Metabolomic signatures of lead exposure in the VA Normative Aging Study

Background: Lead (Pb) is widespread and exposure to this non-essential heavy metal can cause multiple negative health effects; however the mechanisms underlying these effects remain incompletely understood. Objectives: To identify plasma metabolomic signatures of Pb exposure, as measured in blood and toenails. Methods: In a subset of men from the VA Normative Aging Study, mass-spectrometry based plasma metabolomic profiling was performed. Pb levels were measured in blood samples and toenail clippings collected concurrently. Multivariable linear regression models, smoothing splines and Pathway analyses were employed to identify metabolites associated with Pb exposure. Results: In 399 men, 858 metabolites were measured and passed QC, of which 154 (17.9%) were significantly associated with blood Pb (p < 0.05). Eleven of these passed stringent correction for multiple testing, including pro-hydroxy-pro (beta(95%CI): 1.52 (0.93,2.12), p = 7.18x10(-7)), N-acetylglycine (beta(95%CI): 1.44 (0.85,2.02), p = 1.12x10(-6)), tartarate (P(95%CI): 0.68 (0.35,1.00), p = 4.84x10(-5)), vanillylmandelate (beta(95%CI): 1.05 (0.47,1.63), p = 4.44x10(-7)), and lysine (beta(95%CI): 1.88 (-2.8,-0.95),p = 9.10x10(-5)). A subset of 48 men had a second blood sample collected a mean of 6.1 years after their first. Three of the top eleven metabolites were also significant in this second blood sample. Furthermore, we identified 70 plasma metabolites associated with Pb as measured in toenails. Twenty-three plasma metabolites were significantly associated with both blood and toenail measures, while others appeared to be specific to the biosample in which Pb was measured. For example, benzanoate metabolism appeared to be of importance with the longer-term exposure assessed by toenails. Discussion: Pb exposure is responsible for 0.6% of the global burden of disease and metabolomics is particularly well-suited to explore its pathogenic mechanisms. In this study, we identified metabolites and metabolomic pathways associated with Pb exposure that suggest that Pb exposure acts through oxidative stress and immune dysfunction. These findings help us to better understand the biology of this important public health burden.