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We have previously found that acute and chronic intestinal inflammation causes DNA damage to circulating peripheral leukocytes, manifesting a systemic effect in genetically and chemically induced models of intestinal inflammation. Our study addresses the scope of tissue targets and genotoxic damage induced by inflammation\u2010associated genotoxicity. Using several experimental models of intestinal inflammation, we analyzed various types of DNA damage in leukocyte subpopulations of the blood, spleen, mesenteric and peripheral lymph nodes and in intestinal epithelial cells, hepatocytes and the brain. Genotoxicity in the form of DNA single\u2010 and double\u2010stranded breaks accompanied by oxidative base damage was found in leukocyte subpopulations of the blood, diverse lymphoid organs, intestinal epithelial cells and hepatocytes. The brain did not demonstrate significant levels of DNA double\u2010stranded breaks as measured by \u03b3\u2010H2AX immunostaining. CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T\u2010cells were most sensitive to DNA damage <jats:italic>versus<\/jats:italic> other cell types in the peripheral blood. <jats:italic>In vivo<\/jats:italic> measurements and <jats:italic>in vitro<\/jats:italic> modeling suggested that genotoxicity was induced by increased levels of systemically circulating proinflammatory cytokines. Moreover, genotoxicity involved increased damage rather than reduced repair, as it is not associated with decreased expression of the DNA double\u2010strand break recognition and repair protein, ataxia telangiectasia mutated. These findings suggest that levels of intestinal inflammation contribute to the remote tissue burden of genotoxicity, with potential effects on nonintestinal diseases and cancer.<\/jats:p>","DOI":"10.1002\/ijc.26146","type":"journal-article","created":{"date-parts":[[2011,4,25]],"date-time":"2011-04-25T13:25:54Z","timestamp":1303737954000},"page":"1815-1825","source":"Crossref","is-referenced-by-count":25,"title":["Intestinal inflammation induces genotoxicity to extraintestinal tissues and cell types in mice"],"prefix":"10.1002","volume":"129","author":[{"given":"Aya M.","family":"Westbrook","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Braun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Schiestl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,8,2]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.48.4.526"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(20010215)91:4<854::AID-CNCR1073>3.0.CO;2-Z"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.35.11.1590"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncpgasthep0528"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.14.378"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrrev.2010.03.001"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0695-143"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxg135"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2007.02629.x"},{"key":"e_1_2_6_11_2","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1053\/j.gastro.2010.04.045","article-title":"Pathogenic and protective roles of MyD88 in leukocytes and epithelial cells in mouse models of inflammatory bowel disease","volume":"139","author":"Asquith MJ","journal-title":"Gastroenterology"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.2000.278.6.G829"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20101330"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-4416"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/18.1.45"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/geg038"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(87)90285-7"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2006.5"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-2584"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/mutage\/gel019"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2005.12.002"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.93"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(90)90290-H"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/21.4.757"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-5147"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.10.015"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)80068-P"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118861"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1002\/jlb.61.4.389"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2004.05.001"},{"key":"e_1_2_6_31_2","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.4049\/jimmunol.158.3.1068","article-title":"G (alpha) i2\u2010deficient mice with colitis exhibit a local increase in memory CD4+ T cells and proinflammatory Th1\u2010type cytokines","volume":"158","author":"Hornquist C","year":"1997","journal-title":"J Immunol"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2003.02193.x"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20082251"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0027-5107(03)00114-3"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0b013e3282f163fe"},{"key":"e_1_2_6_36_2","first-page":"11","article-title":"Systemic inflammation in chronic obstructive pulmonary disease: May adipose tissue play a role? 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