Science Inventory

Baseline gene expression in conjunction with GSTM1 status predicts ozone exposure response

Citation:

Smith, H., E. Bowers, L. Dailey, AND S. McCullough. Baseline gene expression in conjunction with GSTM1 status predicts ozone exposure response. Gordon Research Conference in Cellular and Molecular Mechanisms of Toxicity, Andover, NH, August 12 - 18, 2017.

Impact/Purpose:

Improves our understanding of the biological mechanisms of inter-individual variability in the susceptibility to chemical exposure effects.

Description:

Air pollution exposure causes increased cardiopulmonary morbidity and mortality and has been linked to the deaths of 7 million people every year by the World Health Organization. Approximately 40% of the population lack expression of the antioxidant enzyme glutathione S-transferase mu 1 (GSTM1) due to a genetic polymorphism. These GSTM1-null individuals are more susceptible to experiencing exposure-induced adverse health effects; however, individuals within the null population exhibit a range in the magnitude of their inflammatory and oxidative stress responses to toxicant exposure. Despite its prevalence and penetrance, the mechanisms underlying the differential susceptibility in GSTM1-null individuals have not been well explained and thus we are unable to effectively predict their magnitude of exposure response. We hypothesized that the relationship between basal and induced expression of exposure-responsive genes would vary between GSTM1-null and sufficient individuals. To test this hypothesis, we exposed fully-differentiated primary bronchial epithelial cells from a panel of GSTM1 null and sufficient human donors to either filtered air or the model oxidant pollutant ozone in an air-liquid interface culture model. We quantified both basal and induced expression of the ozone-responsive genes IL-8, IL-6, COX-2 and HMOX-1 and analyzed induced expression as a function of basal expression. In doing so we determined that the basal and induced expression of IL-8 (R2=0.998), COX-2 (R2=0.812), and HMOX1 (R2=0.615) were strongly correlated in GSTM1 null donors, but not in GSTM1 sufficient donors. While neither GSTM1 genotype nor basal expression alone is sufficient to predict ozone-induced gene expression alone, we demonstrate that the use of the use of both parameters may predict the induced expression of certain ozone-responsive genes. As a result, our findings suggest that these readily obtainable data may predict individuals that will be more responsive to oxidative and pro-inflammatory stress induced by exposure to ozone, and potentially other toxicants. Predicting variability in the response of known susceptible individuals to toxicant exposures will promote public health by facilitating the enhanced protection of at-risk populations.

Record Details:

Record Type: DOCUMENT (PRESENTATION/POSTER)
Product Published Date: 08/18/2017
Record Last Revised: 09/21/2017
OMB Category: Other
Record ID: 337652

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY

ENVIRONMENTAL PUBLIC HEALTH DIVISION

CLINICAL RESEARCH BRANCH