Lipid peroxidation and DNA adduct formation in lymphocytes of premenopausal women: Role of estrogen metabolites and fatty acid intake.
A diet high in linoleic acid (an ω-6 PUFA) increased the formation of miscoding etheno (ε)--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 ω-6 PUFA intake and estrogen catabolism, via redox-cycling of 4-hydroxyestradiol (4-OH-E(2) ) 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, εdA, εdC and M(1) dG were quantified by immuno-enriched (32) P-postlabelling and estradiol metabolites by ultra-sensitive GC-mass spectrometry. Mean M(1) dG levels in WBC-DNA were distinctly higher than those of εdA and εdC, and all were positively and significantly interrelated. Serum levels of 4-OH-E(2) , but not of 2-OH-E(2) , metabolites were positively related to etheno DNA adduct formation. Positive correlations existed between M(1) dG levels and linoleic acid intake or the ratios of dietary linoleic acid/oleic acid and PUFA/MUFA. Aerobic incubation of 4-OH-E(2) , arachidonic acid and calf thymus DNA yielded two to threefold higher etheno DNA adduct levels when compared with assays containing 2-OH-E(2) instead. In conclusion, this study is the first to compare M(1) dG 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 ω-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.
Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, DKFZ, Heidelberg 69120, Germany. sunxin@chinacdc.cn
Xin
X
Sun
Jagadeesan
J
Nair
Jakob
J
Linseisen
Robert W
RW
Owen
Helmut
H
Bartsch
D000328:Adult; D015331:Cohort Studies; D018736:DNA Adducts / Q000096:biosynthesis*; D004249:DNA Damage; D004041:Dietary Fats / Q000008:administration & dosage*; D004958:Estradiol / Q000031:analogs & derivatives / Q000097:blood; D004967:Estrogens / Q000097:blood / Q000378:metabolism*; D002393:Estrogens, Catechol; D043371:Fatty Acids, Omega-6 / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D019787:Linoleic Acid / Q000008:administration & dosage / Q000378:metabolism; D015227:Lipid Peroxidation; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism*; D019301:Oleic Acid / Q000378:metabolism; D017697:Premenopause
D018736:DNA Adducts; D004041:Dietary Fats; D004967:Estrogens; D002393:Estrogens, Catechol; D043371:Fatty Acids, Omega-6; D019301:Oleic Acid; D004958:Estradiol; D019787:Linoleic Acid; C001390:2-hydroxyestradiol; C014036:4-hydroxyestradiol