title: Inorganic arsenic in drinking water accelerates N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder tissue damage in mice.
abstract: Epidemiological studies have revealed that exposure to an arsenic-contaminated environment correlates with the incidence of bladder cancer. Bladder cancer is highly recurrent after intravesical therapy, and most of the deaths from this disease are due to invasive metastasis. In our present study, the role of inorganic arsenic in bladder carcinogenesis is characterized in a mouse model. This work provides the first evidence that inorganic arsenic in drinking water promotes N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced bladder tissue damage, including the urothelium and submucosal layer. This damage to the bladder epithelium induced by BBN includes thickening of the submucosal layer, the loss of the glycosaminoglycan layer and an increase in both the deoxyguanosine oxidation and cytosine methylation levels in the DNA. Further, when 10ppm inorganic arsenic is combined with BBN, the number of bladder submucosal capillaries is increased. In addition, inorganic arsenic also increases the deoxyguanosine oxidation level, alters the cytosine methylation state, decreases the activities of glutathione reductase and glucose-6-phosphate dehydrogenase, decreases the protein expression of NAD(P)H quinone oxidoreductase-1 (NQO-1) and increases the protein expression of specific protein 1 (Sp1) in bladder tissues. In summary, our data reveal that inorganic arsenic in drinking water promotes the BBN-induced pre-neoplastic damage of bladder tissue in mice, and that the 8-hydroxy-2'-deoxyguanosine, 5-methylcytosine, NQO-1 protein and Sp1 protein levels may be pre-neoplastic markers of bladder tumors.
authors.affiliation: Department of Pathology, Chang Gung Memorial Hospital at Chiayi, Chang Gung University, Chiayi, Taiwan.
authors.forename: Paul-Yann
authors.initials: PY
authors.lastname: Lin
authors.forename: Yung-Lun
authors.initials: YL
authors.lastname: Lin
authors.forename: Chin-Chin
authors.initials: CC
authors.lastname: Huang
authors.forename: Sin-Syu
authors.initials: SS
authors.lastname: Chen
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Liu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D018053:Arsenites / Q000633:toxicity*; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002085:Butylhydroxybutylnitrosamine / Q000633:toxicity*; D003043:Cocarcinogenesis; D003596:Cytosine / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation; D003849:Deoxyguanosine / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D016329:Sp1 Transcription Factor / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D001749:Urinary Bladder Neoplasms; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D000975:Antioxidants; D018053:Arsenites; D016329:Sp1 Transcription Factor; D014874:Water Pollutants, Chemical; D002085:Butylhydroxybutylnitrosamine; D003596:Cytosine; D003849:Deoxyguanosine