| Autor: |
Smith JW; Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, United States., O'Meally RN; Department of Biological Chemistry, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, United States., Burke SM; Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, United States., Ng DK; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, United States., Chen JG; Qidong Liver Cancer Institute, Qidong People's Hospital, Affiliated Qidong Hospital of Nantong University, Qidong, Jiangsu 226200, P. R. China., Kensler TW; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, United States., Groopman JD; Department of Environmental Health and Engineering, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, United States., Cole RN; Department of Biological Chemistry, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, United States. |
| Abstrakt: |
Assessing personal exposure to environmental toxicants is a critical challenge for predicting disease risk. Previously, using human serum albumin (HSA)-based biomonitoring, we reported dosimetric relationships between adducts at HSA Cys 34 and ambient air pollutant levels (Smith et al., Chem. Res. Toxicol . 2021 , 34 , 1183). These results provided the foundation to explore modifications at other sites in HSA to reveal novel adducts of complex exposures. Thus, the Pan-Protein Adductomics (PPA) technology reported here is the next step toward an unbiased, comprehensive characterization of the HSA adductome. The PPA workflow requires <2 μL serum/plasma and uses nanoflow-liquid chromatography, gas-phase fractionation, and overlapping-window data-independent acquisition high-resolution tandem mass spectrometry. PPA analysis of albumin from nonsmoking women exposed to high levels of air pollution uncovered 68 unique location-specific modifications (LSMs) across 21 HSA residues. While nearly half were located at Cys 34 (33 LSMs), 35 were detected on other residues, including Lys, His, Tyr, Ser, Met, and Arg. HSA adduct relative abundances spanned a ∼400 000-fold range and included putative products of exogenous (SO 2 , benzene, phycoerythrobilin) and endogenous (oxidation, lipid peroxidation, glycation, carbamylation) origin, as well as 24 modifications without annotations. PPA quantification revealed statistically significant changes in LSM levels across the 84 days of monitoring (∼3 HSA lifetimes) in the following putative adducts: Cys 34 trioxidation, β-methylthiolation, benzaldehyde, and benzene diol epoxide; Met 329 oxidation; Arg 145 dioxidation; and unannotated Cys 34 and His 146 adducts. Notably, the PPA workflow can be extended to any protein. Pan-Protein Adductomics is a novel and powerful strategy for untargeted global exploration of protein modifications. |
