Transgenic overexpression of aryl hydrocarbon receptor repressor (AhRR) and AhR-mediated induction of CYP1A1, cytokines, and acute toxicity

Christoph F A Vogel, W. L. William Chang, Sarah Kado, Kelly McCulloh, Helena Vogel, Dalei Wu, Thomas Haarmann-Stemmann, Guo Xiang Yang, Patrick S Leung, Fumio Matsumura, M. Eric Gershwin

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Abstract

Background: The aryl hydrocarbon receptor repressor (AhRR) is known to repress aryl hydro-carbon receptor (AhR) signaling, but very little is known regarding the role of the AhRR in vivo. oBjective: This study tested the role of AhRR in vivo in AhRR overexpressing mice on molecular and toxic end points mediated through a prototypical AhR ligand. Methods: We generated AhRR-transgenic mice (AhRR Tg) based on the genetic background of C57BL/6J wild type (wt) mice. We tested the effect of the prototypical AhR ligand 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD) on the expression of cytochrome P450 (CYP)1A1 and cytokines in various tissues of mice. We next analyzed the infiltration of immune cells in adipose tissue of mice after treatment with TCDD using flow cytometry. results: AhRR Tg mice express significantly higher levels of AhRR compared to wt mice. Activation of AhR by TCDD caused a significant increase of the inflammatory cytokines Interleukin (IL)-1β, IL-6 and IL-10, and CXCL chemokines in white epididymal adipose tissue from both wt and AhRR Tg mice. However, the expression of IL-1β, CXCL2 and CXCL3 were significantly lower in AhRR Tg versus wt mice following TCDD treatment. Exposure to TCDD caused a rapid accumulation of neutrophils and macrophages in white adipose tissue of wt and AhRR Tg mice. Furthermore we found that male AhRR Tg mice were protected from high-dose TCDD-induced lethality associated with a reduced inflammatory response and liver damage as indicated by lower levels of TCDD-induced alanine aminotransferase and hepatic triglycerides. Females from both wt and AhRR Tg mice were less sensitive than male mice to acute toxicity induced by TCDD. conclusion: In conclusion, the current study identifies AhRR as a previously uncharacterized regulator of specific inflammatory cytokines, which may protect from acute toxicity induced by TCDD.

Original languageEnglish (US)
Pages (from-to)1071-1083
Number of pages13
JournalEnvironmental Health Perspectives
Volume124
Issue number7
DOIs
StatePublished - Jul 1 2016

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Aryl Hydrocarbon Receptors
Cytochrome P-450 CYP1A1
Carbon
Cytokines
White Adipose Tissue
Interleukin-1
Ligands
1,4-dioxin
Poisons
Liver
Alanine Transaminase
Chemokines
Interleukin-10
Cytochrome P-450 Enzyme System
Transgenic Mice
Adipose Tissue
Interleukin-6

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Health, Toxicology and Mutagenesis

Cite this

Transgenic overexpression of aryl hydrocarbon receptor repressor (AhRR) and AhR-mediated induction of CYP1A1, cytokines, and acute toxicity. / Vogel, Christoph F A; William Chang, W. L.; Kado, Sarah; McCulloh, Kelly; Vogel, Helena; Wu, Dalei; Haarmann-Stemmann, Thomas; Yang, Guo Xiang; Leung, Patrick S; Matsumura, Fumio; Gershwin, M. Eric.

In: Environmental Health Perspectives, Vol. 124, No. 7, 01.07.2016, p. 1071-1083.

Research output: Contribution to journalArticle

Vogel, CFA, William Chang, WL, Kado, S, McCulloh, K, Vogel, H, Wu, D, Haarmann-Stemmann, T, Yang, GX, Leung, PS, Matsumura, F & Gershwin, ME 2016, 'Transgenic overexpression of aryl hydrocarbon receptor repressor (AhRR) and AhR-mediated induction of CYP1A1, cytokines, and acute toxicity', Environmental Health Perspectives, vol. 124, no. 7, pp. 1071-1083. https://doi.org/10.1289/ehp.1510194
Vogel, Christoph F A ; William Chang, W. L. ; Kado, Sarah ; McCulloh, Kelly ; Vogel, Helena ; Wu, Dalei ; Haarmann-Stemmann, Thomas ; Yang, Guo Xiang ; Leung, Patrick S ; Matsumura, Fumio ; Gershwin, M. Eric. / Transgenic overexpression of aryl hydrocarbon receptor repressor (AhRR) and AhR-mediated induction of CYP1A1, cytokines, and acute toxicity. In: Environmental Health Perspectives. 2016 ; Vol. 124, No. 7. pp. 1071-1083.
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AU - Kado, Sarah

AU - McCulloh, Kelly

AU - Vogel, Helena

AU - Wu, Dalei

AU - Haarmann-Stemmann, Thomas

AU - Yang, Guo Xiang

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AU - Matsumura, Fumio

AU - Gershwin, M. Eric

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