Lipid peroxidation and DNA adduct formation in lymphocytes of premenopausal women: Role of estrogen metabolites and fatty acid intake

Int J Cancer. 2012 Nov 1;131(9):1983-90. doi: 10.1002/ijc.27479. Epub 2012 Mar 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cohort Studies
  • DNA Adducts / biosynthesis*
  • DNA Damage
  • Dietary Fats / administration & dosage*
  • Estradiol / analogs & derivatives
  • Estradiol / blood
  • Estrogens / blood
  • Estrogens / metabolism*
  • Estrogens, Catechol
  • Fatty Acids, Omega-6 / administration & dosage*
  • Female
  • Humans
  • Linoleic Acid / administration & dosage
  • Linoleic Acid / metabolism
  • Lipid Peroxidation*
  • Lymphocytes / cytology
  • Lymphocytes / metabolism*
  • Oleic Acid / metabolism
  • Premenopause*


  • DNA Adducts
  • Dietary Fats
  • Estrogens
  • Estrogens, Catechol
  • Fatty Acids, Omega-6
  • Oleic Acid
  • Estradiol
  • Linoleic Acid
  • 2-hydroxyestradiol
  • 4-hydroxyestradiol