title: Increased alkylation of liver DNA and cell turnover in young versus old rats exposed to vinyl chloride correlates with cancer susceptibility.
abstract: To investigate the factors responsible for the high sensitivity of the livers of young rats to the carcinogenic stimulus of vinyl chloride (VC) adult and 11-day-old Wistar rats were exposed to [1,2-14C] VC. Adult rats received either a single 6-h exposure, or 2 single 6-h exposures separated by a treatment-free time interval of 15 h. Eleven-day-old rats received 2 single 6-h exposures, according to the same treatment schedule. The animals were sacrificed 1 h after the end of the corresponding exposure period; liver DNA was isolated, enzymatically hydrolyzed and analyzed by column chromatography. Incorporation of [14C]VC-derived radioactivity into the physiological deoxyribonucleosides (presumably reflecting the activity of DNA replication) was observed for all three sets of experiments. Virtually no difference in 14C-incorporation was observed between adult rats sacrificed immediately after one single 6-h exposure to [14C]VC and those which received a second exposure on the following day. In contrast, an about 8-fold increase in 14C-incorporation into the physiological purines of DNA of young versus adult rats was detected. This difference is indicative of a significantly elevated DNA synthesis/cell replication in the liver of young (11-d) rats. Radioactivity associated with 7-(2-oxoethyl)guanine was taken as an indicator of DNA alkylation by [14C]VC. Analysis of 7-(2-oxoethyl)guanine revealed that in adult animals the amount of this alkylation product formed is increased by a second exposure to VC. About 5-fold of the amount of 7-(2-oxoethyl)guanine present in adults could be determined in liver DNA of young (11-d) animals exposed under the same exposure conditions. Our results suggest that the high sensitivity of young rats to VC-induced hepatocarcinogenesis can reasonably be explained by enhanced DNA-alkylation and by increased cellular proliferation at an early age.
authors.affiliation: Institut für Arbeitsphysiologie, Universität Dortmund, F.R.G.
authors.forename: R J
authors.initials: RJ
authors.lastname: Laib
authors.forename: H M
authors.initials: HM
authors.lastname: Bolt
authors.forename: R
authors.initials: R
authors.lastname: Cartier
authors.forename: H
authors.initials: H
authors.lastname: Bartsch
mesh_terms: D000367:Age Factors; D000478:Alkylation; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives / Q000032:analysis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014752:Vinyl Chloride / Q000633:toxicity*; D014753:Vinyl Compounds / Q000633:toxicity*
chemical_list: D014753:Vinyl Compounds; D006147:Guanine; C032220:7-N-(2-oxoethyl)guanine; D004247:DNA; D014752:Vinyl Chloride