Abstract
ABSTRACT: Previous studies revealed that postnatally developing rats are resilient to the lethal effects of chlordecone (CD) + carbon letrachloride (CCI4) 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 CCI4 (100 μL/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 CCI4 or corn oil. Hepatocellular regeneration was assessed by [3H]thymidine ([3H]T) incorporation into hepatic nuclear DNA. In CD + CCI4 treatment, ALT, SDH, and bilirubin levels peaked between 36 and 48 h after CCI4. All 20-d-old rats survived the challenge of CD + CCI4. CD-potentiated hepatotoxicity and lethality of CCI4 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 CCI4 treatment. The rapid recovery of 20-d-old rats was associated with a combination of higher level of ongoing cell division and additional sustained stimulation of [3H]T incorporation from 24 to 72 h after the administration of CCI4. In the older rats (45− or 60-d-old) this response was significantly delayed and attenuated. Ongoing cell division and CCI4-stimulated regeneration were inversely related to postnatal development (20-, 45-, or 60-d). These biochemical, histopathological, and [3H]T incorporation studies suggest that the liver of younger rats has greater plasticity for repair after toxic injury whereas adult liver is much more quiescent in this regard.
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Dalu, A., Warbritton, A., Bucci, T. et al. Age-Related Susceptibility to Chlordecone-Potentiated Carbon Tetrachloride Hepatotoxicity and Lethality Is Due to Hepatic Quiescence. Pediatr Res 38, 140–148 (1995). https://doi.org/10.1203/00006450-199508000-00002
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DOI: https://doi.org/10.1203/00006450-199508000-00002