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Role of oxidative stress in the selective toxicity of dieldrin in the mouse liver
S Bachowski1, Y Xu, D E Stevenson
1Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis 46202-5196, USA.
Abstract:
Dieldrin, an organochlorine insecticide, induces hepatic tumors in mice but not in rats. Although the mechanism(s) responsible for this species specificity is not fully understood, accumulating evidence indicates that oxidative stress may be involved. This study examined the association of dieldrin-induced hepatic DNA synthesis with the modulation of biomarkers of oxidative damage to lipids (malondialdehyde [MDA]) and DNA (8-hydroxy-2-deoxyguanosine [oh8dG]), in male B6C3F1 mice and F344 rats fed dieldrin (0.1, 1.0, or 10 mg/kg diet) for 7, 14, 28, and 90 days. The nonenzymatic components of the antioxidant defense system (ascorbic acid, glutathione, and alpha-tocopherol) were also examined. Increased urinary MDA was observed in mice fed 0.1, 1.0, or 10 mg dieldrin/kg diet for 7, 14, 28, and 90 days; while increased hepatic MDA was seen only after 7 days in mice fed 0.1, 1.0, or 10 mg dieldrin/kg diet and after 14 days in mice fed 10 mg/kg diet. In rats, dieldrin had no effect on either hepatic MDA or urine MDA levels after 7, 14, and 28 days of treatment. A dose-dependent increase in urinary MDA was observed in rats at the 90-day sampling time. The only significant elevation in urinary or hepatic oh8dG content was limited to urinary oh8dG in mice fed 10 mg/kg dieldrin diet for 14 days. Dietary dieldrin produced sustained decreases in hepatic and serum alpha-tocopherol and sustained elevations in hepatic ascorbic acid in both mice and rats. Rats, however, possessed a three- to four-fold higher content of endogenous or basal (control) hepatic alpha-tocopherol; and, even when fed 10 mg dieldrin/kg diet, the levels of hepatic alpha-tocopherol were maintained at higher levels than those of mice fed control diet. In both rats and mice fed dieldrin, transient (14 and 28 days on diet) elevations in hepatic glutathione were observed. These data support the hypothesis that the species specificity of dieldrin-induced hepatotoxicity may be related to dieldrin's ability to induce oxidative stress in the liver of mice, but not in rats. Only in mice fed dieldrin was a temporal association of increases in hepatic MDA content and hepatic DNA synthesis seen, suggesting that oxidative damage (shown by increased lipid peroxidation) may be involved in early events in dieldrin-induced hepatocarcinogenesis. Rats may be protected from dieldrin-induced oxidative stress by a more effective antioxidant defense system, characterized by higher basal levels of hepatic alpha-tocopherol and ascorbic acid than that seen in the mouse.
Insights
Dieldrin causes liver tumors in mice but not rats, likely due to oxidative stress. Mice showed increased lipid peroxidation and DNA synthesis, while rats were protected by a stronger antioxidant system, explaining the species-specific toxicity.
Area of Science:
- Toxicology
- Hepatocarcinogenesis
- Oxidative Stress
Background:
- Dieldrin, an organochlorine insecticide, exhibits species-specific hepatocarcinogenesis, inducing tumors in mice but not rats.
- The underlying mechanisms for this species specificity remain unclear, though oxidative stress is implicated.
Purpose of the Study:
- To investigate the association between dieldrin-induced hepatic DNA synthesis and oxidative stress biomarkers in mice and rats.
- To examine the impact of dieldrin on lipid and DNA oxidative damage markers and antioxidant defense systems.
Main Methods:
- Male B6C3F1 mice and F344 rats were fed dieldrin (0.1, 1.0, or 10 mg/kg diet) for 7, 14, 28, and 90 days.
- Assessed biomarkers of oxidative damage: malondialdehyde (MDA) and 8-hydroxy-2-deoxyguanosine (oh8dG).
- Evaluated nonenzymatic antioxidant components: ascorbic acid, glutathione, and alpha-tocopherol.
Main Results:
- Mice exhibited increased urinary MDA across all time points and doses, with hepatic MDA elevated at early time points.
- Rats showed no significant MDA changes until 90 days; oh8dG elevation was only in mice at 14 days (10 mg/kg).
- Dieldrin decreased alpha-tocopherol but increased ascorbic acid in both species; rats had higher basal hepatic alpha-tocopherol and ascorbic acid levels.
Conclusions:
- Species-specific hepatotoxicity of dieldrin may stem from its differential induction of oxidative stress in mice versus rats.
- Oxidative damage, indicated by lipid peroxidation, appears linked to early events in dieldrin-induced hepatocarcinogenesis in mice.
- Rats' enhanced antioxidant defense, particularly higher alpha-tocopherol and ascorbic acid, likely protects against dieldrin-induced oxidative stress.