title: DNA adducts and liver DNA replication in rats during chronic exposure to N-nitrosodimethylamine (NDMA) and their relationships to the dose-dependence of NDMA hepatocarcinogenesis.
abstract: Exposure of rats to the hepatocarcinogen N-nitrosodimethylamine (NDMA) (0.2-2.64 ppm in the drinking water) for up to 180 days resulted in rapid accumulation of N7- and O6-methylguanine in liver and white blood cell DNA, maximum adduct levels being reached within 1-7 days, depending on the dose. The levels of both adducts remained constant up to treatment day 28, subsequently declining slowly to about 40% of maximal levels for the liver and 60% for white blood cells by day 180. In order to elucidate the role of DNA replication in NDMA hepatocarcinogenesis, changes in liver cell labeling index (LI) were also measured on treatment days 21, 120 and 180. Although the time- and dose-dependence of the observed effects were complex, a clear trend towards increased rates of hepatocyte LI, as indicated by BrdU incorporation, with increasing NDMA doses was evident, particularly above 1 ppm, a concentration above which NDMA hepatocarcinogenicity is known to increase sharply. In contrast, no increase in Kupffer cell DNA replication was found at any of the doses employed, in accordance with the low susceptibility of these cells to NDMA-induced carcinogenesis. No significant increase in the occurrence of necrotic or apoptotic cells was noted under the treatment conditions employed. These results suggest that, in addition to the accumulation of DNA damage, alterations in hepatocyte DNA replication during the chronic NDMA exposure may influence the dose-dependence of its carcinogenic efficacy.
authors.affiliation: National Hellenic Research Foundation, Institute of Biological Research and Biotechnology, 48 Vassileos Constantinou Avenue, Athens 11635, Greece. vls@eie.gr
authors.forename: Vassilis L
authors.initials: VL
authors.lastname: Souliotis
authors.forename: John R
authors.initials: JR
authors.lastname: Henneman
authors.forename: Carl D
authors.initials: CD
authors.lastname: Reed
authors.forename: Saranjit K
authors.initials: SK
authors.lastname: Chhabra
authors.forename: Bhalchandra A
authors.initials: BA
authors.lastname: Diwan
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Anderson
authors.forename: Soterios A
authors.initials: SA
authors.lastname: Kyrtopoulos
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D018736:DNA Adducts / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007962:Leukocytes / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008113:Liver Neoplasms / Q000139:chemically induced*; D009603:Nitroso Compounds / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D009603:Nitroso Compounds; C008651:4-nitrosodimethylaniline