Abstract
It has been suggested that methyl mercury may express its neurotoxicity by way of iron-mediated oxidative damage. Therefore, the effect of deferoxamine, a potent iron-chelator, on methyl mercury-induced increases in reactive oxygen species formation was studied in rat brain. The generation rate of reactive oxygen species was estimated in crude synaptosomal fractions using the probes 2′,7′-dichlorofluorescin diacetate and dihydrorhodamine 123. The formation rate of the fluorescent oxidation products was used as the measure of reactive oxygen species generation. Seven days after a single injection of methyl mercury (5 mg/kg, ip), the formation rate of reactive oxygen species was significantly increased in the cerebellum. Pretreatment with deferoxamine (500 mg/kg, ip) completely prevented the methyl mercury-induced increase in cerebellar reactive oxygen species generation rates. The oxidative consequences of in vitro exposure to methyl mercury (20 μ m) were also inhibited by deferoxamine (100 μ m). The formation of the iron-saturated complex ferrioxamine was not affected by a 10-fold excess of methylmercuric chloride or mercuric chloride, suggesting that a deferoxamine-mercurial complex does not form. The findings in this study: (1) provide evidence that iron-catalyzed oxygen radical-producing reactions play a role in methyl mercury neurotoxicity, (2) demonstrate the potential of fluorescent probes as a measure of reactive oxygen species formation, and (3) provide support for iron-chelator therapy in protection against xenobiotic-induced oxidative damage.
Highlights
Reactive oxygen species such as superoxide anion, hydrogen peroxide, ferry! ion, and hydroxyl radical, if present in excess, are thought to be initiators ofperoxidative cell damage (Freeman and Crapo, 1982; Halliwell and Gutteridge, 1984, 1986)
This laboratory has recently demonstrated that both in vivo and in vitro exposures to MeHg increased the formation rate of reactive oxygen species in mouse brain (LeBel et al, 1990), effects that were observed only in the cerebellum, the brain region believed to be selectively vulnerable to MeHg (Syverson et al, 1981 )
The advantage of utilizing DCFH-DA is that it provides a direct measure of the formation rate of reactive oxygen species and, conclusions regarding the role of these species are not based on secondary mechanisms such as lipid peroxidation
Summary
Reactive oxygen species such as superoxide anion, hydrogen peroxide, ferry! ion, and hydroxyl radical, if present in excess, are thought to be initiators ofperoxidative cell damage (Freeman and Crapo, 1982; Halliwell and Gutteridge, 1984, 1986). Studies have reported that MeHg stimulates lipid peroxidation (Yonaha et al, 1983) and the lipoperoxidative effects of MeHg are mitigated by the antioxidant a-tocopherol (vitamin E; Halliwell and Gutteridge, 1985; Kasuya, 1975; Bondy and McKee, 1990) This laboratory has recently demonstrated that both in vivo and in vitro exposures to MeHg increased the formation rate of reactive oxygen species in mouse brain (LeBel et al, 1990), effects that were observed only in the cerebellum, the brain region believed to be selectively vulnerable to MeHg (Syverson et al, 1981 ). Radical reactions in rat brain, measured using fluorescent probes, following in vivo and in vitro exposure to MeHg
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