Comparative effects of endrin on hepatic lipid peroxidation and DNA damage, and nitric oxide production by peritoneal macrophages from C57BL/6J and DBA/2 mice

Abstract

1. Endrin is a polyhalogenated cyclic hydrocarbon which produces hepatic and neurologic toxicity. In order to further assess the mechanism of toxicity ofendrin, the dose-dependent effects of endrin on hepatic lipid peroxidation and DNA damage, and nitric oxide (NO) production by peritoneal exudate cells (primarily macrophages) were investigated in C57BL/6J and DBA/2 mice which vary at the Ah receptor genetic locus. C57BL/6J mice are dioxin-responsive, while DBA/2 mice are dioxin-insensitive.

2. Mice of both strains were treated with 0, 1, 2 or 4 mg endrin kg⁻¹ as a single oral dose in corn oil, and the animals were killed 24 hr post-treatment. At doses of 1,2 and 4 mg endrin kg⁻¹ in C57BL/6J mice, hepatic mitochondrial lipid peroxidation increased 1.2-, 2.2- and 3.2-fold, respectively, and 1.8-, 2.3- and 3.5-fold with microsomes, respectively. At these same doses in DBA/2 mice, hepatic mitochondrial lipid peroxidation increased 1.3-, 2.0- and 2.6-fold, respectively, and 1.5-, 1.9- and 2.5-fold with microsomes, respectively.

3. Increases of 2.3-, 2.4- and 4.9-fold were observed in hepatic DNA damage (elution constants) in C57BL/6J mice at doses of 1, 2 and 4 mg endrin kg⁻¹, respectively, while at these same three doses, increases of 1.9-, 2.1- and 2.3-fold were observed for DBA/2 mice, respectively.

4. Nitric oxide production by peritoneal macrophages from C57BL/6J increased by 1.3-, 1.7- and 2.0-fold with doses of 1, 2 and 4 mg endrin kg⁻¹, respectively, while in macrophages from DBA/2 mice at these same doses, increases of 1.7-, 1.7- and 1.8-fold, respectively, were observed.

5. The results indicate that the responsiveness of peritoneal macrophages with respect to both DNA damage and nitric oxide production are more dose-dependent in C57BL/6J mice as compared to DBA/2 mice, while similar results are observed with the lipid peroxidation of hepatic mitochondria and microsomes of the two mouse strains. The results suggest that the toxicity of endrin is less reliant on a mechanism which may involve the Ah receptor system as compared to dioxins as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).