Mutation accumulation in the intestine and colon of mice deficient in two intracellular glutathione peroxidases.

Mutation accumulation in the intestine and colon of mice deficient in two intracellular glutathione peroxidases. Research Abstract Details 

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Mutation accumulation in the intestine and colon of mice deficient in two intracellular glutathione peroxidases. Abstract Text:

Dong-Hyun Lee,R Steven Esworthy,Christy Chu,Gerd P Pfeifer,Fong-Fong Chu,

Mice deficient in two glutathione peroxidases (GPX), Gpx1 and Gpx2, [Gpx1/2-double knockout (DKO) mice] are prone to ileocolitis on a mixed C57BL/6 and 129S1/SvJ (B6.129) genetic background. We reported previously that approximately 25% of B6.129 Gpx1/2-DKO mice develop ileocolonic tumors by 6 to 9 months of age, when their non-DKO littermates [having at least one wild-type (WT) Gpx1 or Gpx2 allele] rarely have inflammation and none have tumors. Because genetic background affects tumor susceptibility, we have generated a B6 Gpx1/2-DKO colony and discovered that these mice have fewer inflammatory cells, milder ileocolitis, and low mortality, and only 2.5% of B6 mice developed tumors. The mutant frequency of a cII reporter gene was about 2- to 3-fold higher in 28-day-old Gpx1/2-DKO and 4-fold higher in 8-month-old Gpx1/2-DKO ileal mucosa than in controls in both genetic backgrounds. In contrast, mutant frequencies in the unaffected B6 liver were not significantly different between WT and Gpx1/2-DKO mice. The mutant frequency of 8-month-old B6.129 Gpx1/2-DKO ileum was 38.94 +/- 15.5(-5), which was not significantly higher than the age-matched B6 ileum, 25.54 +/- 10.33(-5). The mutation spectra analysis has shown that B6 Gpx1/2-DKO ileum had a 3-fold increase in small nucleotide deletions at mononucleotide repeats over control B6, which are a signature mutation associated with oxidative stress. Unexpectedly, B6 Gpx1/2-DKO mice had fewer C to T transitions at CpG dinucleotides than the WT B6 (18.0% versus 40.1%; P < 0.001). Our results suggest that inflammation drives gene mutations, which leads to neoplastic transformation of intestinal epithelium in the B6.129 Gpx1/2-DKO mice but rarely in the B6 Gpx1/2-DKO mice.

Mutation accumulation in the intestine and colon of mice deficient in two intracellular glutathione peroxidases. Publishing Authors By Initials

DH Lee,RS Esworthy,C Chu,GP Pfeifer,FF Chu,

For similar genetic phenomena: variation (genetics): mutation research abstracts see: genetic phenomena: variation (genetics): mutation research

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Mutation accumulation in the intestine and colon of mice deficient in two intracellular glutathione peroxidases. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Cancer research

VOLUME: 66

Page Numbers: 9845-51

Journal Abbreviation: Cancer Res.

ISSN: 0008-5472

DAY: 15

MONTH: Oct

YEAR: 2006

Mutation accumulation in the intestine and colon of mice deficient in two intracellular glutathione peroxidases. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2984705

Mutation accumulation in the intestine and colon of mice deficient in two intracellular glutathione peroxidases. Keywords Mesh Terms:

KEYWORDS: Mutation

MESH TERMS: physiology

Chemical & Substance for Abstract: Mutation accumulation in the intestine and colon of mice deficient in two intracellular glutathione peroxidases. Information

Substance Name: Glutathione Peroxidase

Registry Number: EC 1.11.1.9

Grant and Affiliation Information for Mutation accumulation in the intestine and colon of mice deficient in two intracellular glutathione peroxidases.

AFFILIATION: Department of Biology and Department of Radiation Biology, City of Hope Cancer Center, Duarte, California 91010, USA.

Country: United States

AGENCY: United States NCI

GRANT: CA84469

ACRONYM: CA

MEDLINETA: Cancer Res

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