AGE-RELATED SUSCEPTIBILITY TO CHLORDECONE-POTENTIATED CARBON-TETRACHLORIDE HEPATOTOXICITY AND LETHALITY IS DUE TO HEPATIC QUIESCENCE

Previous studies revealed that postnatally developing rats are resilie nt to the lethal effects of chlordecone (CD) + carbon tetrachloride (C Cl4) combination. The objective of this study was to investigate the u nderlying mechanism. We hypothesized that ongoing cell division and ce ll cycle progression as well as additional toxicant-induced stimulatio n of tissue repair help in restraining the progression of injury on th e one hand, and in recovery through speedy healing on the other. Postn atally developing (20- and 45-d) and adult (60-d) male Sprague-Dawley rats were challenged with a nontoxic single dose of CCl4 (100 mu L/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 me asuring serum enzymes [alanine transaminase (ALT), sorbitol dehydrogen ase (SDH)], and bilirubin, as well as by histopathologic examination o f liver sections during a time course of 0-96 h after the administrati on of CCl4 or corn oil. Hepatocellular regeneration was assessed by [H -3]thymidine ([H-3]T) incorporation into hepatic nuclear DNA, in CD CCl4 treatment, ALT, SDH, and bilirubin levels peaked between 36 and 4 8 h after CCl4. All 20-d-old rats survived the challenge of CD + CCl4. CD-potentiated hepatotoxicity and lethality of CCl4 begin to be manif ested in 45-d-old rats at 48 h and later times (25% mortality), wherea s adult rats experience progressive hepatotoxic injury and 100% mortal ity by 72 h. In contrast, regardless of pretreatment, 20-d-old rats re cover fully from injury by 72 h after CCl4 treatment. The rapid recove ry of 20-d-old rats was associated with a combination of higher level of ongoing cell division and additional sustained stimulation of [H-3] T incorporation from 24 to 72 h after the administration of CCl4. In t he older rats (45- or 60-d-old) this response was significantly delaye d and attenuated. Ongoing cell division and CCl4-stimulated regenerati on were inversely related to postnatal development (20-, 45-, or 60-d) . These biochemical, histopathological, and [H-3]T incorporation studi es suggest that the liver of younger rats has greater plasticity for r epair after toxic injury whereas adult liver is much more quiescent in this regard.