Induction of apoptosis by 2,3,7,8-tetrachlorodibenzo- p-dioxin following endotoxin exposure

2,3,7,8-Tetrachlorodibenzo- p-dioxin (TCDD) is a potent and persistent environmental toxin that induces hepatotoxicity and increases endotoxin-induced liver injury. The objective of this study was to evaluate whether TCDD could modulate apoptosis and cytokine-controlled apoptotic signaling pathways following lipopolysaccharide (LPS) exposure in female B6C3F1 mice. The effects of TCDD treatment were most dramatic late in the time course (10–14 days posttreatment). Serum enzyme activities were elevated at day 10 (100 μg TCDD/40 μg LPS treatment) and day 14 (100 μg TCDD/saline treatment), indicating peak liver damage occurred at those times. Histological examination of perfused livers showed an increase in apoptotic cells at day 14 in animals treated with 10 μg TCDD. Caspase-1 activity was suppressed at 14 days in mice treated with 100 μg TCDD/40 μg LPS and 100 μg TCDD/4 μg LPS compared to the respective corn oil (CO)/LPS-treated controls. Caspase-3 activity was suppressed at 14 days in 100 μg TCDD/saline-100 μg TCDD/40 μg LPS- and 100 μg TCDD/4 μg LPS-treated mice compared to respective CO/saline- or CO/LPS-treated control mice. At 40 μg LPS, caspase activity was stimulated in TCDD (100 μg)-exposed mice at 3 and 7 days and then suppressed at 10 and 14 days. Western blot analysis, electrophoretic mobility shift assay, and ELISA did not show any effect by TCDD (100 μg) on IκB-β and IκB-α protein expression or on DNA binding activity of the nuclear NFκB protein. These data indicate that TCDD induces apoptosis 14 days posttreatment; however, we found no evidence of suppression of the antiapoptotic transcription factor NFκB.