Age‐Related Susceptibility to Chlordecone‐Potentiated Carbon Tetrachloride Hepatotoxicity and Lethality Is Due to Hepatic Quiescence
作者:
ABRAHAM DALU,
ALAN WARBRITTON,
THOMAS BUCCI,
HARIHARA MEHENDALE,
期刊:
Pediatric Research
(OVID Available online 1995)
卷期:
Volume 38,
issue 2
页码: 140-148
ISSN:0031-3998
年代: 1995
出版商: OVID
关键词: CD, chlordecone;TGF, transforming growth factor;ND, normal diet;ALT, alanine transaminase;[3H]T, [3H]thymidine;SDH, sorbitol dehydrogenase;AUC, area under the curves
数据来源: OVID
摘要:
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 CCI4or corn oil. Hepatocellular regeneration was assessed by [3H]thymidine ([3H]T) incorporation into hepatic nuclear DNA. In CD + CCI4treatment, 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 CCI4begin 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 CCI4treatment. 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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