Resiliency to amplification of carbon tetrachloride hepatotoxicity by chlordecone during postnatal development in rats.
The interactive hepatotoxicity of CCl4 and chlordecone, at an individually nontoxic dosage, was studied in neonatal and young developing rats. The well-documented amplification of CCl4 (100 microL/kg) hepatotoxicity and lethality by prior dietary exposure to chlordecone (10 ppm, for 15 d) was absent in neonatal and developing rats through 35 d of age. The chlordecone-potentiated hepatotoxicity and lethality of CCl4 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 chlordecone-treated 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 3H-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 CCl4, in terms of 14CO2 production derived from 14CCl4 and 14CCl4 metabolites bound to hepatic tissue, was not significantly different between 35-, 45-, and 60-d-old chlordecone-treated rats, whereas CCl4-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 CCl4 toxicity by chlordecone in postnatally developing rats is well correlated with the presence of ongoing and stimulatable hepatocellular regenerative activity.
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Division of Pharmacology and Toxicology, College of Pharmacy and Health Sciences, Northeast Louisiana University, Monroe 71209-0470.
Mehendale
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HM
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000633:toxicity*; D007631:Chlordecone / Q000008:administration & dosage / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004357:Drug Synergism; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008938:Mitosis; D009336:Necrosis; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D002251:Carbon Tetrachloride; D007631:Chlordecone