Strain differences in tissue repair response to 1,2-dichlorobenzene

Abstract

 Fischer 344 (F344) rats are reportedly 75-fold more sensitive than Sprague Dawley (S-D) rats to 1,2-dichlorobenzene (o-DCB) hepatotoxicity. Lethality studies were conducted since no information was available regarding the ultimate consequence of this sensitivity in terms of animal survival in the two strains. LD₅₀s for o-DCB (1.66 ml/kg and 1.76 ml/kg in male F344 and S-D rats, respectively) did not differ. Several studies have shown the importance of tissue repair on animal survival following exposure to toxic chemicals. The objective of this study was to investigate if differential rates of cell division and tissue repair might explain the lack of difference in LD₅₀ dose between the two strains despite higher hepatotoxic injury in F344 rats. Age-matched male S-D and F344 rats were administered o-DCB (0.2, 0.6, 1.2 ml/kg, i.p.); injury and tissue repair occurring as two dynamic but opposing events were measured over time. Liver injury was assessed by measuring plasma alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities and by liver histopathology. Higher plasma ALT elevations were observed in F344 rats following administration of 0.2 and 0.6 ml o-DCB/kg. Using SDH as a marker of liver injury, the strain difference was evident only at 0.2 ml o-DCB/kg. Liver regeneration was estimated by ³H-thymidine incorporation into hepatonuclear DNA and via proliferating cell nuclear antigen (PCNA) assay. Prompt and significantly higher hepatocellular regeneration beginning at 36 h was evident in F344 rats following administration of 0.2 and 0.6 ml o-DCB/kg. The significantly higher depletion of hepatic glycogen observed in F344 rats following administration of 0.2 and 0.6 ml o-DCB/kg occurred without significant changes in plasma glucose and is consistent with highly stimulated tissue repair seen in these rats at the corresponding doses. However, increasing the dose further to 1.2 ml o-DCB/kg results in a delayed (S-phase synthesis begins at 48 h) and diminished response to o-DCB. These findings suggest that a significantly higher rate of tissue repair in F344 rats helps them overcome higher liver injury inflicted by o-DCB. This differential in tissue repair in the two strains may play a vital role in equalizing the ultimate outcome of toxicity in the two strains.