title: Inflammation increases oxidative DNA damage repair and stimulates preneoplastic changes in colons of newborn rats.
abstract: Oxidative DNA damage may be a risk factor for development of various pathologies, including malignancy. We studied inflammation triggered modulation of repair activity in the intestines of three weeks old rats injected i.p. with E.coli or S. typhimurium lipopolysaccharides (LPS) at doses of 1, 5 or 10 mg/kg. Subsequent formation in these animals of colonic preneoplastic lesions, aberrant crypt foci (ACF) was also investigated. Five days after LPS administration no differences were observed in repair rate of 1,N(6)-ethenoadenine (εA), 3,N(4)-ethenocytosine (εC) and 8-oxoguanine (8-oxoG) in intestines of these rats, as measured by the nicking assay. However a significant increase in all three repair activities was found within one and two months after S. typhimurium LPS treatment. E. coli LPS significantly increased only the 8-oxoG repair. S. typhimurium LPS stimulated mRNA transcription of pro-inflammatory proteins, lipooxygenase-12 and cyclooxygenase-2, as well as some DNA repair enzymes like AP-endonuclease (Ape1) and εC-glycosylase (Tdg). mRNA level of DNA glycosylases excising εA (MPG) and 8-oxoG (OGG1) was also increased by LPS treatment, but only at the highest dose. Transcription of all enzymes increased for up to 30 days after LPS, and subsequently decreased to the level observed before treatment, with the exception of APE1, which remained elevated even two months after LPS administration. Thus, the repair efficiency of εA, εC and 8-oxoG depends on the availability of APE1, which increases OGG1 and TDG turnover on damaged DNA, and presumably stimulates MPG. One and two months after administration of E. coli or S. typhimurium LPS, the number of aberrant crypt foci in rat colons increased in a dose and time dependent manner. Thus, inflammation stimulates the repair capacity for εA, εC and 8-oxoG, but simultaneously triggers the appearance of preneoplastic changes in the colons. This may be due to increased oxidative stress and imbalance in DNA repair.
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: P
authors.initials: P
authors.lastname: Kowalczyk
authors.affiliation: Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Collegium Medicum, Cracow, Poland.
authors.forename: J
authors.initials: J
authors.lastname: Jaworek
authors.affiliation: Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Collegium Medicum, Cracow, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Kot
authors.affiliation: Department of Respiratory Research, Medical Research Center, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: B
authors.initials: B
authors.lastname: Sokolowska
authors.affiliation: present address: Cancer Research UK, Clare Hall Laboratories, Blanche Lane, South Mimms, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Bielen
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: B
authors.initials: B
authors.lastname: Janowska
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: J M
authors.initials: JM
authors.lastname: Ciesla
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: G
authors.initials: G
authors.lastname: Szparecki
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: B
authors.initials: B
authors.lastname: Sados
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.|Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland. tudek@ibb.waw.pl.
authors.forename: B
authors.initials: B
authors.lastname: Tudek
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms; D051546:Cyclooxygenase 2 / Q000235:genetics; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D004926:Escherichia coli; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D017208:Rats, Wistar; D012486:Salmonella typhimurium
chemical_list: C018289:3,N(4)-ethenocytosine; D008070:Lipopolysaccharides; C004981:1,N(6)-ethenoadenine; C024829:8-hydroxyguanine; D006147:Guanine; D003596:Cytosine; D001092:Arachidonate 12-Lipoxygenase; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D000225:Adenine