LB1034 Chromatin remodeling by warfare arsenicals in porcine skin

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