Histone-induced damage of a mammalian epithelium: the conductive effect

Human semen has been reported to be cytotoxic to rat descending colon by a mechanism involving polyamines (cationic molecules) and collagenase. In this study, we report that histones, cationic proteins found in human semen, can contribute to semen's cytotoxicity. Histones H1, H4, and H5, when added to the mucosal side of rabbit urinary bladder epithelium, were found to alter the transepithelial conductance (Gt) in a voltage-sensitive manner. When the cell interior was negative, the conductance rapidly increased and plateaued. When the cell interior was positive, the induced conductance decreased to control values. Histone increased the Gt by increasing the apical membrane conductance rather than the tight junction conductance. The magnitude of the Gt increase was dose dependent, and the histone-induced conductance was nonselective for Na+, K+, and Cl-. The induced conductance could be reversed by either increasing mucosal Ca2+ concentration or by removal of histone from the mucosal solution. Prolonged exposure of the epithelium to histone was toxic as determined by the irreversible loss of transepithelial resistance. These results indicate that histone increases membrane ionic permeability, is cytotoxic, and thus may contribute to human semen's toxic effect on colonic epithelium.