Oxidative stress is produced by free radicals, both radicals that occur normally in all organisms and those introduced by toxic substances. The extremely toxic environmental chemical 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent inducer of oxidative stress. TCDD is not converted to free radicals, but may, however, inhibit one or more of the antioxidant enzymes which detoxify endogenous free radicals. The investigators propose the hypothesis that TCDD may synergize the toxicity of other environmental contaminants that do produce radicals. The goal of the proposed research is to test this hypothesis and to validate a set of biochemical markers that may be useful in future research on the effects of complex environmental mixtures on organisms, including humans.
The specific aims of the proposed research are to: Optimize biochemical markers for detecting and quantifying oxidative stress induced by TCDD in rainbow trout in vivo; use these markers to assess the potential of the pesticides paraquat and diclone to produce oxidative stress, both alone and in combination with TCDD; and statistically assess the interactions between TCDD and the other two model chemicals to determine whether these effects are additive, synergistic or inhibitory. The overall objective is to contribute to the development of a battery of mechanism-based biochemical assays that can be used to characterize the complex mixtures of chemicals in different potentially toxic environments and to thus enhance our ability to assess the long-term risk of environmental contaminants to human health.
| Hsing, A; Faller, D V; Vaziri, C (2000) DNA-damaging aryl hydrocarbons induce Mdm2 expression via p53-independent post-transcriptional mechanisms. J Biol Chem 275:26024-31 |
