Dioxin causes a sustained oxidative stress response in the mouse

Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) is the prototype for env ironmental agonists of the aromatic hydrocarbon receptor (AHR) that are kno wn to produce multiple adverse effects in laboratory animals as well as hum ans. Although not directly genotoxic, dioxin is known to increase transform ation and mutations in mammalian cell culture and to cause an exaggerated o xidative stress response in the female rat. In humans and mice, however, di oxin-mediated oxidative stress appears to be more subtle, causing a respons e that has been poorly characterized. Using the female C57BL/6J inbred mous e, we show here that intraperitoneal treatment of 5 mu g TCDD per kilogram on 3 consecutive days produces a striking, prolonged oxidative stress respo nse: hepatic oxidized glutathione levels increase a-fold within 1 week, and these effects persist for at least 8 weeks despite no further dioxin treat ment. Urinary levels of 8-hydroxydeoxyguanosine-a product of DNA base oxida tion and subsequent excision repair-remain elevated about 20-fold at 8 week s after dioxin treatment, consistent with chronic and potentially promutage nic DNA base damage. These results demonstrate that dioxin exposure does pr oduce a sustained oxidative stress response in the mouse. (C) 1998 Academic Press.