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Responses of the small and large intestine to oxidative stress and modulation by dietary n-3 polyunsaturated fatty acids
Abstract
Colon cancer is the second leading cause of cancer-related deaths in the United States, whereas cancer of the small intestine is a relatively rare event (Greenlee et al. 2001). The response to oxidative stress may be a key to cancer susceptibility since oxidative DNA damage, specifically 8-oxo-2'-deoxyguanosine (8-oxodG), is highly mutagenic and elevated in colonic tumors. We hypothesized that the small and large intestine differentially resist or repair 8-oxodG. In addition, since we have recently shown that fish oil (FO), rich in n-3 polyunsaturated fatty acids (PUFA), reduces methylation-induced DNA damage in the colon compared to corn oil (CO), rich in n-6 PUFA (Hong et al. 2000), we hypothesized that FO confers protection against DNA oxidation in the intestine by modulating OGG1 repair and/or up-regulating apoptosis. To investigate our hypotheses, male Sprague Dawley rats were provided a 15% FO or CO diet for 2 wk ± 3% dextran sodium sulfate (DSS) in the drinking water for 48 h. Half of the treated rats were given an additional 48 h non-treated water prior to termination. Both the duodenum and distal colon had ~2-fold increases in 8-oxodG as a result of DSS treatment. Nuclear and mitochondrial OGG1 mRNA expression, used as an index of repair response, was elevated in both tissues following oxidative insult, with the distal colon having significantly (P=0.0004) higher levels of the nuclear OGG1 transcript compared to the duodenum. With regard to diet, FO-fed rats had less oxidative DNA damage in both the small and large intestine compared with CO (P=0.04), but did not enhance nuclear and mitochondrial OGG1 mRNA expression. Apoptosis was increased in the upper one-third of colonic crypts and in surface cells during oxidative stress (P=0.05, 0.002), reaching significance only within the FO fed rats (P=0.05). Following withdrawal of DSS, FO, compared to CO, resulted in a significant sloughing of the epithelium (P=0.05). The results of this study indicate that both the small and large intestine are susceptible to 8-oxodG formation during oxidative stress and, in response, upregulate OGG1 mRNA. Additionally, n-3 PUFA protect against 8-oxodG in the intestine, specifically in the distal colon by promoting cell deletion.
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Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to digital@library.tamu.edu, referencing the URI of the item.Includes bibliographical references (leaves 95-110).
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Citation
Bancroft, Laura Katherine (2002). Responses of the small and large intestine to oxidative stress and modulation by dietary n-3 polyunsaturated fatty acids. Master's thesis, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /ETD -TAMU -2002 -THESIS -B36.
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