In vivo mutagenicity and initiation following oxidative DNA lesion in the kidneys of rats given potassium bromate.
To clarify the role of 8-OHdG formation as a starting point for carcinogenesis, we examined the dose-dependence and time-course of changes of OGG1 mRNA expression, 8-OHdG levels and in vivo mutations in the kidneys of gpt delta rats given KBrO3 in their drinking water for 13 weeks. There were no remarkable changes in OGG1 mRNA in spite of some increments being statistically significant. Increases of 8-OHdG occurred after 1 week at 500 p.p.m. and after 13 weeks at 250 p.p.m. Elevation of Spi- mutant frequency, suggestive of deletion mutations, occurred after 9 weeks at 500 p.p.m. In a two-stage experiment, F344 rats were given KBrO3 for 13 weeks then, after a 2-week recovery, treated with 1% NTA in the diet for 39 weeks. The incidence and multiplicity of renal preneoplastic lesions in rats given KBrO3 at 500 p.p.m. followed by NTA treatment were significantly higher than in rats treated with NTA alone. Results suggest that a certain period of time might be required for 8-OHdG to cause permanent mutations. The two-step experiment shows that cells exposed to the alteration of the intranuclear status by oxidative stress including 8-OHdG formation might be able to form tumors with appropriate promotion.
Umemura
Takashi
T
Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Tokyo 158-8501, Japan. umemura@nihs.go.jp
Kanki
Keita
K
Kuroiwa
Yuichi
Y
Ishii
Yuji
Y
Okano
Keita
K
Nohmi
Takehiko
T
Nishikawa
Akiyoshi
A
Hirose
Masao
M
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D030801:Animals, Genetically Modified; D001959:Bromates / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D045647:DNA Glycosylases / Q000096:biosynthesis / Q000187:drug effects; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D009571:Nitrilotriacetic Acid / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D011230:Precancerous Conditions / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D001959:Bromates; D002273:Carcinogens; D012333:RNA, Messenger; C019536:potassium bromate; D000080242:8-Hydroxy-2'-Deoxyguanosine; D045647:DNA Glycosylases; C483741:OGG1 protein, rat; D003849:Deoxyguanosine; D009571:Nitrilotriacetic Acid