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Lipid peroxidation and DNA adduct formation in lymphocytes of premenopausal women: Role of estrogen metabolites and fatty acid intake.
Int. J. Cancer 131, 1983-1990 (2012)
A diet high in linoleic acid (an ?-6 PUFA) increased the formation of miscoding etheno (e) - DNA adducts in WBC-DNA of women, but not in men (Nair et al., Cancer Epidemiol Biomark Prev 1997;6:597-601). This gender specificity could result from an interaction between ?-6 PUFA intake and estrogen catabolism, via redox-cycling of 4-hydroxyestradiol (4-OH-E2) and subsequent lipid peroxidation (LPO). In this study, we investigated whether in premenopausal women LPO-derived adducts in WBC-DNA are affected by serum concentration of 2- and 4-hydroxyestradiol metabolites and by fatty acid intake. DNA extracted from buffy coat and plasma samples, both blindly coded from healthy women (N = 124, median age 40 year) participating in the EPIC-Heidelberg cohort study were analyzed. Three LPO-derived exocyclic DNA adducts, edA, edC and M1dG were quantified by immuno-enriched 32P-postlabelling and estradiol metabolites by ultra-sensitive GC-mass spectrometry. Mean M1dG levels in WBC-DNA were distinctly higher than those of edA and edC, and all were positively and significantly interrelated. Serum levels of 4-OH-E2, but not of 2-OH-E2, metabolites were positively related to etheno DNA adduct formation. Positive correlations existed between M1dG levels and linoleic acid intake or the ratios of dietary linoleic acid/oleic acid and PUFA/MUFA. Aerobic incubation of 4-OH-E2, arachidonic acid and calf thymus DNA yielded two to threefold higher etheno DNA adduct levels when compared with assays containing 2-OH-E2 instead. In conclusion, this study is the first to compare M1dG and etheno-DNA adducts and serum estradiol metabolites in human samples in the same subjects. Our results support a novel mechanistic link between estradiol catabolism, dietary ?-6 fatty acid intake and LPO-induced DNA damage supported by an in vitro model. Similar studies in human breast epithelial tissue and on amplification of DNA-damage in breast cancer patients are in progress.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Lipid Peroxidation ; Lpo ; Dna Adducts ; Fatty Acids ; Estrogen ; Metabolism ; Premenopausal Women; WHITE BLOOD-CELLS; BREAST-CANCER; DAMAGE; HUMANS; DEOXYGUANOSINE; MALONALDEHYDE; PRODUCTS; TISSUES; CARCINOGENESIS; OXYRADICALS
ISSN (print) / ISBN
0020-7136
e-ISSN
1097-0215
Journal
International Journal of Cancer
Quellenangaben
Volume: 131,
Issue: 9,
Pages: 1983-1990
Publisher
Wiley
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Epidemiology (EPI)