Tolerance of aged Fischer 344 rats against chlordecone-amplified carbon tetrachloride toxicity

Abstract

We have investigated the effects of chlordecone 1( CD)+ CCl 4 combination in adult (3 months), middle aged (14 months), and old aged (24 months) male Fischer 344 (F344) rats. After a non-toxic dietary regimen of CD (10 ppm) or normal powdered diet for 15 days, rats received a single non-toxic dose of CCl 4 (100 μl/kg, i.p., 1:4 in corn oil) or corn oil (500 μl/kg, i.p.) alone on day 16. Liver injury was assessed by plasma ALT, AST, and histopathology during a time course of 0–96 h. Liver tissue repair was measured by [ 3 H -CH 3]-thymidine ( 3 H -T) incorporation into hepatic nuclear DNA and proliferating cell nuclear antigen (PCNA) immunohistochemistry. Hepatomicrosomal CYP2E1 protein, enzyme activity, and covalent binding of 14 CCl 4 -derived radiolabel were measured in normal and CD fed rats. Exposure to CCl 4 alone caused modest liver injury only in 14- and 24-month-old rats but neither progression of injury nor mortality. The CD+CCl 4 combination led to 100% mortality in 3-month-old rats by 72 h, whereas none of the 14- and 24-month-old rats died. Both 3- and 14-month-old rats exposed to CD+CCl 4 had identical liver injury up to 36 h indicating that bioactivation-mediated CCl 4 injury was the same in the two age groups. Thereafter, liver injury escalated only in 3-month-old while it declined in 14-month-old rats. In 24-month-old rats initial liver injury at 6 h was similar to the 3- and 14-month-old rats and thereafter did not develop to the level of the other two age groups, recovering from injury by 96 h as in the 14-month-old rats. Neither hepatomicrosomal CYP2E1 protein nor the associated p-nitrophenol hydroxylase activity or covalent binding of 14 CCl 4 -derived radiolabel to liver tissue differed between the age groups or diet regimens 2 h after the administration of 14 CCl 4 . Compensatory liver tissue repair ( 3 H -T, PCNA) was prompt and robust soon after CCl 4 liver injury in the 14- and 24-month-old rats. In stark contrast, in the 3-month-old rats it failed allowing unabated progression of liver injury. These findings suggest that stimulation of early onset and robust liver tissue repair rescue the 14- and 24-month-old F344 rats from the lethal effect of the CD+CCl 4 combination.