{
    "abstract": "Mammographic breast density (MBD), a strong predictor of breast cancer, is highly influenced by body mass index (BMI) in childhood and early adulthood, but the mechanisms underlying these associations are not fully understood. Our goal is to identify biomarkers that mediate the associations of BMI at ages 10 and 18 with MBD in premenopausal women.\nThis study consists of 705 premenopausal women who had their screening mammogram at Washington University in St. Louis, MO, and provided a fasting blood sample. Our comprehensive metabolomic and lipidomic profiling yielded complete data for 828 metabolites and 857 lipid species after imputation. We used Volpara to determine volumetric measures of MBD. We performed high dimensional mediation analysis using the HIMA R package, adjusted for confounders, to determine whether lipid species and metabolites mediate the associations of BMI at 10 and 18 with MBD. We applied a false discovery rate (FDR) p-value\u2009<\u20090.1.\nFour metabolites (glutamate, \u03b2-cryptoxanthin, cortolone glucuronide (1), phytanate) significantly mediated the association of BMI at 10 with volumetric percent density (VPD), and two (glutamate, \u03b2-cryptoxanthin) mediated the association of BMI at 18 with VPD. Glutamate was the strongest mediator across time points. Glutamate mediated 6.7% (FDR p-value\u2009=\u20090.06) and 9.3% (FDR p-value\u2009=\u20090.008) of the association between BMI at age 10 and 18, respectively. Four lipid species (CER(18:0), LCER(14:0), LPC(18:1), PC(18:1/18:1)), mediated the association of BMI at 10 with VPD, while five lipid species (CER(18:0), LCER(14:0), PC(18:1/18:1), TAG56:5-FA22:5, TAG52:2-FA16:0) mediated the association of BMI at 18 with VPD. The strongest mediator was PC(18:1/18:1), which mediated 9.7%, (FDR-p\u2009=\u20090.009) and 7.7%, (FDR-p\u2009=\u20090.04) of the association of BMI at age 10 and 18 with VPD, respectively.\nMetabolites in amino acid, lipid, cofactor/vitamin, and xenobiotic super-pathways as well as lipid species across the phospholipid, neutral complex lipid and sphingolipid super-pathways mediated the associations of BMI in early-life and MBD in premenopausal women. This study offers insight into the biological mechanisms underlying the link between early-life adiposity and MBD, which can support future research into breast cancer prevention.",
    "authors": [
        {
            "affiliation": "Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Box 8100, St. Louis, MO, USA.",
            "firstname": "Kayla R",
            "initials": "KR",
            "lastname": "Getz"
        },
        {
            "affiliation": "Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Box 8100, St. Louis, MO, USA.\nSiteman Cancer Center Biostatistics Shared Resource, Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.",
            "firstname": "Myung Sik",
            "initials": "MS",
            "lastname": "Jeon"
        },
        {
            "affiliation": "Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.",
            "firstname": "Lili",
            "initials": "L",
            "lastname": "Liu"
        },
        {
            "affiliation": "Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA.",
            "firstname": "Lei",
            "initials": "L",
            "lastname": "Liu"
        },
        {
            "affiliation": "Center for Applied Mathematics, Tianjin University, Tianjin, 300072, China.",
            "firstname": "Haixiang",
            "initials": "H",
            "lastname": "Zhang"
        },
        {
            "affiliation": "Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Box 8100, St. Louis, MO, USA.\nSiteman Cancer Center Biostatistics Shared Resource, Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.",
            "firstname": "Chongliang",
            "initials": "C",
            "lastname": "Luo"
        },
        {
            "affiliation": "Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Box 8100, St. Louis, MO, USA.\nSiteman Cancer Center Biostatistics Shared Resource, Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA.",
            "firstname": "Jingqin",
            "initials": "J",
            "lastname": "Luo"
        },
        {
            "affiliation": "Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Box 8100, St. Louis, MO, USA. a.toriola@wustl.edu.\nSiteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA. a.toriola@wustl.edu.",
            "firstname": "Adetunji T",
            "initials": "AT",
            "lastname": "Toriola"
        }
    ],
    "conclusions": null,
    "copyrights": "\u00a9 2025. The Author(s).",
    "doi": "10.1186/s13058-025-01970-6",
    "journal": "Breast cancer research : BCR",
    "keywords": [
        "Age 10",
        "Age 18",
        "Body mass index",
        "Early-life",
        "Lipidomics",
        "Mammographic breast density",
        "Metabolomics",
        "Premenopausal"
    ],
    "methods": null,
    "publication_date": "2025-02-05",
    "pubmed_id": "39905412\n32727722\n29500187\n28702890\n32373777\n16921475\n34791348\n31777189\n28758405\n22070478\n31626640\n26709969\n34641844\n31915678\n32986697\n38122846\n37737303\n37814330\n36536390\n30352839\n10742377\n29029202\n11395428\n16632515\n27357171\n25254000\n26085512\n33438144\n30450120\n31668457\n28119455\n20534324\n22085304\n22584034\n31877415\n17228047\n31184422\n8333427\n25053404\n17548785\n36642094",
    "results": "Four metabolites (glutamate, \u03b2-cryptoxanthin, cortolone glucuronide (1), phytanate) significantly mediated the association of BMI at 10 with volumetric percent density (VPD), and two (glutamate, \u03b2-cryptoxanthin) mediated the association of BMI at 18 with VPD. Glutamate was the strongest mediator across time points. Glutamate mediated 6.7% (FDR p-value\u2009=\u20090.06) and 9.3% (FDR p-value\u2009=\u20090.008) of the association between BMI at age 10 and 18, respectively. Four lipid species (CER(18:0), LCER(14:0), LPC(18:1), PC(18:1/18:1)), mediated the association of BMI at 10 with VPD, while five lipid species (CER(18:0), LCER(14:0), PC(18:1/18:1), TAG56:5-FA22:5, TAG52:2-FA16:0) mediated the association of BMI at 18 with VPD. The strongest mediator was PC(18:1/18:1), which mediated 9.7%, (FDR-p\u2009=\u20090.009) and 7.7%, (FDR-p\u2009=\u20090.04) of the association of BMI at age 10 and 18 with VPD, respectively.",
    "title": "Metabolites and lipid species mediate the associations of adiposity in childhood and early adulthood with mammographic breast density in premenopausal women.",
    "xml": "<Element 'PubmedArticle' at 0x788503c48db0>"
}