Time course of the incidence/multiplicity and histopathological features of murine colonic dysplasia, adenoma and adenocarcinoma induced by benzo[<i>a</i>]pyrene and dextran sulfate sodium

Abstract

Benzo[a]pyrene (BP) is mutagenic but noncarcinogenic in the murine colon. Recently, we reported rapid induction of colonic tumors by treatment of CD2F1 mice with BP (125 mg/kg for 5 days) followed by a colitis inducer, dextran sulfate sodium (DSS) (4% in drinking water for 1 or 2 weeks). However, there are no reports on detailed time course and histopathological features of colonic proliferative lesions in this model. Here, we show the detailed time course of colonic dysplasia, adenoma and adenocarcinoma induced by treatment with BP, DSS, and a combination of the two (BP/DSS). In the colon of mice exposed to BP/DSS, 14.6 dysplastic foci per mouse were present one week after DSS treatment (week 4). The number of dysplastic foci decreased with time to 3.1 at week 9 and thereafter remained almost constant. At week 4, 1.5 adenocarcinomas were also observed, with a marked increase in numbers with time, reaching 29.3 at week 14. In contrast, the number of dysplastic foci induced by DSS alone showed a time course similar to that following BP/DSS treatment; however, only a few tumors appeared. Neither dysplastic foci nor neoplastic lesions were induced by BP only. In mice exposed to BP/DSS, β-catenin was demonstrated immunohistochemically in the nucleus and/or cytoplasm of the tumor cells, and this translocation from the cell membrane was evident in subsets of dysplastic foci. In dysplastic foci induced by DSS alone, β-catenin was absent in the nucleus/cytoplasm. These finding suggest that aberrant β-catenin accumulation in dysplastic foci is associated with tumor progression in this BP/DSS model.

DNA polymerase kappa counteracts inflammation‐induced mutagenesis in multiple organs of mice

“…The number of experimental groups and numbers of mice in the experimental groups were limited by the availability of Pok −/− mice. However, the numbers of mice used in the study were consistent with previous studies (Hakura et al, ; Sonoda et al, ; Masumura et al, ). The overall study design was approved by the Institutional Animal Care and Use Committee of the test site Sunplanet Co. and the experiments were carried out according to the Sunplanet animal experimentation regulations.…”

Polymethoxyflavones prevent benzo[a]pyrene/dextran sodium sulfate‐induced colorectal carcinogenesis through modulating xenobiotic metabolism and ameliorate autophagic defect in ICR mice

“…To examine the preventive effect of PMFs in dietary intake on B a P in combination with DSS‐induced colorectal tumorigenesis, we referred to a previous report published by Sonoda et al . to design this experimental model shown in Figure a . After the end of the 8 weeks, all mice were sacrificed and the results of body and organ weight were shown in Supporting Information, Figure S2 and Table S3.…”

Benzo(a)pyrene induces oxidative stress, pro-inflammatory cytokines, expression of nuclear factor-kappa B and deregulation of wnt/beta-catenin signaling in colons of BALB/c mice

“…p38 is a group of mitogen activated protein kinase which plays a crucial role in the production of pro-inflammatory cytokines and induction of COX-2 and has been associated with inflammatory diseases (Schieven 2005). develop colon cancer following exposure to colonic carcinogens including azoxymethane and 1,2-dimethylhydrazine (Mori et al, 2004;Ochiai et al, 2003;Suzui et al, 2013) as well as coexposure of mice to B[a]P and dextran sulfate sodium (Sonoda et al, 2015). Over-expression of β-catenin has been implicated in the development of colitis associated cancer (White et al, 2011;Keerthivasan 2014).…”