title: Dioxin causes a sustained oxidative stress response in the mouse.
abstract: Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) is the prototype for environmental agonists of the aromatic hydrocarbon receptor (AHR) that are known to produce multiple adverse effects in laboratory animals as well as humans. Although not directly genotoxic, dioxin is known to increase transformation and mutations in mammalian cell culture and to cause an exaggerated oxidative stress response in the female rat. In humans and mice, however, dioxin-mediated oxidative stress appears to be more subtle, causing a response that has been poorly characterized. Using the female C57BL/6J inbred mouse, we show here that intraperitoneal treatment of 5 micrograms TCDD per kilogram on 3 consecutive days produces a striking, prolonged oxidative stress response: hepatic oxidized glutathione levels increase 2-fold within 1 week, and these effects persist for at least 8 weeks despite no further dioxin treatment. Urinary levels of 8-hydroxydeoxyguanosine--a product of DNA base oxidation and subsequent excision repair--remain elevated about 20-fold at 8 weeks after dioxin treatment, consistent with chronic and potentially promutagenic DNA base damage. These results demonstrate that dioxin exposure does produce a sustained oxidative stress response in the mouse.
authors.affiliation: Department of Environmental Health, Center for Environmental Genetics, University of Cincinnati Medical Center, Ohio 45267-0056, USA. shertzhg@ucmail.uc.edu
authors.forename: H G
authors.initials: HG
authors.lastname: Shertzer
authors.forename: D W
authors.initials: DW
authors.lastname: Nebert
authors.forename: A
authors.initials: A
authors.lastname: Puga
authors.forename: M
authors.initials: M
authors.lastname: Ary
authors.forename: D
authors.initials: D
authors.lastname: Sonntag
authors.forename: K
authors.initials: K
authors.lastname: Dixon
authors.forename: L J
authors.initials: LJ
authors.lastname: Robinson
authors.forename: E
authors.initials: E
authors.lastname: Cianciolo
authors.forename: T P
authors.initials: TP
authors.lastname: Dalton
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects*; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D013438:Sulfhydryl Compounds / Q000378:metabolism
chemical_list: D000072317:Polychlorinated Dibenzodioxins; D013438:Sulfhydryl Compounds; D000080242:8-Hydroxy-2'-Deoxyguanosine; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D003849:Deoxyguanosine; D005978:Glutathione; D019803:Glutathione Disulfide