Resiliency to Amplification of Carbon Tetrachloride Hepatotoxicity by Chlordecone during Postnatal Development in Rats

Abstract

ABSTRACT. The interactive hepatotoxicity of C C 4 and chlordecone, at an individually nontoxic dosage, was studied in neonatal and young developing rats. The well-documented amplification of CCI4 (100 pL/kg) hepatotoxicity and lethality by prior dietary exposure to chlordecone (10 ppm, for 1 5 d) was absent in neonatal and developing rats through 3 5 d of age. The chlordecone-potentiated hepatotoxicity and lethality of C C 4 was partially expressed in 45-d-old rats and fully expressed in 60-d-old rats. Although hepatic microsomal cytochrome P-450 content in 2-or 5-d-old rats was significantly lower than that in older age groups, the cytochrome P-450 content was not significantly different between 35-, 45-, and 60-d-old chlordeconetreated rats. During postnatal development, the ongoing hepatocellular proliferation declined in a biphasic manner, more rapidly up to 20 d and slowly thereafter, as indicated by %-thymidine incorporation in hepatic nuclear DNA. This pattern of postnatal liver proliferation and growth was not altered by exposure to chlordecone. In vivo metabolism of CC14, in terms of I4CO2 production derived from I4CCl4 and I4CCl4 metabolites bound to hepatic tissue, was not significantly different between 35-, 45-, and 60-d-old chlordecone-treated rats, whereas CC14-stimulated hepatocellular regeneration in 35-d-old chlordecone-treated rats was significantly higher than in 45-or 60-d-old chlordecone-treated rats, as indicated by 3H-thymidine incorporation into hepatic DNA and histomorphometric analysis. These data suggest that the absence of potentiation of CC14 toxicity by chlordecone in postnatally developing rats is well correiated with the presence of ongoing and itimulatable hepatocellular regenerative activity. (Pediatr Res 33: 225-232,1993) Abbreviations CD, chlordecone PB, phenobarbital %I-T, 3H-thymidine ALT, alanine transaminase ND, normal diet TGF, transforming growth factorThe remarkable potentiation of CCI4 hepatotoxicity by prior exposure to nontoxic levels of CD (10 ppm in diet for 15 d) is well documented in male and female adult rats, as indicated by greatly increased hepatotoxicity and lethality of CCI4 at ordinarily nontoxic doses in CD-treated rats (1-3). A number of candidate mechanisms for this interaction have been considered (4). Increased bioactivation of CCI4 followed by increased lipid peroxidation is the foremost of these mechanisms in view of their wide acceptance with respect to PB, alcohol, ketone, and other xenobiotic-induced enhancement of CC14 toxicity (5-7). Studies of in vitro (8) and in vivo (9) metabolism of CC14 in rats indicated that, although enhanced metabolism of CCI4 induced by cytochrome P-450 inducers such as PB and CD resulted in increased hepatotoxic effects of CCI4 initially, the alterations in CCI4 metabolism in PB-and CD-pretreated rats were not paralleled by the increase of C C 4 lethal effects. These studies revealed that a 3-fold increase in CC14 metabolism with a statistically nonsignificant 1.7-fold increase in CCI4 lethality for PB rats was c...

Upregulation of calpastatin in regenerating and developing rat liver: Role in resistance against hepatotoxicity

“…14,15 Whereas 20-day-old newborns are completely resilient to a lethal combination of chlordecone ϩ CCl 4, 60-day-old adult rats exhibit 100% mortality. 15,16 Livers of 20-day-old rat pups examined in the current study showed remarkably high CAST expression as compared with the livers of 60-day-old adults (same controls used for the other two models of cell division investigated in the current study). These findings endorse the hypothesis that higher CAST in the dividing cells is essential to prevent progression of injury and acute liver failure on exposure to overdose of hepatotoxic drugs.…”

“…The 20-dayold male rat pups (NB) known to exhibit extensive liver growth during this early development [14][15][16] were chosen for this study.…”

“…Liver cell division during postnatal development in newborns is known to impart resistance against toxicity. 11,[15][16][17] Hepatocytes isolated from the regenerating liver exhibit resistance against hepatotoxicants in vitro. 18,19 Although evidence suggests that the dividing cells in the regenerating liver are resistant to hepatotoxicity, the exact mechanism has remained elusive.…”

Role of tissue repair in toxicologic interactions among hepatotoxic organics.

“…Several studies have demonstrated that neonate and postnatally developing rats are resilient to a wide variety of structurally and mechanistically dissimilar hepatotoxicants such as galactosamine, acetaminophen, allyl alcohol, and CC4 (49,(73)(74)(75)(76)(77)(78). Most interestingly, young rats survive exposure to the lethal combination of chlordecone and CC14, which causes 100% lethality in adult male and female rats (49,76,77).…”

“…Most interestingly, young rats survive exposure to the lethal combination of chlordecone and CC14, which causes 100% lethality in adult male and female rats (49,76,77). In a study where postnatally developing (20-and 45-day), and adult (60- Examination of growth factors and protooncogene expression revealed a 3-and 3.5-fold increase in TGF-a and H-ras mRNA expression, respectively, coinciding with maximal hepatocyte DNA synthesis in 20-day rats fed a normal diet, as opposed to only 2-and 2.5-fold increases observed in 60-day rats fed a normal diet, respectively (77).…”