Characterization of changes in gene expression and biochemical pathways at low levels of benzene exposure.
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.
Superfund Research Program, School of Public Health, University of California, Berkeley, California, United States of America.
Reuben
R
Thomas
Superfund Research Program, School of Public Health, University of California, Berkeley, California, United States of America.
Alan E
AE
Hubbard
Superfund Research Program, School of Public Health, University of California, Berkeley, California, United States of America.
Cliona M
CM
McHale
Superfund Research Program, School of Public Health, University of California, Berkeley, California, United States of America.
Luoping
L
Zhang
Superfund Research Program, School of Public Health, University of California, Berkeley, California, United States of America.
Stephen M
SM
Rappaport
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Qing
Q
Lan
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
Nathaniel
N
Rothman
Institute of Risk assessment Sciences, Utrecht University, Utrecht, The Netherlands.
Roel
R
Vermeulen
National Center for Environmental Assessment, Office of Research and Development, US EPA, Washington, DC, United States of America.
Kathryn Z
KZ
Guyton
National Center for Environmental Assessment, Office of Research and Development, US EPA, Washington, DC, United States of America.
Jennifer
J
Jinot
National Center for Environmental Assessment, Office of Research and Development, US EPA, Washington, DC, United States of America.
Babasaheb R
BR
Sonawane
Superfund Research Program, School of Public Health, University of California, Berkeley, California, United States of America.
Martyn T
MT
Smith
D000395:Air Pollutants, Occupational / Q000009:adverse effects; D001554:Benzene / Q000009:adverse effects*; D001772:Blood Cell Count; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D016273:Occupational Exposure / Q000009:adverse effects*
D000395:Air Pollutants, Occupational; D001554:Benzene