Biomedical subjects

Steffen Loft

Publications and source records attributed to Steffen Loft.

59 records · Page 4Linked to original sources

PubMed2002

Mutagenicity of 2-amino-3-methylimidazo[4,5-f]quinoline in colon and liver of Big Blue rats: role of DNA adducts, strand breaks, DNA repair and oxidative stress.

The contribution of oxidative stress, different types of DNA damage and expression of DNA repair enzymes in colon and liver mutagenesis induced by 2-amino-3-methylimidazo [4,5-f]quinoline (IQ) was investigated in four groups of six Big Blue rats fed diets with 0, 20, 70, and 200 mg IQ/kg for 3 weeks. There were dose-response relationships of DNA adducts ((32)P-postlabeling) and DNA strand breaks (comet assay) in colon and liver tissues, with the highest levels of DNA adducts and strand breaks in the colon. There was dose-dependent induction of mutations in both the colon and the liver, and the same IQ dose produced two-fold more cII mutations in the liver compared with the colon. The IQ-induced mutation spectrum in the colon was not significantly different to that of control rats. The expression of ERCC1 and OGG1 was higher in the colon than liver, and was unaffected by the IQ diet. Investigations of oxidative stress biomarkers produced inconclusive results. Oxidative DNA damage detected by the endonuclease III enzyme and 7-hydro-8-oxo-2'-deoxyguanosine in colon, liver and/or urine was unaltered by IQ. However, there was increased level of gamma-glutamyl semialdehyde in liver proteins, indicating a higher rate of protein oxidation in the liver following IQ administration. In plasma and erythrocytes there were unaltered levels of oxidized protein, malondialdehyde, and antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, catalase, glutathione reductase) indicating no systemic oxidative stress. However, the level of total vitamin C was increased in plasma, with the largest fraction being in the reduced form. In conclusion, our results indicate that DNA adducts rather than oxidative stress are responsible for the initiation of IQ-induced carcinogenesis of the liver and colon. A lower frequency of mutations in the colon than in the liver could be related to higher expression of DNA repair enzymes in the former.

Animals↗

PubMed2002

Inter-individual variation, seasonal variation and close correlation of OGG1 and ERCC1 mRNA levels in full blood from healthy volunteers.

The mRNA levels of the nucleotide excision DNA repair gene ERCC1 and the base excision DNA repair gene OGG1 were quantified in 43 healthy volunteers in a dietary intervention trial as markers for the DNA repair capacity. Nine samples were collected from each subject over a period of 52 days. Sampling took place from January to May. The mRNA levels of OGG1 and ERCC1 correlated closely (r = 0.86, P << 0.0001) after normalization to either 18S ribosomal RNA or to beta-actin mRNA. The levels of OGG1 and ERCC1 mRNA were relatively constant within an individual with intra-individual correlation (R(2) = 0.45-0.46) in a General Linear Model. The amounts of ERCC1 and OGG1 relative to 18S RNA were doubled in May compared with January. This coincided with an increase in the monthly influx of sunlight from 18 MJ/m(2) in January to 242 MJ/m(2) in May. The mRNA levels of both ERCC1 and OGG1 were positively correlated to the average daily influx of sunlight in the previous 30 and 5 days (r = 0.49; r = 0.37, respectively, P << 0.001). There were no significant effects of the dietary interventions. The inter-individual variation was 5-10-fold, which is more than the observed 2-3-fold seasonal variation. Thus, despite seasonal variation of the individual mRNA levels, the inter-person variation is still far larger than the intra-person variation, supporting the use as biomarkers.

Adult↗

PubMed2002

Receptor-mediated ethinylestradiol-induced oxidative DNA damage in rat testicular cells.

Estrogenic chemicals are suspected of affecting cancer risk and male reproduction, possibly involving oxidative DNA damage. In this study, formation of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG), was measured in testicular cells from rats after 17 alpha-ethinylestradiol (EE) exposure in vivo and in vitro after incubation with EE with or without an antiestrogen. In vivo, preadult (30-35 days) and adult (110-120 days) Wistar rats received 0, 2.8, or 56 mg EE/kg body weight as intraperitoneal injections (n=6). After 1 or 4 h, the 8-oxodG/10(6) dG ratio was measured in the liver, kidneys, and testes. Testes DNA analysis revealed an age-related effect (adult animals had a higher ratio than the young animals) and a concentration effect in preadult rats (increased EE-concentration caused increased ratio), but no time effect. No differences were found in the liver or kidneys. In vitro, testicular cells were isolated and incubated with EE concentrations ranging from 0.1 to 1000 nM. The results indicated an increase in 8-oxodG/10(6) dG from 0 to 10 nM estrogen. At 1000 nM, the level was close to control level. Coincubation of 10 nM EE (maximum damage) with an estrogen antagonist, ICI 182.780, abolished the effect at 10 nM, indicating that the damaging effect is estrogen receptor mediated.

8-Hydroxy-2'-Deoxyguanosine↗

PubMedDate not supplied

Biomarkers.

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Amino Acids↗

PubMedDate not supplied

Oxidative DNA damage and human cancer: need for cohort studies.

Research of the role of oxidative DNA damage is well established in experimental carcinogenesis. A large number of human studies on biomarkers of oxidative DNA damage, in particular related to guanine oxidation, have been published. The level of oxidative DNA damage and repair activity can be quite different between tumor and normal tissues; case-control studies have shown increased levels of oxidative DNA damage and decreased repair capacity in leukocytes from cases. Similarly, the urinary biomarkers of oxidative DNA damage may be elevated in patients with cancer. However, such studies are likely to be associated with reverse causality. Case-control studies of genetic polymorphisms in DNA repair enzymes suggest that the common variant Ser326Cys in OGG1 may be a risk factor for lung cancer, whereas a rare variant in OGG1 and germ line mutations in the corresponding mismatch repair gene MYH are risk factors for hereditary colon cancer. Cohort studies are required to provide evidence that a high level of oxidative DNA damage implies a high risk of cancer. However, this represents a real challenge considering the large number of subjects and long followup time required with likely spurious oxidation of DNA during collection, assay and/or storage of samples.

Biomarkers↗