Epigenetic therapy: Novel translational implications for arrest of environmental dioxin-Induced disease in females

Zaraq Khan, Ye Zheng, Tiffanny L. Jones, Abigail A. Delaney, Luiz F. Correa, Chandra C. Shenoy, Khashayarsha Khazaie, Gaurang S. Daftary

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Increased toxicant exposure and resultant environmentally induced diseases are a tradeoff of industrial productivity. Dioxin [2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD)], a ubiquitous byproduct, is associated with a spectrum of diseases including endometriosis, a common, chronic disease in women. TCDD activates cytochrome (CYP) p450 metabolic enzymes that alter organ function to cause disease. In contrast, the transcription factor, Krüppel-like factor (KLF) 11, represses these enzymes via epigenetic mechanisms. In this study, we characterized these opposing mechanisms in vitro and in vivo as well as determining potential translational implications of epigenetic inhibitor therapy. KLF11 antagonized TCDD-mediated activation of CYP3A4 gene expression and function in endometrial cells. The repression was pharmacologically replicated by selective use of an epigenetic histone acetyltransferase inhibitor (HATI). We further showed phenotypic relevance of this mechanism using an animal model for endometriosis. Fibrotic extent in TCDD-exposed wild-type animals was similar to that previously observed in Klf112/2 animals. When TCDD-exposed animals were treated with a HATI, Cyp3 messenger RNA levels and protein expression decreased along with disease progression. Fibrotic progression is ubiquitous in environmentally induced chronic, untreatable diseases; this report shows that relentless disease progression can be arrested through targeted epigenetic modulation of protective mechanisms.

Original languageEnglish (US)
Pages (from-to)477-489
Number of pages13
JournalEndocrinology
Volume159
Issue number1
DOIs
StatePublished - Jan 1 2018

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Dioxins
Epigenomics
Histone Acetyltransferases
Endometriosis
Cytochrome P-450 Enzyme System
Disease Progression
Chronic Disease
Therapeutics
Cytochrome P-450 CYP3A
Wild Animals
Transcription Factors
Animal Models
Polychlorinated Dibenzodioxins
Gene Expression
Messenger RNA
Enzymes
Proteins

ASJC Scopus subject areas

  • Endocrinology

Cite this

Khan, Z., Zheng, Y., Jones, T. L., Delaney, A. A., Correa, L. F., Shenoy, C. C., ... Daftary, G. S. (2018). Epigenetic therapy: Novel translational implications for arrest of environmental dioxin-Induced disease in females. Endocrinology, 159(1), 477-489. https://doi.org/10.1210/en.2017-00860

Epigenetic therapy : Novel translational implications for arrest of environmental dioxin-Induced disease in females. / Khan, Zaraq; Zheng, Ye; Jones, Tiffanny L.; Delaney, Abigail A.; Correa, Luiz F.; Shenoy, Chandra C.; Khazaie, Khashayarsha; Daftary, Gaurang S.

In: Endocrinology, Vol. 159, No. 1, 01.01.2018, p. 477-489.

Research output: Contribution to journalArticle

Khan, Z, Zheng, Y, Jones, TL, Delaney, AA, Correa, LF, Shenoy, CC, Khazaie, K & Daftary, GS 2018, 'Epigenetic therapy: Novel translational implications for arrest of environmental dioxin-Induced disease in females', Endocrinology, vol. 159, no. 1, pp. 477-489. https://doi.org/10.1210/en.2017-00860
Khan, Zaraq ; Zheng, Ye ; Jones, Tiffanny L. ; Delaney, Abigail A. ; Correa, Luiz F. ; Shenoy, Chandra C. ; Khazaie, Khashayarsha ; Daftary, Gaurang S. / Epigenetic therapy : Novel translational implications for arrest of environmental dioxin-Induced disease in females. In: Endocrinology. 2018 ; Vol. 159, No. 1. pp. 477-489.
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