Dioxin‐Activated AHR: Toxic Responses and the Induction of Oxidative Stress

Stohs, Sidney J.; Hassoun, Ezdihar A.

doi:10.1002/9781118140574.ch15

Cited by 3 publications

(5 citation statements)

References 142 publications

(230 reference statements)

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“…The described findings are in contrast to the well-known increase in oxidative stress in response to AhR activation, for instance, induced by TCDD (for reviews, see [21, 43]). It has to be emphasized that the observed effects on DNA damage in vitro seem to depend on the cell type tested and are generally quite small [98–100].…”

Section: Discussioncontrasting

confidence: 76%

“…The second explanation for AhR-mediated activation of Nrf2 is based on the observation that activation of the AhR may increase intracellular ROS levels (for review, see [21, 43]). As stated above, production of ROS can be explained in vitro by AhR-mediated induction of CYP1A1 (for review, see [21]).…”

Section: The Ahr-nrf2 Pathwaymentioning

confidence: 99%

“…As stated above, production of ROS can be explained in vitro by AhR-mediated induction of CYP1A1 (for review, see [21]). An increase in intracellular ROS should lead to both oxidation of Keap1 and release of Nrf2 from the complex.…”

Section: The Ahr-nrf2 Pathwaymentioning

confidence: 99%

“…This redox cycling of the B[ a ]P metabolite B[ a ]P-7,8-diol leads to the release of superoxide anions and H 2 O 2 thereby rapidly inducing oxidative DNA damage [20]. In vitro , production of reactive oxygen species (ROS) can also be explained, among other mechanisms, by the induction of CYP1A1 (and CYP1B1), uncoupling of electron transfer, and hence superoxide release (for review, see [21]). However, there is increasing evidence that the AhR also displays protective functions against oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

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Antioxidant Functions of the Aryl Hydrocarbon Receptor

Dietrich

2016

Stem Cells International

121

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The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the basic helix-loop-helix/PER-ARNT-SIM family. It is activated by a variety of ligands, such as environmental contaminants like polycyclic aromatic hydrocarbons or dioxins, but also by naturally occurring compounds and endogenous ligands. Binding of the ligand leads to dimerization of the AhR with aryl hydrocarbon receptor nuclear translocator (ARNT) and transcriptional activation of several xenobiotic phase I and phase II metabolizing enzymes. It is generally accepted that the toxic responses of polycyclic aromatic hydrocarbons, dioxins, and structurally related compounds are mediated by activation of the AhR. A multitude of studies indicate that the AhR operates beyond xenobiotic metabolism and exerts pleiotropic functions. Increasing evidence points to a protective role of the AhR against carcinogenesis and oxidative stress. Herein, I will highlight data demonstrating a causal role of the AhR in the antioxidant response and present novel findings on potential AhR-mediated antioxidative mechanisms.

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Section: Discussioncontrasting

confidence: 76%

Section: The Ahr-nrf2 Pathwaymentioning

confidence: 99%

Section: The Ahr-nrf2 Pathwaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antioxidant Functions of the Aryl Hydrocarbon Receptor

Dietrich

2016

Stem Cells International

121

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“…On the other hand, pathways enriched more significantly or in a greater magnitude by the subacute than acute exposure included oxidoreductase activity, hydrogen peroxide biosynthetic process, oxidative demethylation, and electron carrier activity, collectively pointing to a response to oxidative stress. This is not unexpected, because oxidative stress is a common and, largely, tissue-independent consequence of TCDD exposure in rodents [71], and production of reactive oxygen species is synergistically augmented in the simultaneous presence of FICZ and ultraviolet A irradiation [72,73]. Interestingly, the gene showing the greatest increase in its expression level ( Slc7a11 ) was also induced by LAQ in mouse splenocytes 6 days after treatment [9].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Impact of IMA-08401, a Novel AHR Agonist Resembling Laquinimod, on Rat Liver

Prokopec

Pohjanvirta

Mahiout

et al. 2019

IJMS

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IMA-08401 (C2) is a novel aryl hydrocarbon receptor (AHR) agonist and selective AHR modulator (SAHRM) that is structurally similar to laquinimod (LAQ). Both compounds are converted to the AHR-active metabolite DELAQ (IMA-06201) in vivo. SAHRMs have been proposed as therapeutic options for various autoimmune disorders. Clinical trials on LAQ have not reported any significant toxic outcomes and C2 has shown low toxicity in rats; however, their functional resemblance to the highly toxic AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) raises questions. Here, we characterize the hepatic transcriptomic changes induced by acute (single-dose) and subacute exposure (repeated dosing for 5 days followed by a 5-day recovery period) to C2 in Sprague-Dawley rats. Exposure to C2 leads to activation of the AHR, as shown by altered transcription of Cyp1a1. We identify a heightened response early after exposure that drops off by day 10. Acute exposure to C2 leads to changes to transcription of genes involved in antiviral and antibacterial responses, which highlights the immunomodulator effects of this AHR agonist. Subacute exposure causes an oxidative stress response in the liver, the consequences of which require further study on target tissues such as the CNS and immune system, both of which may be compromised in this patient population.

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The aryl hydrocarbon receptor shapes monocyte transcriptional responses to interleukin-4 by prolonging STAT6 binding to promoters

de Juan,

Tabtim-On,

Coillard

et al. 2024

Sci. Signal.

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Cytokines induce functional and metabolic adaptations in immune cells, typically through transcriptional responses that can be influenced by other extracellular signals and by intracellular factors. The binding of the cytokine interleukin-4 (IL-4) to its receptor induces the phosphorylation and activation of the transcription factor STAT6. The aryl hydrocarbon receptor (AhR), a transcription factor activated by various endogenous and microbe-derived metabolites, modulates the responses of immune cells to danger signals or inflammatory mediators such as cytokines. Here, we investigated cross-talk between the AhR and signaling stimulated by IL-4 in human and mouse monocytes. AhR activation was required for a subset of IL-4–induced transcriptional responses and inhibited the IL-4–induced metabolic switch to fatty acid β-oxidation. The promoters of the genes that were induced by IL-4 in an AhR-dependent manner lacked canonical AhR binding sites, implying a nongenomic mechanism of AhR action. Mechanistically, AhR activation reduced the activity of SHP-1, a phosphatase that targets and inhibits STAT6, and prolonged STAT6 phosphorylation and binding to specific target loci, thus extending the duration of STAT6 activity. Our results identify AhR as a key player in the molecular control of responses to IL-4 in monocytes and suggest a nongenomic mechanism through which AhR ligands may influence the functional responses of cells to IL-4.

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Dioxin‐Activated AHR: Toxic Responses and the Induction of Oxidative Stress

Cited by 3 publications

References 142 publications

Antioxidant Functions of the Aryl Hydrocarbon Receptor

Antioxidant Functions of the Aryl Hydrocarbon Receptor

Transcriptomic Impact of IMA-08401, a Novel AHR Agonist Resembling Laquinimod, on Rat Liver

The aryl hydrocarbon receptor shapes monocyte transcriptional responses to interleukin-4 by prolonging STAT6 binding to promoters

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