITE, induces regulatory T cells and ameliorates experimental colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 2018;315:G220–G230. 10.1152/ajpgi.00413.2017. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
150. Gutiérrez-Vázquez C., Quintana F.J. Regulation of the Immune Response by the Aryl Hydrocarbon Receptor. Immunity. 2018;48:19–33. 10.1016/j.immuni.2017.12.012. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
151. Hauben E., Gregori S., Draghici E., Migliavacca B., Olivieri S., Woisetschläger M., Roncarolo M.G. Activation of the aryl hydrocarbon receptor promotes allograft-specific tolerance through direct and dendritic cell–mediated effects on regulatory T cells. Blood. 2008;112:1214–1222. 10.1182/blood-2007-08-109843. [Abstract] [CrossRef] [Google Scholar]
152. King N.J.C., Thomas S.R. Molecules in focus: Indoleamine 2,3-dioxygenase. Int. J. Biochem. Cell Biol. 2007;39:2167–2172. 10.1016/j.biocel.2007.01.004. [Abstract] [CrossRef] [Google Scholar]
153. Mezrich J.D., Fechner J.H., Zhang X., Johnson B.P., Burlingham W.J., Bradfield C.A. An Interaction between Kynurenine and the Aryl Hydrocarbon Receptor Can Generate Regulatory T Cells. J. Immunol. 2010;185:3190–3198. 10.4049/jimmunol.0903670. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
154. Nguyen N.T., Kimura A., Nakahama T., Chinen I., Masuda K., Nohara K., Fujii-Kuriyama Y., Kishimoto T. Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism. Proc. Natl. Acad. Sci. USA. 2010;107:19961–19966. 10.1073/pnas.1014465107. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
155. Haase S., Haghikia A., Wilck N., Müller D.N., Linker R.A. Impacts of microbiome metabolites on immune regulation and autoimmunity. Immunology. 2018;154:230–238. 10.1111/imm.12933. [Abstract] [CrossRef] [Google Scholar]
156. Venkatesh M., Mukherjee S., Wang H., Li H., Sun K., Benechet A.P., Qiu Z., Maher L., Redinbo M.R., Phillips R.S., et al. Symbiotic Bacterial Metabolites Regulate Gastrointestinal Barrier Function via the Xenobiotic Sensor PXR and Toll-like Receptor 4. Immunity. 2014;41:296–310. 10.1016/j.immuni.2014.06.014. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
157. Quintana F.J., Basso A.S., Iglesias A.H., Korn T., Farez M.F., Bettelli E., Caccamo M., Oukka M., Weiner H.L. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature. 2008;453:65–71. 10.1038/nature06880. [Abstract] [CrossRef] [Google Scholar]
158. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 2006;6:295–307. 10.1038/nri1806. [Abstract] [CrossRef] [Google Scholar]
159. Kerkvliet N.I., Steppan L.B., Vorachek W., Oda S., Farrer D., Wong C.P., Pham D., Mourich D.V. Activation of aryl hydrocarbon receptor by TCDD prevents diabetes in NOD mice and increases Foxp3+ T cells in pancreatic lymph nodes. Immunotherapy. 2009;1:539–547. 10.2217/imt.09.24. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
160. Singh N.P., Singh U.P., Singh B., Price R.L., Nagarkatti M., Nagarkatti P.S. Activation of Aryl Hydrocarbon Receptor (AhR) Leads to Reciprocal Epigenetic Regulation of FoxP3 and IL-17 Expression and Amelioration of Experimental Colitis. PLoS ONE. 2011;6:e23522. 10.1371/journal.pone.0023522. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
161. Wei P., Hu G., Kang H., Yao H., Kou W., Liu H., Zhang C., Hong S. An aryl hydrocarbon receptor ligand acts on dendritic cells and T cells to suppress the Th17 response in allergic rhinitis patients. Lab. Investig. 2014;94:528–535. 10.1038/labinvest.2014.8. [Abstract] [CrossRef] [Google Scholar]
162. Apetoh L., Quintana F.J., Pot C., Joller N., Xiao S., Kumar D., Burns E.J., Sherr D.H., Weiner H.L., Kuchroo V.K. The aryl hydrocarbon receptor interacts with c-Maf to promote the differentiation of type 1 regulatory T cells induced by IL-27. Nat. Immunol. 2010;11:854–861. 10.1038/ni.1912. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
163. Gandhi R., Kumar D., Burns E.J., Nadeau M., Dake B., Laroni A., Kozoriz D., Weiner H.L., Quintana F.J. Activation of the aryl hydrocarbon receptor induces human type 1 regulatory T cell–like and Foxp3+ regulatory T cells. Nat. Immunol. 2010;11:846–853. 10.1038/ni.1915. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
164. Mascanfroni I.D., Takenaka M.C., Yeste A., Patel B., Wu Y., Kenison J.E., Siddiqui S., Basso A.S., Otterbein L.E., Pardoll D.M., et al. Metabolic control of type 1 regulatory (Tr1) cell differentiation by AHR and HIF1-α Nat. Med. 2015;21:638–646. 10.1038/nm.3868. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
165. DiNatale B.C., Schroeder J.C., Perdew G.H. Ah receptor antagonism inhibits constitutive and cytokine inducible IL6 production in head and neck tumor cell lines. Mol. Carcinog. 2011;50:173–183. 10.1002/mc.20702. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
166. Hollingshead B.D., Beischlag T.V., Dinatale B.C., Ramadoss P., Perdew G.H. Inflammatory signaling and aryl hydrocarbon receptor mediate synergistic induction of interleukin 6 in MCF-7 cells. Cancer Res. 2008;68:3609–3617. 10.1158/0008-5472.CAN-07-6168. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
167. Podechard N., Lecureur V., Le Ferrec E., Guenon I., Sparfel L., Gilot D., Gordon J.R., Lagente V., Fardel O. Interleukin-8 induction by the environmental contaminant benzo(a)pyrene is aryl hydrocarbon receptor-dependent and leads to lung inflammation. Toxicol. Lett. 2008;177:130–137. 10.1016/j.toxlet.2008.01.006. [Abstract] [CrossRef] [Google Scholar]
168. Sciullo E.M., Dong B., Vogel C.F.A., Matsumura F. Characterization of the pattern of the nongenomic signaling pathway through which TCDD-induces early inflammatory responses in U937 human macrophages. Chemosphere. 2009;74:1531–1537. 10.1016/j.chemosphere.2008.11.010. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
169. Keshavarzi M., Moradbeygi F., Mobini K., Ghaffarian Bahraman A., Mohammadi P., Ghaedi A., Mohammadi-Bardbori A. The interplay of aryl hydrocarbon receptor/WNT/CTNNB1/Notch signaling pathways regulate amyloid beta precursor mRNA/protein expression and effected the learning and memory of mice. Toxicol. Res. 2022;11:147–161. 10.1093/toxres/tfab120. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
170. Kimura E., Tohyama C. Embryonic and Postnatal Expression of Aryl Hydrocarbon Receptor mRNA in Mouse Brain. Front. Neuroanat. 2017;11:4. 10.3389/fnana.2017.00004. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
171. Filbrandt C.R., Wu Z., Zlokovic B., Opanashuk L., Gasiewicz T.A. Presence and Functional Activity of the Aryl Hydrocarbon Receptor in Isolated Murine Cerebral Vascular Endothelial Cells and Astrocytes. NeuroToxicology. 2004;25:605–616. 10.1016/j.neuro.2003.08.007. [Abstract] [CrossRef] [Google Scholar]
172. Kubota A., Stegeman J.J., Woodin B.R., Iwanaga T., Harano R., Peterson R.E., Hiraga T., Teraoka H. Role of zebrafish cytochrome P450 CYP1C genes in the reduced mesencephalic vein blood flow caused by activation of AHR2. Toxicol. Appl. Pharmacol. 2011;253:244–252. 10.1016/j.taap.2011.03.025. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
173. Li Y., Chen G., Zhao J., Nie X., Wan C., Liu J., Duan Z., Xu G. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces microglial nitric oxide production and subsequent rat primary cortical neuron apoptosis through p38/JNK MAPK pathway. Toxicology. 2013;312:132–141. 10.1016/j.tox.2013.08.008. [Abstract] [CrossRef] [Google Scholar]
174. Rzemieniec J., Litwa E., Wnuk A., Lason W., Krzeptowski W., Kajta M. Selective Aryl Hydrocarbon Receptor Modulator 3,3′-Diindolylmethane Impairs AhR and ARNT Signaling and Protects Mouse Neuronal Cells Against Hypoxia. Mol. Neurobiol. 2016;53:5591–5606. 10.1007/s12035-015-9471-0. [Abstract] [CrossRef] [Google Scholar]
175. Sánchez-Martín F.J., Fernández-Salguero P.M., Merino J.M. 2,3,7,8-Tetrachlorodibenzo-p-dioxin induces apoptosis in neural growth factor (NGF)-differentiated pheochromocytoma PC12 cells. NeuroToxicology. 2010;31:267–276. 10.1016/j.neuro.2010.03.005. [Abstract] [CrossRef] [Google Scholar]
176. Sánchez-Martín F.J., Fernández-Salguero P.M., Merino J.M. Aryl hydrocarbon receptor-dependent induction of apoptosis by 2,3,7,8-tetrachlorodibenzo-p-dioxin in cerebellar granule cells from mouse. J. Neurochem. 2011;118:153–162. 10.1111/j.1471-4159.2011.07291.x. [Abstract] [CrossRef] [Google Scholar]
177. Juricek L., Coumoul X. The Aryl Hydrocarbon Receptor and the Nervous System. Int. J. Mol. Sci. 2018;19:2504. 10.3390/ijms19092504. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
178. Rothhammer V., Borucki D.M., Tjon E.C., Takenaka M.C., Chao C.-C., Ardura-Fabregat A., de Lima K.A., Gutiérrez-Vázquez C., Hewson P., Staszewski O., et al. Microglial control of astrocytes in response to microbial metabolites. Nature. 2018;557:724–728. 10.1038/s41586-018-0119-x. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
179. Rothhammer V., Mascanfroni I.D., Bunse L., Takenaka M.C., Kenison J.E., Mayo L., Chao C.-C., Patel B., Yan R., Blain M., et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat. Med. 2016;22:586–597. 10.1038/nm.4106. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
180. Yeste A., Nadeau M., Burns E.J., Weiner H.L., Quintana F.J. Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA. 2012;109:11270–11275. 10.1073/pnas.1120611109. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
181. Zamali I., Rekik R., Belhadj Hmida N., Ben Hmid A., Kammoun O., Barbouche M.-R., Ben Ahmed M. An endogenous aryl hydrocarbon receptor ligand enhances de novo generation of regulatory T cells in humans. J. Leukoc. Biol. 2019;105:291–295. 10.1002/JLB.2AB0518-205RR. [Abstract] [CrossRef] [Google Scholar]
182. Dopkins N., Becker W., Miranda K., Walla M., Nagarkatti P., Nagarkatti M. Tryptamine Attenuates Experimental Multiple Sclerosis Through Activation of Aryl Hydrocarbon Receptor. Front. Pharmacol. 2021;11:619265. 10.3389/fphar.2020.619265. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
183. Rothhammer V., Borucki D.M., Kenison J.E., Hewson P., Wang Z., Bakshi R., Sherr D.H., Quintana F.J. Detection of aryl hydrocarbon receptor agonists in human samples. Sci. Rep. 2018;8:4970. 10.1038/s41598-018-23323-4. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
184. Rothhammer V., Borucki D.M., Garcia Sanchez M.I., Mazzola M.A., Hemond C.C., Regev K., Paul A., Kivisäkk P., Bakshi R., Izquierdo G., et al. Dynamic regulation of serum aryl hydrocarbon receptor agonists in MS. Neurol. Neuroimmunol. Neuroinflamm. 2017;4:e359. 10.1212/NXI.0000000000000359. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
185. Tsaktanis T., Beyer T., Nirschl L., Linnerbauer M., Grummel V., Bussas M., Tjon E., Mühlau M., Korn T., Hemmer B., et al. Aryl Hydrocarbon Receptor Plasma Agonist Activity Correlates with Disease Activity in Progressive MS. Neurol. Neuroimmunol. Neuroinflamm. 2020;8:e933. 10.1212/NXI.0000000000000933. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
186. Kaye J., Piryatinsky V., Birnberg T., Hingaly T., Raymond E., Kashi R., Amit-Romach E., Caballero I.S., Towfic F., Ator M.A., et al. Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. USA. 2016;113:E6145–E6152. 10.1073/pnas.1607843113. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
187. Rothhammer V., Kenison J.E., Li Z., Tjon E., Takenaka M.C., Chao C.-C., de Lima K.A., Borucki D.M., Kaye J., Quintana F.J. Aryl Hydrocarbon Receptor Activation in Astrocytes by Laquinimod Ameliorates Autoimmune Inflammation in the CNS. [(accessed on 11 February 2022)];Neurol. Neuroimmunol. Neuroinflamm. 2021 8:e946. 10.1212/NXI.0000000000000946. Available online: https://nn.neurology.org/content/8/2/e946. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
188. Rannug A., Rannug U., Rosenkranz H.S., Winqvist L., Westerholm R., Agurell E., Grafström A.K. Certain photooxidized derivatives of tryptophan bind with very high affinity to the Ah receptor and are likely to be endogenous signal substances. J. Biol. Chem. 1987;262:15422–15427. 10.1016/S0021-9258(18)47743-5. [Abstract] [CrossRef] [Google Scholar]
189. Tsuji G., Hashimoto-Hachiya A., Kiyomatsu-Oda M., Takemura M., Ohno F., Ito T., Morino-Koga S., Mitoma C., Nakahara T., Uchi H., et al. Aryl hydrocarbon receptor activation restores filaggrin expression via OVOL1 in atopic dermatitis. Cell Death Dis. 2017;8:e2931. 10.1038/cddis.2017.322. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
190. Furue M., Tsuji G., Mitoma C., Nakahara T., Chiba T., Morino-Koga S., Uchi H. Gene regulation of filaggrin and other skin barrier proteins via aryl hydrocarbon receptor. J. Dermatol. Sci. 2015;80:83–88. 10.1016/j.jdermsci.2015.07.011. [Abstract] [CrossRef] [Google Scholar]
191. Sutter C.H., Bodreddigari S., Campion C., Wible R.S., Sutter T.R. 2,3,7,8-Tetrachlorodibenzo-p-dioxin Increases the Expression of Genes in the Human Epidermal Differentiation Complex and Accelerates Epidermal Barrier Formation. Toxicol. Sci. 2011;124:128–137. 10.1093/toxsci/kfr205. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
192. Rudyak S.G., Usakin L.A., Tverye E.A., Orekhov A.S., Belushkina N.N., Paus R., Paltsev M.A., Panteleyev A.A. Retinoic acid co-treatment aggravates severity of dioxin-induced skin lesions in hairless mice via induction of inflammatory response. Biochem. Biophys. Res. Commun. 2018;506:854–861. 10.1016/j.bbrc.2018.10.126. [Abstract] [CrossRef] [Google Scholar]
193. Smith S.H., Jayawickreme C., Rickard D.J., Nicodeme E., Bui T., Simmons C., Coquery C.M., Neil J., Pryor W.M., Mayhew D., et al. Tapinarof Is a Natural AhR Agonist that Resolves Skin Inflammation in Mice and Humans. J. Investig. Dermatol. 2017;137:2110–2119. 10.1016/j.jid.2017.05.004. [Abstract] [CrossRef] [Google Scholar]
194. van den Bogaard E.H., Podolsky M.A., Smits J.P., Cui X., John C., Gowda K., Desai D., Amin S.G., Schalkwijk J., Perdew G.H., et al. Genetic and Pharmacological Analysis Identifies a Physiological Role for the AHR in Epidermal Differentiation. J. Investig. Dermatol. 2015;135:1320–1328. 10.1038/jid.2015.6. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
195. Rico-Leo E.M., Lorenzo-Martín L.F., Román Á.C., Bustelo X.R., Merino J.M., Fernández-Salguero P.M. Aryl hydrocarbon receptor controls skin homeostasis, regeneration, and hair follicle cycling by adjusting epidermal stem cell function. Stem Cells. 2021;39:1733–1750. 10.1002/stem.3443. [Abstract] [CrossRef] [Google Scholar]
196. Haas K., Weighardt H., Deenen R., Köhrer K., Clausen B., Zahner S., Boukamp P., Bloch W., Krutmann J., Esser C. Aryl Hydrocarbon Receptor in Keratinocytes Is Essential for Murine Skin Barrier Integrity. J. Investig. Dermatol. 2016;136:2260–2269. 10.1016/j.jid.2016.06.627. [Abstract] [CrossRef] [Google Scholar]
197. Uberoi A., Bartow-McKenney C., Zheng Q., Flowers L., Campbell A., Knight S.A.B., Chan N., Wei M., Lovins V., Bugayev J., et al. Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor. Cell Host Microbe. 2021;29:1235–1248.e8. 10.1016/j.chom.2021.05.011. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
198. Pollet M., Shaik S., Mescher M., Frauenstein K., Tigges J., Braun S.A., Sondenheimer K., Kaveh M., Bruhs A., Meller S., et al. The AHR represses nucleotide excision repair and apoptosis and contributes to UV-induced skin carcinogenesis. Cell Death Differ. 2018;25:1823–1836. 10.1038/s41418-018-0160-1. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
199. Saint-Georges F., Abbas I., Billet S., Verdin A., Gosset P., Mulliez P., Shirali P., Garçon G. Gene expression induction of volatile organic compound and/or polycyclic aromatic hydrocarbon-metabolizing enzymes in isolated human alveolar macrophages in response to airborne particulate matter (PM2.5) Toxicology. 2008;244:220–230. 10.1016/j.tox.2007.11.016. [Abstract] [CrossRef] [Google Scholar]
200. Shivanna B., Maity S., Zhang S., Patel A., Jiang W., Wang L., Welty S.E., Belmont J., Coarfa C., Moorthy B. Gene Expression Profiling Identifies Cell Proliferation and Inflammation as the Predominant Pathways Regulated by Aryl Hydrocarbon Receptor in Primary Human Fetal Lung Cells Exposed to Hyperoxia. Toxicol. Sci. 2016;152:155–168. 10.1093/toxsci/kfw071. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
201. Zhang S., Patel A., Chu C., Jiang W., Wang L., Welty S.E., Moorthy B., Shivanna B. Aryl hydrocarbon receptor is necessary to protect fetal human pulmonary microvascular endothelial cells against hyperoxic injury: Mechanistic roles of antioxidant enzymes and RelB. Toxicol. Appl. Pharmacol. 2015;286:92–101. 10.1016/j.taap.2015.03.023. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
202. Luebke R.W., Copeland C.B., Daniels M., Lambert A.L., Gilmour M.I. Suppression of Allergic Immune Responses to House Dust Mite (HDM) in Rats Exposed to 2,3,7,8-TCDD. Toxicol. Sci. 2001;62:71–79. 10.1093/toxsci/62.1.71. [Abstract] [CrossRef] [Google Scholar]
203. Lund A.K., Peterson S.L., Timmins G.S., Walker M.K. Endothelin-1–Mediated Increase in Reactive Oxygen Species and NADPH Oxidase Activity in Hearts of Aryl Hydrocarbon Receptor (AhR) Null Mice. Toxicol. Sci. 2005;88:265–273. 10.1093/toxsci/kfi284. [Abstract] [CrossRef] [Google Scholar]
204. Thatcher T.H., Maggirwar S.B., Baglole C.J., Lakatos H.F., Gasiewicz T.A., Phipps R.P., Sime P.J. Aryl Hydrocarbon Receptor-Deficient Mice Develop Heightened Inflammatory Responses to Cigarette Smoke and Endotoxin Associated with Rapid Loss of the Nuclear Factor-κB Component RelB. Am. J. Pathol. 2007;170:855–864. 10.2353/ajpath.2007.060391. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
205. Wong P.S., Vogel C.F., Kokosinski K., Matsumura F. Arylhydrocarbon Receptor Activation in NCI-H441 Cells and C57BL/6 Mice. Am. J. Respir. Cell Mol. Biol. 2010;42:210–217. 10.1165/rcmb.2008-0228OC. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
206. Shivanna B., Jiang W., Wang L., Couroucli X.I., Moorthy B. Omeprazole Attenuates Hyperoxic Lung Injury in Mice via Aryl Hydrocarbon Receptor Activation and Is Associated with Increased Expression of Cytochrome P4501A Enzymes. J. Pharmacol. Exp. Ther. 2011;339:106–114. 10.1124/jpet.111.182980. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
207. Sheridan J.A., Zago M., Nair P., Li P.Z., Bourbeau J., Tan W.C., Hamid Q., Eidelman D.H., Benedetti A.L., Baglole C.J. Decreased expression of the NF-κB family member RelB in lung fibroblasts from Smokers with and without COPD potentiates cigarette smoke-induced COX-2 expression. Respir. Res. 2015;16:54. 10.1186/s12931-015-0214-6. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
208. Thorley A.J., Tetley T.D. Pulmonary epithelium, cigarette smoke, and chronic obstructive pulmonary disease. Int. J. Chronic Obstr. Pulm. Dis. 2007;2:409–428. [Europe PMC free article] [Abstract] [Google Scholar]
209. Tsai M.-J., Hsu Y.-L., Wang T.-N., Wu L.-Y., Lien C.-T., Hung C.-H., Kuo P.-L., Huang M.-S. Aryl hydrocarbon receptor (AhR) agonists increase airway epithelial matrix metalloproteinase activity. J. Mol. Med. 2014;92:615–628. 10.1007/s00109-014-1121-x. [Abstract] [CrossRef] [Google Scholar]
210. Morales-Hernández A., Nacarino-Palma A., Moreno-Marín N., Barrasa E., Paniagua-Quiñones B., Catalina-Fernández I., Alvarez-Barrientos A., Bustelo X.R., Merino J.M., Fernández-Salguero P.M. Lung regeneration after toxic injury is improved in absence of dioxin receptor. Stem Cell Res. 2017;25:61–71. 10.1016/j.scr.2017.10.009. [Abstract] [CrossRef] [Google Scholar]
211. Xiong J., Zhang X., Zhang Y., Wu B., Fang L., Wang N., Yi H., Chang N., Chen L., Zhang J. Aryl hydrocarbon receptor mediates Jak2/STAT3 signaling for non-small cell lung cancer stem cell maintenance. Exp. Cell Res. 2020;396:112288. 10.1016/j.yexcr.2020.112288. [Abstract] [CrossRef] [Google Scholar]
212. Mao C., Wang M., Qian B., Ouyang L., Shi Y., Liu N., Chen L., Xiao D., Wang X., Cao Y., et al. Aryl hydrocarbon receptor activated by benzo (a) pyrene promotes SMARCA6 expression in NSCLC. Am. J. Cancer Res. 2018;8:1214–1227. [Europe PMC free article] [Abstract] [Google Scholar]
213. Lin P., Chang H., Ho W.L., Wu M.-H., Su J.-M. Association of aryl hydrocarbon receptor and cytochrome P4501B1 expressions in human non-small cell lung cancers. Lung Cancer. 2003;42:255–261. 10.1016/S0169-5002(03)00359-3. [Abstract] [CrossRef] [Google Scholar]
214. Lin P., Chang H., Tsai W.-T., Wu M.-H., Liao Y.-S., Chen J.-T., Su J.-M. Overexpression of Aryl Hydrocarbon Receptor in Human Lung Carcinomas. Toxicol. Pathol. 2003;31:22–30. 10.1080/01926230309746. [Abstract] [CrossRef] [Google Scholar]
215. Nothdurft S., Thumser-Henner C., Breitenbücher F., Okimoto R.A., Dorsch M., Opitz C.A., Sadik A., Esser C., Hölzel M., Asthana S., et al. Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis. Oncogenesis. 2020;9:102. 10.1038/s41389-020-00286-8. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
216. Lee C.-C., Yang W.-H., Li C.-H., Cheng Y.-W., Tsai C.-H., Kang J.-J. Ligand independent aryl hydrocarbon receptor inhibits lung cancer cell invasion by degradation of Smad4. Cancer Lett. 2016;376:211–217. 10.1016/j.canlet.2016.03.052. [Abstract] [CrossRef] [Google Scholar]
217. Giovannoni F., Li Z., Remes-Lenicov F., Dávola M.E., Elizalde M., Paletta A., Ashkar A.A., Mossman K.L., Dugour A.V., Figueroa J.M., et al. AHR signaling is induced by infection with coronaviruses. Nat. Commun. 2021;12:5148. 10.1038/s41467-021-25412-x. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
218. Giovannoni F., Quintana F.J. SARS-CoV-2-induced lung pathology: AHR as a candidate therapeutic target. Cell Res. 2021;31:1–2. 10.1038/s41422-020-00447-9. [Europe PMC free article] [Abstract] [CrossRef] [Google Scholar]
Articles from International Journal of Molecular Sciences are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

Full text links 

Read article at publisher's site: https://doi.org/10.3390/ijms232314919

Read article for free, from open access legal sources, via Unpaywall: https://www.mdpi.com/1422-0067/23/23/14919/pdf?version=1669705260Unpaywall

Citations & impact 

Impact metrics

6
Citations
Jump to Citations

Citations of article over time

Alternative metrics

Altmetric item for https://www.altmetric.com/details/139379331
Altmetric
Discover the attention surrounding your research
https://www.altmetric.com/details/139379331

Article citations

Go to all (6) article citations

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Funding 

Funders who supported this work.

European Union FEDER

    Junta de Extremadura (3)

    Junta de Extremadura and Programa Talento AECC

      Ministry of Science and Innovation

        Spanish Ministry of Economy and Competitiveness (3)