Intestinal Mucosal Inflammation Leads to Systemic Genotoxicity in Mice

Abstract

Inflammatory bowel disease, including ulcerative colitis and Crohn's disease, substantially increases the risk of colorectal cancer. However, mechanisms linking mucosal inflammation to the sequence of dysplasia are incompletely understood. Whereas studies have shown oxidative damage to the colon, this study tests whether genotoxicity is elicited systemically by acute and chronic intestinal inflammation. In this study, genotoxic endpoints were assessed in peripheral leukocytes (DNA single-and double-stranded breaks and oxidative DNA damage) and normochromatic erythrocytes (micronuclei) during chemical or immune-mediated colitis. During three consecutive cycles of intestinal inflammation induced by dextran sulfate sodium administration, genotoxicity to peripheral leukocytes and erythroblasts was detected in both acute and chronic phases of dextran sulfate sodium-induced inflammation. Reactive oxygen species-mediated oxidative stress and DNA damage was confirmed with positive 8-oxoguanine and nitrotyrosine staining in peripheral leukocytes. Levels of DNA damage generally decreased during remission and increased during treatment, correlating with clinical symptoms and systemic inflammatory cytokine levels. In GAi2 À/À and interleukin-10 À/À transgenic mice susceptible to immune-mediated colitis and inflammation-associated adenocarcinoma, similar levels of peripheral leukocyte and erythroblast genotoxicity were also observed. Moreover, this systemic genotoxicity was observed in mice with subclinical inflammation, which was further elevated in those with severe mucosal inflammation. We propose that mucosal inflammation, by eliciting substantial and ongoing systemic DNA damage, contributes early on to genetic instability necessary for progression to inflammatory bowel disease-associated dysplasia and the development of cancer.

DNA repair is indispensable for survival after acute inflammation

“…In fact, patients with IBD exhibit 2-to 20-fold increases in εC adducts in colonic tissue compared with that in healthy controls (19). Evidence of systemic DNA damage is also suggested from the observation of increased DNA damage in peripheral leukocytes as well as the presence of DNA adducts in the urine during chronic inflammation (18,20).…”

Effect of colchicine on experimental acetic acid induced colitis

“…Hovewer, colchicine's antioxidant effect was not found in our study. Excessive production of oxidants has been well described in the plasma, colonic mucosa and peripheral blood leukocytes of IBD patients [29,30]. In addition, the oxidant activity was found to be correlated with IBD activity [29] and Ozyilmaz et al suggested that the oxidants produced in the bowel in IBD could migrate to other sites of the body [31].…”

New insights from animal models of colon cancer: inflammation control as a new facet on the tumor suppressor APC gem

“…ROS are genotoxic and increase DNA mutation rates. 55,58,114,115 Inhibiting NO production reduces intestinal polyp formation in Apc Min/+ mice as well as inflammatory models of colitis. 116,117 Notably, activation of the NF-κB pathway by constitutive activation of its upstream activator, IKKβ, enhances intestinal polyposis and elevates DNA damage in Apc 580D/+ mice.…”