Shertzer H G, Nebert D W, Puga A, Ary M, Sonntag D, Dixon K, Robinson L J, Cianciolo E, Dalton T P
Department of Environmental Health, Center for Environmental Genetics, University of Cincinnati Medical Center, Ohio 45267-0056, USA.
Biochem Biophys Res Commun. 1998 Dec 9;253(1):44-8. doi: 10.1006/bbrc.1998.9753.
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.
二噁英（2,3,7,8-四氯二苯并对二噁英；TCDD）是芳烃受体（AHR）环境激动剂的原型，已知其会在实验动物和人类中产生多种不良反应。尽管二噁英无直接基因毒性，但已知其会增加哺乳动物细胞培养中的转化和突变，并在雌性大鼠中引发过度的氧化应激反应。然而，在人类和小鼠中，二噁英介导的氧化应激似乎更为微妙，其引发的反应尚未得到充分表征。我们在此使用雌性C57BL/6J近交系小鼠表明，连续3天腹腔注射每千克5微克TCDD会产生显著且持久的氧化应激反应：肝脏中氧化型谷胱甘肽水平在1周内增加2倍，尽管不再进行二噁英处理，这些影响仍持续至少8周。二噁英处理8周后，尿液中8-羟基脱氧鸟苷（DNA碱基氧化及后续切除修复的产物）水平仍升高约20倍，这与慢性且可能具有促突变性的DNA碱基损伤一致。这些结果表明，二噁英暴露确实会在小鼠中产生持续的氧化应激反应。
