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- W4285992241 abstract "Accidental or deliberate exposure to highly toxic chemical warfare agents and many industrial chemicals pose significant threat to environment and human health. Skin exposure to arsenical vesicants, developed as chemical weapons in World War I/II, causes painful inflammation and skin wounds. The lack of human relevant animal models has been a key impediment for defining the underlying mechanism/s of these devastating chemicals. The Gottingen minipig skin closely resembles to human skin and we demonstrate that cutaneous exposure to molar equivalent doses of lewisite or structurally related arsenicals [diphenylchlorarsine (DPCA), diphenylcyanoarsine (DPCYA), diethylchlorarsine (DECA)] leads to skin inflammation and wound that progresses in dose- and time-dependent manner. Cutaneous arsenical exposure leads to overexpression of BRD4, an epigenetic reader. This results in lysine hyperacetylation of H3 and H4 histone target proteins, H3K9ac, H4k5ac and H4k8ac. IHC analysis confirmed that BRD4, H3 and H4 histone hyperacetylation were not only confined to epidermal cells but were also seen in dermally infiltrated immune cells. Transcriptomic analysis of lewisite-challenged skin demonstrated significant alterations in expression of BRD4-regulated inflammatory and tissue damage related genes. Although, lewisite and other structurally related arsenicals manifested similar molecular changes, they differed in magnitude. The response was lewisite>DPCA =DPCYA>DECA. Employing human skin keratinocytes in cultures, we demonstrated that BRD4 inhibitors CPI0610, ZL0420, JQ1 and iBET significantly reduced arsenical-induced changes in the expression of BRD4 and acetylation H3 and H4. Expression of pro-inflammatory cytokines was also decreased. Our data suggest that the porcine skin model can recapitulate the molecular pathogenesis of vesicants that is observed in humans. BRD4 is a critical epigenetic regulator of arsenical-mediated cutaneous inflammation and can serve as a viable druggable target for developing antidotes against these and similar chemicals." @default.
- W4285992241 created "2022-07-21" @default.
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- W4285992241 date "2022-08-01" @default.
- W4285992241 modified "2023-09-28" @default.
- W4285992241 title "LB1034 Chromatin remodeling by warfare arsenicals in porcine skin" @default.
- W4285992241 doi "https://doi.org/10.1016/j.jid.2022.05.1072" @default.
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