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 microg TCDD/40 microg LPS treatment) and day 14 (100 microg 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 microg TCDD. Caspase-1 activity was suppressed at 14 days in mice treated with 100 microg TCDD/40 microg LPS and 100 microg TCDD/4 microg LPS compared to the respective corn oil (CO)/LPS-treated controls. Caspase-3 activity was suppressed at 14 days in 100 microg TCDD/saline-100 microg TCDD/40 microg LPS- and 100 microg TCDD/4 microg LPS-treated mice compared to respective CO/saline- or CO/LPS-treated control mice. At 40 microg LPS, caspase activity was stimulated in TCDD (100 microg)-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 microg) on IkappaB-beta and IkappaB-alpha protein expression or on DNA binding activity of the nuclear NFkappaB protein. These data indicate that TCDD induces apoptosis 14 days posttreatment; however, we found no evidence of suppression of the antiapoptotic transcription factor NFkappaB.
Patterson
Rachel M
RM
Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Stachlewitz
Robert
R
Germolec
Dori
D
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D020672:I-kappa B Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000008:administration & dosage / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D004785:Environmental Pollutants; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases