DNA damage in colon mucosa of Pirc rats, an Apc-driven model of colon tumorigenesis.

APC mutation is the first event triggering colon carcinogenesis (CRC). The contribution of APC to colon mucosa DNA damage is not well characterized yet. Similarly, the role of genotoxin-producer gut microorganisms is unclear. DNA strand breaks and oxidative damage were measured in Pirc rats, mutated in Apc, with the COMET assay at age 1 (T ₁ ) and 11 months (T ₁₁ ), i.e. in absence and presence of colon adenomas. In Pirc colon mucosa a 2-fold increase in the mean level of DNA oxidative damage was found at T ₁₁ compared to T ₁ . Moreover, the analysis of DNA damage distribution showed that the proportion of Pirc mucosa cells in the highest DNA damage class was increased compared to wt rats at T ₁ and T ₁₁ months (p < 0.05 and <0.001, respectively). The analysis of colon mucosa-associated microbiota composition showed that this result was not attributable to the presence of genotoxin-producer bacteria B. fragilis nor E. coli. However, Pirc colon mucosa was enriched in Clostridium cluster XI, harmful bacteria in the large intestine, while the wt colon mucosa was enriched in Clostridium cluster IV. This work provides an original way to investigate the interplay between Apc and gut microbiota in affecting DNA stability during CRC.
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