Constitutive activation of the aryl hydrocarbon receptor in T-lineage cells induces thymus involution independently of the Fas/Fas ligand signaling pathway

Nagai, Haruko; Kubo, Masato; Ryo, Akihide; Yamamoto, Masayuki; Nohara, Keiko

doi:10.1016/j.intimp.2005.08.015

Cited by 11 publications

(2 citation statements)

References 36 publications

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“…Hence, the decrease of pAKT by TCDD in the thymus could also contribute to changes in subpopulations of developing thymocytes after TCDD treatment (Fig 2G ) as well as to decreased glycolysis by TCDD. The changes in thymus subpopulations by TCDD shown here are consistent with findings of others for TCDD effects on thymic subpopulations in mouse models [18,38,39].…”

Section: Discussionsupporting

confidence: 92%

Organ-specific effects on glycolysis by the dioxin-activated aryl hydrocarbon receptor

2020

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Activation of the aryl hydrocarbon receptor (AHR) by the environmental toxin dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) causes diverse toxicities, including thymus atrophy and hepatosteatosis. The mechanisms by which AHR activation by TCDD leads to these toxicities are not fully understood. Here we studied the effects of TCDD on a major energy pathway, glycolysis, using the chick embryo close to hatching, a well-established model for studying dioxin toxicity. We showed that 24 hr of TCDD treatment causes changes in glycolysis in both thymus and liver. In thymus glands, TCDD decreased mRNAs for glycolytic genes and glucose transporters, glycolytic indices and levels of IL7 mRNA, phosphorylated AKT (pAKT) and HIF1A, stimulators of glycolysis and promoters of survival and proliferation of thymic lymphocytes. In contrast, in liver, TCDD increased mRNA levels for glycolytic genes and glucose transporters, glycolytic endpoints and pAKT levels. Similarly, increases by TCDD in mRNA levels for glycolytic genes and glucose transporters in human primary hepatocytes showed that effects in chick embryo liver pertain also to human cells. Treatment with the glycolytic inhibitor 2-deoxy-d-glucose exacerbated the effects on thymus atrophy by TCDD, supporting a role for decreased glycolysis in thymus atrophy by TCDD, but did not prevent hepatosteatosis. NAD+ precursors abolished TCDD effects on glycolytic endpoints in both thymus and liver. In summary, we report here that dioxin disrupts glycolysis mediated energy metabolism in both thymus and liver, and that it does so in opposite ways, decreasing it in the thymus and increasing it in the liver. Further, the findings support NAD+ boosting as a strategy against metabolic effects of environmental pollutants such as dioxins.

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Section: Discussionsupporting

confidence: 92%

Organ-specific effects on glycolysis by the dioxin-activated aryl hydrocarbon receptor

2020

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“…A partial explanation for these seemingly dichotomous functions may lie in how the AhR is activated. Studies performed by Nagai et al (2006) suggest that dioxin-like compounds that cause the AhR to be permanently active lead to toxic effects, whereas dietary components that promote temporal activation, without persistent binding of the AhR/AhR nuclear translocator complex to dioxin response element sequences, might avoid toxic effects while promoting beneficial effects. More research is needed into how various ligands activate the AhR, and how this can result in variable and clinical relevant outcomes.…”

Section: Discussionmentioning

confidence: 99%

Using Nutrition for Intervention and Prevention against Environmental Chemical Toxicity and Associated Diseases

Hennig

Ettinger²,

Jandacek

et al. 2007

Environ Health Perspect

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BackgroundNutrition and lifestyle are well-defined modulators of chronic diseases. Poor dietary habits (such as high intake of processed foods rich in fat and low intake of fruits and vegetables), as well as a sedentary lifestyle clearly contribute to today’s compromised quality of life in the United States. It is becoming increasingly clear that nutrition can modulate the toxicity of environmental pollutants.ObjectivesOur goal in this commentary is to discuss the recommendation that nutrition should be considered a necessary variable in the study of human disease associated with exposure to environmental pollutants.DiscussionCertain diets can contribute to compromised health by being a source of exposure to environmental toxic pollutants. Many of these pollutants are fat soluble, and thus fatty foods often contain higher levels of persistent organics than does vegetable matter. Nutrition can dictate the lipid milieu, oxidative stress, and antioxidant status within cells. The modulation of these parameters by an individual’s nutritional status may have profound affects on biological processes, and in turn influence the effects of environmental pollutants to cause disease or dysfunction. For example, potential adverse health effects associated with exposure to polychlorinated biphenyls may increase as a result of ingestion of certain dietary fats, whereas ingestion of fruits and vegetables, rich in antioxidant and anti-inflammatory nutrients or bioactive compounds, may provide protection.ConclusionsWe recommend that future directions in environmental health research explore this nutritional paradigm that incorporates a consideration of the relationships between nutrition and lifestyle, exposure to environmental toxicants, and disease. Nutritional interventions may provide the most sensible means to develop primary prevention strategies of diseases associated with many environmental toxic insults.

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Discovery and Mechanistic Characterization of a Select Modulator of AhR-regulated Transcription (SMAhRT) with Anti-cancer Effects

et al. 2021

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Background: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and a member of the bHLH/PAS (basic Helix-Loop-Helix/Per-Arnt-Sim) family of proteins. The AhR was cloned and characterized for its role in mediating the toxicity of dioxins. Subsequent research has identi ed AhR's role in the suppression of cancer cell growth. We hypothesized that that the AhR is a molecular target for therapeutic interventions, and that activation of the AhR by select AhR modulators in cancer cells could have anti-cancer properties including cell death. This study describes the discovery and characterization of a new class of anti-cancer agents targeting the AhR.Methods: We employed two independent small molecule screening approaches to identify novel modulators of the AhR with unique anti-cancer properties. We established the AhR selective effects of a highly selective modulator in cancer cells with or without the AhR expression and identi ed the mechanism of action of this anti-cancer compound.Results: We report the identi cation of CGS-15943, uniquely selective AhR modulator, that activates AhR signaling and induces apoptosis in an AhR-dependent manner in liver and breast cancer cell models.Investigation of the downstream signaling pathway of this newly identi ed modulator revealed novel upregulation of Fas-ligand, which is required for AhR-mediated apoptosis.Conclusions: We identi ed CGS-15943 as a novel AhR-selective modulator with anti-cancer properties using two parallel and distinct screening strategies. This compound induced AhR-dependent apoptosis in multiple mouse and human liver cancer cells. Our results provide a basis for the development of a new class of anti-cancer therapeutics targeting an underappreciated molecular target, the AhR.

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Constitutive activation of the aryl hydrocarbon receptor in T-lineage cells induces thymus involution independently of the Fas/Fas ligand signaling pathway

Cited by 11 publications

References 36 publications

Organ-specific effects on glycolysis by the dioxin-activated aryl hydrocarbon receptor

Organ-specific effects on glycolysis by the dioxin-activated aryl hydrocarbon receptor

Using Nutrition for Intervention and Prevention against Environmental Chemical Toxicity and Associated Diseases

Discovery and Mechanistic Characterization of a Select Modulator of AhR-regulated Transcription (SMAhRT) with Anti-cancer Effects

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