Air pollution, metabolomic response, and bone mineral density among Women’s Health Initiative participants

BACKGROUND: Ambient air pollution has been associated with bone damage. However, no studies have evaluated the metabolomic changes linked to air pollutants and their potential influence on bone damage in postmenopausal women. METHODS: We analyzed data available among Woman’s Health Initiative (WHI) participants. We used log-normal, ordinary kriging to estimate daily mean concentrations of PM10 (μg/m3) and NOx, NO2, and SO2 (ppm) at their geocoded addresses. We averaged the means over 1-, 3-, and 5-year periods before metabolomic assessments. We measured whole-body, total hip, femoral neck, and spine bone mineral density (BMD) via dual-energy X-ray absorptiometry. We processed 2,129 plasma samples using liquid chromatography-tandem mass spectrometry (LC-MS) to estimate the concentration of approximately 500 metabolites. We used multivariable linear models adjusted for age, body mass index, ethnicity, education, and coronary heart disease to identify metabolome-wide significant cross-sectional associations between air pollutants, metabolites, and BMD at an FDR-corrected threshold of 0.05. We then used a hypergeometric enrichment test hosted on Metaboanalyst to conduct pathway analysis with the KEGG metabolic map as reference. RESULTS: The mean (standard deviation) age of participants was 67.0 (7.1) years. Air pollutants were associated with several metabolite concentrations. For example, 1-year mean NOx exposure was associated with 104 metabolites after adjusting for multiple comparisons, including homoarginine, sphingosine-1-phosphate, uridine diphosphate glucose (UDP), UDP-galactose, alpha-glycerophosphate, kynurenine, cytidine monophosphate, malonylcarnitine, docosatrienoic acid, carboxybuprofen, and others. These NOx-associated metabolites enriched the arachidonic acid, purine, glycerophospholipid, and arginine metabolic pathways. Likewise, 17 metabolites were significantly associated with BMD, particularly total hip and whole body. Homoarginine was associated with both NOx and BMD. CONCLUSIONS: This initial study of air pollutant-associated metabolites and bone mineral density in the Women’s Health Initiative highlights potential metabolomic mechanisms by which air pollution may negatively affect bone health among postmenopausal women. KEYWORDS: Air pollution, Metabolomics, BMD, Postmenopausal, Women.