Benzene is a recognized hematotoxin and leukemogen; however, its mechanism of action in humans remain unclear. To provide insight into the processes underlying
benzene hematotoxicity, we performed high-resolution metabolomic profiling of plasma collected from a cross-sectional study of 33 healthy workers exposed to
benzene (median 8-h time-weighted average exposure; 20 ppma), and 25 unexposed controls in Shanghai, China. Metabolic features associated with
benzene were identified using a metabolome-wide association study (MWAS) that tested for the relationship between feature intensity and
benzene exposure. MWAS identified 478 mass spectral features associated with
benzene exposure at false discovery rate < 20%. Comparison to a list of 13 known
benzene metabolites and metabolites predicted using a multi-component biotransformation algorithm showed five metabolites were detected, which included the known metabolites
phenol and
benzene diolepoxide. Metabolic pathway enrichment identified 41 pathways associated with
benzene exposure, with altered pathways including
carnitine shuttle,
fatty acid metabolism,
sulfur amino acid metabolism, glycolysis, gluconeogenesis and
branched chain amino acid metabolism. These results suggest disruption to
fatty acid uptake, energy metabolism and increased oxidative stress, and point towards pathways related to
mitochondrial dysfunction, which has previously been linked to
benzene exposure in animal models and human studies. Taken together, these results suggest
benzene exposure is associated with disruption of mitochondrial pathways, and provide promising, systems biology
biomarkers for risk assessment of
benzene-induced hematotoxicity in humans.