Epigenetic Therapy: Novel Translational Implications for Arrest of Environmental Dioxin-Induced Disease in Females

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 Klf11-/- 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.

Associations between Exposure to Organochlorine Chemicals and Endometriosis: A Systematic Review of Experimental Studies and Integration of Epidemiological Evidence

“…1996 ; Johnson et al. 1997 ; Khan et al. 2018 ), the results were not consistent nor significant enough across all studies and models to merit an increase in confidence for dose response or magnitude of effect.…”

“…There were also inconsistencies for in vivo lesion size, but we found that these could be explained by differences in experimental design and animal models. Despite the often significant increases in lesion size, especially for murine models, in a monotonic dose-response manner (Cummings and Metcalf 1995b;Cummings et al 1996;Johnson et al 1997;Khan et al 2018), the results were not consistent nor significant enough across all studies and models to merit an increase in confidence for dose response or magnitude of effect. Conversely, the divergence of results on viability/proliferation in vitro using similar doses and assays merited a downgrade in confidence due to unexplained inconsistency.…”

“…2004 ). Interestingly, one group studied the effects of two different vehicle controls ( Khan et al. 2018 ).…”

“…Another study, which tested E2 treatment alone and in combination with TCDD, as well as TCDD alone without E2, found results that corroborate TCDD's antiestrogenic effects (Kitajima et al 2004). Interestingly, one group studied the effects of two different vehicle controls (Khan et al 2018). Though TCDD treatment in both corn oil and DMSO both significantly increased lesion size in comparison with their vehicle controls, authors found that TCDD + DMSO increased lesion size more than TCDD + oil, suggesting that the vehicles selected may have an impact on the magnitude of effects observed.…”

Environmental Factors and Endometriosis

“…In this mechanism, dioxins may be responsible for the pathogenesis of this condition, as they affect histone modification, DNA methylation, and expression of non-coding RNA (ncRNA) [ 18 ]. A study in an animal model has shown that the suppression of the epigenetic histone modification caused by 2,3,7,8-TCDD delays the progression of endometriosis [ 60 ]. However, not all the studies have confirmed the association between the exposure to dioxins and the risk of endometriosis [ 61 , 62 , 63 , 64 ].…”