Background: Identifying biological drivers of mammographic breast density (MBD), a strong risk factor for breast cancer, could provide insight into breast cancer etiology and prevention. Studies on dietary factors and MBD have yielded conflicting results. There are, however, very limited data on the associations of dietary biomarkers and MBD. Objective: We aimed to investigate the associations of vitamins and related cofactor metabolites with MBD in premenopausal women. Methods: We measured 37 vitamins and related cofactor metabolites in fasting plasma samples of 705 premenopausal women recruited during their annual screening mammogram at the Washington University School of Medicine, St. Louis, MO. Volpara was used to assess volumetric percent density (VPD), dense volume (DV), and nondense volume (NDV). We estimated the least square means of VPD, DV, and NDV across quartiles of each metabolite, as well as the regression coefficient of a metabolite in continuous scale from multiple covariate-adjusted linear regression. We corrected for multiple testing using the Benjamini–Hochberg procedure to control the false discover rate (FDR) at a 5% level. Results: Participants’ mean VPD was 10.5%. Two vitamin A metabolites (β-cryptoxanthin and carotene diol 2) were positively associated, and one vitamin E metabolite (γ-tocopherol) was inversely associated with VPD. The mean VPD increased across quartiles of β-cryptoxanthin (Q1 = 7.2%, Q2 = 7.7%, Q3 = 8.4%%, Q4 = 9.2%; P-trend = 1.77E-05, FDR P value = 1.18E-03). There was a decrease in the mean VPD across quartiles of γ-tocopherol (Q1 = 9.4%, Q2 = 8.1%, Q3 = 8.0%, Q4 = 7.8%; P -trend = 4.01E-03, FDR P value = 0.04). Seven metabolites were associated with NDV: 3 vitamin E (γ-CEHC glucuronide, δ-CEHC, and γ-tocopherol) and 1 vitamin C (gulonate) were positively associated, whereas 2 vitamin A (carotene diol 2 and β-cryptoxanthin) and 1 vitamin C (threonate) were inversely associated with NDV. No metabolite was significantly associated with DV. Conclusion: We report novel associations of vitamins and related cofactor metabolites with MBD in premenopausal women.

Original languageEnglish
Pages (from-to)424-434
Number of pages11
JournalJournal of Nutrition
Issue number2
StatePublished - Feb 2024


  • cofactor
  • dense volume
  • mammographic breast density
  • metabolites
  • metabolomics
  • nondense volume
  • vitamins
  • volumetric percent density
  • β-cryptoxanthin
  • γ-tocopherol


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