Age-related susceptibility to chlordecone-potentiated carbon tetrachloride hepatotoxicity and lethality is due to hepatic quiescence.
Previous studies revealed that postnatally developing rats are resilient to the lethal effects of chlordecone (CD) + carbon tetrachloride (CCl4) combination. The objective of this study was to investigate the underlying mechanism. We hypothesized that ongoing cell division and cell cycle progression as well as additional toxicant-induced stimulation of tissue repair help in restraining the progression of injury on the one hand, and in recovery through speedy healing on the other. Postnatally developing (20- and 45-d) and adult (60-d) male Sprague-Dawley rats were challenged with a nontoxic single dose of CCl4 (100 microL/kg, i.p.) or corn oil after pretreatment with either dietary CD (10 ppm) or normal diet (ND) for 15 d. Hepatocellular injury was assessed by measuring serum enzymes [alanine transaminase (ALT), sorbitol dehydrogenase (SDH)], and bilirubin, as well as by histopathologic examination of liver sections during a time course of 0-96 h after the administration of CCl4 or corn oil. Hepatocellular regeneration was assessed by [3H]thymidine ([3H]T) incorporation into hepatic nuclear DNA. In CD+CCl4 treatment, ALT, SDH, and bilirubin levels peaked between 36 and 48 h after CCl4. All 20-d-old rats survived the challenge of CD+CCl4. CD-potentiated hepatotoxicity and lethality of CCl4 begin to be manifested in 45-d-old rats at 48 h and later times (25% mortality), whereas adult rats experience progressive hepatotoxic injury and 100% mortality by 72 h. In contrast, regardless of pretreatment, 20-d-old rats recover fully from injury by 72 h after CCl4 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000503:physiopathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000473:pathology; D007631:Chlordecone / Q000633:toxicity*; D004198:Disease Susceptibility; D004357:Drug Synergism; D008099:Liver / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013268:Stimulation, Chemical; D015996:Survival Rate
D007631:Chlordecone