The interaction of arsenic and N-butyl-N-(4-hydroxybutyl)nitrosamine on urothelial carcinogenesis in mice

Abstract

The bladder is an important organ for the storage of excreted water and metabolites. If metabolites with carcinogenic characteristics are present in urine, the urothelial lining of the bladder could be damaged and genetically altered. In this study, we analyzed the interaction of arsenic and N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) on mouse bladder carcinogenesis. Our previous study found that arsenic affects BBN-altered urothelial enzymatic activity, protein expression, DNA oxidation and global DNA CpG methylation levels. In this study, two mouse models were used. First, after administering a co-treatment of BBN and arsenic for 20 weeks, BBN alone led to a urothelial carcinoma formation of 20%, and arsenic promoted a BBN-induced urothelial carcinoma formation of 10%. The protein expression of GSTM1, GSTO1, NQO1, and p21 did not change by arsenic along with the BBN co-treatment, but the Sp1 expression increased. In the second mouse model, BBN was a pretreatment promoter; arsenic dose-dependently deteriorated BBN-promoted dysplasia by 10% and 40% at 10 ppm and 100 ppm, respectively. Conversely, BBN pretreatment also accelerated arsenic-induced dysplasia by 30%. The urothelial carcinogenic effect reversed after ceasing BBN for a period of 20 weeks. In summary, three conclusions were drawn from this study. The first is the mutual promotion of arsenic and BBN in bladder carcinogenesis. Second, arsenic dosages without bladder carcinogenicity (10 ppm) or with slight carcinogenicity (100 ppm) promote BBN-induced mice bladder cancer progression. Finally, the dysplastic urothelium had reverted to near-normal morphology after ceasing BBN intake for 20 weeks, providing a good suggestion for people who want to quit smoking.

Arsenic promotes the COX2/PGE2–SOX2 axis to increase the malignant stemness properties of urothelial cells

“…We recognize that in vivo animal models are necessary for developing strategies to prevent cancer in human populations exposed to arsenic. However, the inorganic arsenic exposure does not generally induce UCB in the animal models due to their innate insensitivity to arsenic carcinogenesis compared to humans 4,5 , except in selected model systems involving a combined exposure of prenatal arsenic and postnatal diethylstilbestrol 5 and co-administration with another carcinogenic agent 50 . Because arsenic exposure alone did not result in tumors of the bladder even in these selected models, it has proven difficult to elucidate the precise role in carcinogenicity of arsenic as a single agent in the current animal model systems.…”

“…However, the inorganic arsenic exposure does not generally induce UCB in the animal models due to their innate insensitivity to arsenic carcinogenesis compared to humans, 4,5 except in selected model systems involving a combined exposure of prenatal arsenic and postnatal diethylstilbestrol 5 and co-administration with another carcinogenic agent. 50 Because arsenic exposure alone did not result in tumors of the bladder even in these selected models, it has proven difficult to elucidate the precise role in carcinogenicity of arsenic as a single agent in the current animal model systems. In addition, the significant differences in biokinetics between humans and rodents also remain as a major gap in terms of interspecies comparisons of arsenic carcinogenicity.…”

Gene expression and DNA methylation regulation of arsenic in mouse bladder tissues and in human urothelial cells

“…This finding indicated that arsenic induced urothelial cytotoxicity. In addition, arsenic and the carcinogen N -butyl- N -(4-hydroxybutyl)nitrosamine have been revealed to mutually promote mouse urothelial carcinogenesis (16). These studies indicated that the interaction of arsenic with other environmental carcinogens may be an important cause for arsenic-induced bladder cancer.…”

Dose-response for assessing the cancer risk of inorganic arsenic in drinking water: the scientific basis for use of a threshold approach

“…Administration of sodium arsenite after a known carcinogen has also been examined in various model systems such as administration of sodium arsenite in the drinking water after diethylnitrosamine (DEN) administration, but this did not lead to a significant increase of tumor incidences (Shirachi et al 1983). Administration of arsenite or DMA V in the drinking water concurrently with BBN slightly increased urothelial dysplasia, but without statistical significance as the BBN treatment alone produced urothelial alterations in 100% of the mice (Dai et al 2017). Furthermore, there were only ten mice per group.…”