Stimulation of NADPH-dependent reactive oxygen species formation and DNA damage by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat peritoneal lavage cells

Abstract

The toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD] and its congeners involves binding to a specific TCDD [Ah] receptor, interaction of this complex with chromatin, and the ultimate production of pleiotropic responses. The mechanism whereby these effects are produced following interaction of TCDD with the receptor complex is not known. Oxidative stress following the production of reactive oxygen species (ROS) may play an important role in the toxic manifestations of TCDD. Thus, the dose and time-dependent effects of TCDD on the production of superoxide anion by peritoneal lavage cells (primarily macrophages) from rats were examined. A maximum increase in superoxide anion production occurred on day 1 after treatment in rats with 50 and 125 micrograms TCDD/kg. At 6 h after a single dose of 125 micrograms TCDD/kg, a 2.4-fold increase in superoxide anion production was observed in peritoneal lavage cells from rats. A single dose of 5 micrograms TCDD/kg had no effect on superoxide anion production by peritoneal lavage cells. A significant increase in DNA single strand breaks within peritoneal lavage cells occurred at 12 h after the oral administration of 50 micrograms TCDD/kg, and a maximum increase in DNA single strand breaks was observed on days 3-5 after treatment. No DNA damage was detected at a dose of 5 micrograms TCDD/kg. No difference was observed with respect to dose and time in the composition of the peritoneal lavage cells. The results clearly indicate that the oral administration of TCDD activates peritoneal lavage cells in rats, and that the activation precedes the formation of DNA single strand breaks.(ABSTRACT TRUNCATED AT 250 WORDS)

Oxidative Stress Induced by 2,3,7,8-Tetrachlorodibenzo-p-dioxin. An Application of Oxidative Stress Markers to Cancer Risk Assessment of Dioxins.

“…It is well known that reactive oxygen species (ROS), such as the OH radical (· OH) and O 2 -, induce DNA breaks, 8-oxodG, lipid peroxidation 32) , and increase of the GSSG / GSH ratio 30) . A does-response relation was observed in some of these studies 20,23,26,31) , and the dose regimens are shown in Table 1. Considering all of these results as a whole, while TCDD did not induce DNA damage in most genotoxicity tests, it did induce oxidative DNA damage or increase oxidative stress in several situations, which shows that TCDD is able to induce ROS, even if indirectly.…”

“…DNA breaks were detected in the liver of SD female rats [19][20][21] , in the liver of C57BL/6 mice 22) , in rat peritoneal lavage cells 23) , in mouse fetuses and placenta 24,25) , and in mouse brain tissue 26) . Moreover, 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxodG) has been detected in the liver of SD female rats liver 27) and in the urine of C57BL/6J inbred mice 28) .…”

“…Lipid peroxidation or an increase in the oxidized (GSSG) glutathione/reduced (GSH) glutathione ratio, which is a marker of oxidative stress 30) , was also observed when DNA damage occurred 21,27,29) , and increased O 2 -production has been detected in peritoneal lavage cells of SD rats 23) and peritoneal exudate cells of C57BL/6J and DBA/2 mice 31) . It is well known that reactive oxygen species (ROS), such as the OH radical (· OH) and O 2 -, induce DNA breaks, 8-oxodG, lipid peroxidation 32) , and increase of the GSSG / GSH ratio 30) .…”

Differential effects of two lots of aroclor 1254 on enzyme induction, thyroid hormones, and oxidative stress.

“…Oxidative stress from TCDD exposure causes increased production of reactive oxygen species, enhanced lipid peroxidation, decreased glutathione content, decreased hepatic membrane fluidity, and DNA damage (12,13). Persistent organohalogen compounds are tumor promoters (14), and there is evidence that this promotion is mediated at least in part by reactive oxygen species such as superoxide or hydrogen peroxide (15).…”

“…Persistent organohalogen compounds are tumor promoters (14), and there is evidence that this promotion is mediated at least in part by reactive oxygen species such as superoxide or hydrogen peroxide (15). The mechanism by which this effect occurs remains to be elucidated, but it appears to be AhR mediated (13). Markers of oxidative stress were evaluated because PCBs and dioxins induce oxidative stress (16), which has been implicated in the promotion of cancer (17) and developmental toxicity (12); thus, it is important to evaluate both dioxin-like and non-dioxin-like PCBs for similar activity.…”