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New Study Links Intestinal Inflammation to Systemic Genotoxicity

By Laura Hall
July 2009

Aya Westbrook
First author Aya Westbrook is a graduate student pursuing her doctorate in the UCLA Molecular Toxicology Interdepartmental Program at UCLA. She is currently working on her second paper as first author. (Photo courtesy of Aya Westbrook)

Robert Scheistl
During an interview at UCLA, senior author Schiestl explained the significance of the study. "This was not known before - that intestinal inflammation causes damage that can be found throughout the body." (Photo courtesy of UCLA)

Researchers at the University of California, Los Angeles (UCLA) have shown for the first time that intestinal inflammation is linked to systemic DNA damage in mice, and they speculate that indications of DNA genotoxicity could provide a non-invasive way to diagnose inflammatory bowel disease (IBD) in its earliest stages.

According to the researchers, DNA damage from ongoing bowel inflammation can lead to dysplasia and develop into cancer. The study, (http://www.ncbi.nlm.nih.gov/pubmed/19487293?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum)Exit NIEHS which was partially funded by NIEHS, appeared in the June 1 issue of Cancer Research.

Senior author Robert Schiestl, Ph.D., (http://www.uclaaccess.ucla.edu/UCLAACCESS/web/Faculty.aspx?ri=1045) Exit NIEHS a UCLA professor of pathology, radiation oncology and environmental health sciences, said that detecting and treating inflammation early may prevent some abdominal, liver and colorectal cancers, as well as some lymphomas that have been linked to inflammatory diseases. DNA damage may be the "earliest detectable indicator" of intestinal inflammatory disease, explained Jonathan Braun, M.D., Ph.D., (http://www.asip.org/mtgs/EB05/braun.htm) Exit NIEHS a co-author of the study and a professor and chairman of the Department of Pathology and Laboratory Medicine at UCLA.

IBD is an immune-mediated chronic inflammatory disease involving the mucosal cells of the intestinal wall. It includes ulcerative colitis (UC) and Crohn's Disease (CD) and affects an estimated 3.6 million people in the U.S. and Europe. IBD runs in families with multiple clinical subgroups within both UC and CD. Several predisposing genes on multiple chromosomes have been identified. Nevertheless, genetics and environmental factors appear to be about equally responsible for the disease, which significantly increases risk of colorectal cancer and leads to greater risk of developing other cancers such as hepatobiliary carcinoma and hematopoietic cancers.

The study reports a link between bowel inflammation and DNA damage in tissues of the body far from the inflammation site. The researchers induced acute and chronic colitis using several mouse models that enabled them to parallel the symptoms and disease progression of human IBD. Schiestl and coauthors were able to compare bowel inflammation caused by an environmental agent, dextran sulfate sodium (DSS), to inflammation that occurs from genetic factors in knockout mice whose genetic makeup predisposes the animals to bowel inflammation.

Inhibitory cytokines suppress inflammation in the mucosal cells lining the gut. Proinflammatory cytokines are secreted to help destroy invading or damaged cells but, if uncontrolled, can lead to damage in what was healthy tissue. To measure the inflammatory effect of DSS, the researchers assayed for the messenger RNA expression of proinflammatory cytokines, as well as an anti-inflammatory cytokine in peripheral blood. The pattern of cytokine gene expression of chronically DSS treated mice mimicked that seen in IBD.

In contrast to other investigators who looked for damage close to the site of inflammation, the authors assayed for single and double-strand DNA breaks, oxidative DNA damage and cytogenetic damage such as chromosome breaks or abnormal chromosomes in peripheral blood. They found that "systemic genotoxicity is a prevalent feature of subclinical, acute, and chronic colitis."

Greater inflammation was associated with greater DNA damage in the blood, noted first author, Aya Westbrook, a graduate student at the UCLA Molecular Toxicology Interdepartmental Program. In addition, detectable DNA damage in blood cells at higher levels than in control animals could be seen even in treated animals that had mild inflammation without symptoms.

The results of this study show that DNA genotoxicity in peripheral blood cells has the potential to act as a biomarker of bowel inflammation, allowing a non-invasive way to test for IBD even at subclinical levels of the disease. "This may give us the opportunity to ward off the disease early and avoid the subsequent organ damage" and the development of cancer, Braun said. He added, "At present, the only way to diagnose the patients is to do full endoscopic examinations, which are both invasive and expensive."

UCLA researchers have initiated a clinical trial to test these findings in humans.

Citation: Westbrook AM, Wei B, Braun J, and Schiestl RH.(http://www.ncbi.nlm.nih.gov/pubmed/19487293?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum)Exit NIEHS 2009. Intestinal mucosal inflammation leads to systemic genotoxicity in mice. Cancer Res 69 (11): 4827-4834.

(Laura Hall is a biologist in the NIEHS Laboratory of Pharmacology.)



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