STRAIN DIFFERENCES IN TISSUE-REPAIR RESPONSE TO 1,2-DICHLOROBENZENE

Fischer 344 (F344) rats are reportedly 75-fold more sensitive than Spr ague Dawley (S-D) rats to 1,2-dichlorobenzene (o-DCB) hepatotoxicity, Lethality studies were conducted since no information was available re garding the ultimate consequence of this sensitivity in terms of anima l survival in the two strains. LD(50)s 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 wa s to investigate if differential rates of cell division and tissue rep air might explain the lack of difference in LD(50) dose between the tw o 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 e vents 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 9.6 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 H-3-thymidine incorporation into hepatonuclear DNA and via prolife rating cell nuclear antigen (PCNA) assay. Prompt and significantly hig her hepatocellular regeneration beginning at 36 h was evident in F344 rats following administration of 0.2 and 0.6 ml o-DCB/kg. The signific antly higher depletion of hepatic glycogen observed in F344 rats follo wing administration of 0.2 and 0.6 ml o-DCB/kg occurred without signif icant changes in plasma glucose and is consistent with highly stimulat ed tissue repair seen in these rats at the corresponding doses. Howeve r, 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 repa ir 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.