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  • 1
    Keywords: PROTECTION ; BLOOD ; Germany ; IN-VIVO ; LUNG ; VIVO ; EXPOSURE ; RISK ; ENZYMES ; MICE ; DNA ; SERA ; RISK-FACTORS ; animals ; BIOMARKERS ; P-32-postlabelling ; RATS ; TARGET ; PROGRESSION ; DIFFERENCE ; PLASMA ; STRESS ; risk factors ; DAMAGE ; RISK FACTOR ; NUCLEOTIDES ; DNA-DAMAGE ; ADDUCTS ; APOLIPOPROTEIN-E ; ATHEROSCLEROSIS ; LIPOPROTEIN ; LOW-DENSITY-LIPOPROTEIN ; WALL ; ETHENO-DNA ADDUCTS ; LIPID-PEROXIDATION ; OXIDATIVE STRESS ; atherosclerosis,benzo(a)pyrene,etheno-DNA adducts,lipid peroxidation ; LIPOPROTEINS ; OXIDATION ; PARAOXONASE
    Abstract: The genotoxic compound benzo[a]pyrene (B[a]P) enhances atherosclerotic plaque progression, possibly by inducing oxidative stress and subsequent lipid peroxidation (LPO). Since LPO plays a key role in atherosclerosis, stable LPO derived DNA modifications such as 1,N-6-ethenodeoxyadenosine (epsilondA) and 3,N-4-ethenodeoxy-cytidine (epsilondC) may be useful biomarkers for in vivo oxidative stress. In this study, benzo[a]pyrene-diol-epoxide (BPDE)-DNA, epsilondA and epsilondC were determined by P-32-postlabelling in apolipoprotein E knockout (ApoE-KO) mice treated with 5 mg/kg B[a]P by gavage. After 4 days, BPDE-DNA adduct levels were higher in aorta (10.8 +/- 1.4 adducts/10(8) nucleotides) than in lung (3.3 +/- 0.7, P 〈 0.05), which is a known target organ for B[a]P. Levels of εdA were higher in aorta of B[a]P-exposed animals than in unexposed controls (8.1 ± 4.4 vs 3.4 ± 2.1 adducts per 10(8) parent nucleotides, P 〈 0.05). On the other hand, epsilondC levels were not affected by B[a]P exposure. Serum low density lipoprotein (LDL) levels were lower in B[a]P-exposed mice than in controls (9.3 +/- 3.7 and 13.3 +/- 4.0 mmol/l, respectively), whereas high density lipoprotein (HDL) levels were higher (1.4 +/- 1.6 and 0.4 +/- 0.3 mmol/l, respectively). Consequently, a three-fold difference in the LDL/HDL ratio was observed (P = 0.001). epsilondA levels were positively related with plasma HDL concentrations (R = 0.68, P = 0.02), suggesting that the HDL mediated protection of the vessel wall against reactive lipid peroxides was reduced in B[a]P-exposed apoE-KO mice. Our observations show that direct as well as lipid peroxidation induced DNA damage is formed by B[a]P in aorta of apoE-KO mice, which may be involved in atherosclerotic plaque progression. This study further indicates that etheno-DNA adducts are useful biomarkers for in vivo oxidative stress in atherosclerosis
    Type of Publication: Journal article published
    PubMed ID: 14753754
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  • 2
    Keywords: GENE ; DNA ; polymorphism ; SUSCEPTIBILITY ; VARIANTS ; REPAIR ; ALCOHOL-CONSUMPTION ; SMOKERS ; MNSOD ; GPX ACTIVITY
    Abstract: Both endogenous factors (genomic variations) and exogenous factors (environmental exposures, lifestyle) impact the balance of reactive oxygen species (ROS). Variants of the ND3 (rs2853826; G10398A) gene of the mitochondrial genome, manganese superoxide dismutase (MnSOD; rs4880 Val16Ala) and glutathione peroxidase (GPX-1; rs1050450 Pro198Leu), are purported to have functional effects on regulation of ROS balance. In this study, we examined associations of breast and prostate cancer risks and survival with these variants, and interactions between rs4880-rs1050450, and alcohol consumption-rs2853826. Nested case-control studies were conducted in the Breast and Prostate Cancer Cohort Consortium (BPC3), consisting of nine cohorts. The analyses included over 10726 post-menopausal breast and 7532 prostate cancer cases with matched controls. Logistic regression models were used to evaluate associations with risk, and proportional hazard models were used for survival outcomes. We did not observe significant interactions between polymorphisms in MnSOD and GPX-1, or between mitochondrial polymorphisms and alcohol intake and risk of either breast (p-interaction of 0.34 and 0.98, respectively) or prostate cancer (p-interaction of 0.49 and 0.50, respectively). We observed a weak inverse association between prostate cancer risk and GPX-1 Leu198Leu carriers (OR 0.87, 95% CI 0.79-0.97, p = 0.01). Overall survival among women with breast cancer was inversely associated with G10398 carriers who consumed alcohol (HR 0.66 95% CI 0.49-0.88). Given the high power in our study, it is unlikely that interactions tested have more than moderate effects on breast or prostate cancer risk. Observed associations need both further epidemiological and biological confirmation.
    Type of Publication: Journal article published
    PubMed ID: 24437375
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