Characterization of Changes in Gene Expression and Biochemical Pathways at Low Levels of Benzene Exposure

• Published in: PloS one Vol. 9; no. 5; p. e91828
• Main Authors: Thomas, Reuben, Hubbard, Alan E., McHale, Cliona M., Zhang, Luoping, Rappaport, Stephen M., Lan, Qing, Rothman, Nathaniel, Vermeulen, Roel, Guyton, Kathryn Z., Jinot, Jennifer, Sonawane, Babasaheb R., Smith, Martyn T.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.05.2014; Public Library of Science (PLoS)
• Subjects: Acute myeloid leukemia; Air Pollutants, Occupational - adverse effects; B cells; Benzene; Benzene - adverse effects; Biology and Life Sciences; Blood Cell Count; Bone marrow; Cancer; Cluster Analysis; Clustering; Comparative analysis; Diabetes; Epidemiology; Exposure; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation - drug effects; Genes; Hematology; Humans; Hydrocarbons; Leukemia; Leukemia, Myeloid, Acute - blood; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukocytes (mononuclear); Male; Medical research; Medicine and Health Sciences; Metabolic Networks and Pathways - drug effects; Metabolism; Mutation; Myeloid leukemia; Occupational exposure; Occupational Exposure - adverse effects; Peripheral blood mononuclear cells; Phenols; Physical Sciences; Pollutants; Public health; Risk assessment; Rodents; Signal transduction; Studies; Toxicology; United States > US; Maryland; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0091828

Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML). Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across four airborne concentration ranges (from <1 ppm to >10 ppm) compared with 42 subjects with non-workplace ambient exposure levels. Here, we further characterize these dose-dependent effects with continuous benzene exposure in all 125 study subjects. We estimated air benzene exposure levels in the 42 environmentally-exposed subjects from their unmetabolized urinary benzene levels. We used a novel non-parametric, data-adaptive model selection method to estimate the change with dose in the expression of each gene. We describe non-parametric approaches to model pathway responses and used these to estimate the dose responses of the AML pathway and 4 other pathways of interest. The response patterns of majority of genes as captured by mean estimates of the first and second principal components of the dose-response for the five pathways and the profiles of 6 AML pathway response-representative genes (identified by clustering) exhibited similar apparent supra-linear responses. Responses at or below 0.1 ppm benzene were observed for altered expression of AML pathway genes and CYP2E1. Together, these data show that benzene alters disease-relevant pathways and genes in a dose-dependent manner, with effects apparent at doses as low as 100 ppb in air. Studies with extensive exposure assessment of subjects exposed in the low-dose range between 10 ppb and 1 ppm are needed to confirm these findings.