Protein and DNA adducts formed by hazardous chemicals in the environment and diet are key events in toxicity and chemical carcinogenesis. Robust biomarkers of toxic chemicals are required for risk assessment. Our research has been devoted to the development of long-term stable biomarkers of heterocyclic aromatic amines (HAAs) a class of probable human carcinogens formed in cooked meat and tobacco smoke, and Aristolochic acids (AA), upper urinary tract carcinogens found in Aristolochia herbs used for medicinal purposes. Using liquid chromatography with triple quadrupole (TQ), ion trap (IT) or Orbitrap high-resolution (HR)-multistage MSn scanning, we have characterized and measured HAAs, their urinary metabolites, protein, and DNA adducts in humans. For example, the HAA 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) was measured in human hair and its metabolites were quantified in urine by TQ/MS2. By employing IT MSn, we characterized and measured human serum albumin adducts of PhIP. We used HR-MSn to show that PhIP can form DNA adducts in human prostrate while other HAAs do not. Thus, PhIP forms reactive intermediates capable of damaging macromolecules in humans; however, a signature mutation is still sought to link PhIP with cancer. Our investigations on AA conducted with Dr. A.P. Grollman and colleagues at Stony Brook University employing IT MSn showed that AA-DNA adducts are frequently detected in renal tissues of kidney cancer patients in Asia where traditional herbs are often used. AA-DNA adducts combined with the characteristic mutational spectrum induced by AA in P53 gene, provide compelling evidence for a role of AA in upper urothelial tract cancer. We are developing methods to screen for multiple exogenous and endogenous DNA adducts of genotoxicants by untargeted HR-MSn scanning. HR-MS instrumentation has greatly expanded our ability to measure biomarkers of carcinogens and can be employed to identify exposures and assess the etiological role of hazardous chemicals in human cancers.

Advances in human biomonitoring of carcinogens by ion trap and high resolution accurate mass spectrometry

256th National Meeting (2018)

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