Mutation Accumulation in the Intestine and Colon of Mice Deficient in Two Intracellular Glutathione Peroxidases

Abstract

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 f25% 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 F 15.5 À5 , which was not significantly higher than the age-matched B6 ileum, 25.54 F 10.33 À5. 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.

Oxidative Stress and Antioxidant Status in Hypo- and Hyperthyroidism

“…Conversely, selenium, the essential constituent of protective enzymes, prevents tumor development in rats submitted to chemical carcinogenesis [50]. Lack of protective systems in knockout mice such as lack of peroxiredoxin or glutathione (GSH) peroxidases indeed leads to malignant cancers [51,52]. Transfection of an H2O2-generating system transforms epithelial cells [53].…”

Impact of inorganic nutrients on maintenance of genomic stability

“…Interestingly, transgenic mice lacking i 6 A in Sec tRNA [Ser]Sec display decreased liver and colon GPX1 expression, and show increased azoxymethane-induced aberrant crypts in the colon [Irons et al, 2006]. Moreover, there is an accelerated accumulation of mutations in the colon of GPX1 and GPX2 double knockout mice [Lee et al, 2006]. Furthermore, GPX1 expression is decreased in estrogen receptor-positive breast cancer cells [Esworthy et al, 1995] and in the PC-3 prostate cancer cell line, which has been reported to possess a defective BER response [Trzeciak et al, 2004].…”

Size effect of elemental selenium nanoparticles (Nano-Se) at supranutritional levels on selenium accumulation and glutathione S-transferase activity

“…It is known that selenoenzymes are fundamental for redox homeostasis. GPx1 knockout mice are more vulnerable to oxidative stress [15,16], GPx1/GPx2-double-knockout mice have a trend to develop cancer [17], knockout of PHGPx causes early embryonic lethality [18,19], and knockout of TrxR results in embryonic lethality [19]. Therefore, when cells are in a Se deficient state, the avidity of Se uptake mechanisms may be increased to maintain the biosynthesis of selenoenzymes.…”