Because exposures to carcinogens arise from many sources and routes, epidemiology studies should use biomarkers of internal dose as surrogates for carcinogen exposures. However, direct measurement of carcinogens is impractical because these chemicals are usually reactive electrophiles with short life spans in the body. As an alternative, carcinogen doses can be investigated via addition products (adducts) of the electrophiles with blood proteins, especially human serum albumin (HSA) and hemoglobin (Hb). Because these adducts are not repaired, they reflect doses of carcinogens over one to two months. In this project, we envision a 'protein adductome', representing all adducts present on a given protein, as an entity of toxicogenomic importance. Since all electrophilic species are potentially carcinogenic, the protein adductome is arguably more relevant to carcinogen discovery than the proteome or the metabolome. Despite their utility as biomarkers of carcinogen dose, adducts of toxic chemicals with abundant blood proteins, such as human serum albumin (HSA) and Hb, have rarely been used in epidemiology studies or to discover the initiators of human cancers. There are three major reasons for this. First, without substantial adduct enrichment, typical concentrations of HSA and Hb adducts are too low to permit widespread * discovery of new carcinogens. This is the 'needle-in-a-haystack problem' that has also plagued proteomic investigations. Second, state-of-the-art mass spectrometry (MS) has not been exploited to identify unknown protein adducts or to profile adducts with links to human cancers. And third, it is difficult to obtain blood samples with which to assay protein adducts. In this project, we hypothesize that particular subadductomes, such as the free cysteine of HSA (Cys34), can be used to discover new carcinogens and to serve as biomarkers of internal dose in large epidemiology studies. To consider these questions, we will selectively enrich cysteinyl adducts of HSA from human blood and then will use MS to characterize the known and unknown HSA adducts. By comparing adduct maps between lymphoma cases and control subjects, we will pinpoint possible carcinogens. Regarding the use of protein adducts in epidemiology studies, we will collaborate with Project 3 to determine whether it is feasible to quickly measure protein adducts of polycyclic aromatic hydrocarbons (PAH) in a single drop of blood.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54ES016115-02
Application #
7630606
Study Section
Special Emphasis Panel (ZES1)
Project Start
Project End
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
2
Fiscal Year
2008
Total Cost
$406,969
Indirect Cost
Name
University of California Berkeley
Department
Type
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Regazzoni, Luca G; Grigoryan, Hasmik; Ji, Zhiying et al. (2017) Using lysine adducts of human serum albumin to investigate the disposition of exogenous formaldehyde in human blood. Toxicol Lett 268:26-35
Lu, Sixin S; Grigoryan, Hasmik; Edmands, William M B et al. (2017) Profiling the Serum Albumin Cys34 Adductome of Solid Fuel Users in Xuanwei and Fuyuan, China. Environ Sci Technol 51:46-57
Grigoryan, Hasmik; Edmands, William; Lu, Sixin S et al. (2016) Adductomics Pipeline for Untargeted Analysis of Modifications to Cys34 of Human Serum Albumin. Anal Chem 88:10504-10512
Novak, Richard; Ranu, Navpreet; Mathies, Richard A (2013) Rapid fabrication of nickel molds for prototyping embossed plastic microfluidic devices. Lab Chip 13:1468-71
Shuga, Joe; Zeng, Yong; Novak, Richard et al. (2013) Single molecule quantitation and sequencing of rare translocations using microfluidic nested digital PCR. Nucleic Acids Res 41:e159
Jensen, Erik C; Stockton, Amanda M; Chiesl, Thomas N et al. (2013) Digitally programmable microfluidic automaton for multiscale combinatorial mixing and sample processing. Lab Chip 13:288-96
Skucha, K; Gambini, S; Liu, P et al. (2013) Design Considerations for CMOS-Integrated Hall-Effect Magnetic Bead Detectors for Biosensor Applications. J Microelectromech Syst 22:1327-1338
Chung, Ming Kei; Regazzoni, Luca; McClean, Michael et al. (2013) A sandwich ELISA for measuring benzo[a]pyrene-albumin adducts in human plasma. Anal Biochem 435:140-9
Grigoryan, Hasmik; Li, He; Iavarone, Anthony T et al. (2012) Cys34 adducts of reactive oxygen species in human serum albumin. Chem Res Toxicol 25:1633-42
Rappaport, Stephen M (2012) Biomarkers intersect with the exposome. Biomarkers 17:483-9

Showing the most recent 10 out of 31 publications