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Can Erythrocytes Transmit Oxidative Stress Beyond the Lungs? An Adverse Outcome Pathway for the Cardiovascular Effects of Air Pollution.
Thompson, L., Dan Villeneuve, M. Hazari, AND A. Farraj. Can Erythrocytes Transmit Oxidative Stress Beyond the Lungs? An Adverse Outcome Pathway for the Cardiovascular Effects of Air Pollution. Society of Toxicology, San Antonio, Texas, March 11 - 15, 2018.
Over the last several decades, research authorized under the Clean Air Act has driven better, more protective air pollutant standards, resulting in improved air quality and health benefits to the U.S. population. Despite this success, limited data informing risk are available for the wide range of air pollution sources, constituents, and range of potential mixtures, due in part to the absence of high-throughput methods that can quickly test biological effects of exposure that are related to negative public health outcomes. This work focuses on AOPs and laboratory test that measure functional changes in red blood cells that have higher throughput capacity and potential predictive value for negative health effects in human populations. This work is intended to assists US EPA objectives to improve public health effects associated with air pollution by providing accelerated source-specific health determinations, improving confidence in evidence-based research tools, and perhaps most importantly, addressing the “solutions-oriented” focus of the agency by informing strategies for targeting the most toxic air pollution sources.
Adverse outcome pathways (AOPs) are systems biology roadmaps with potential utility in xenobiotic exposure risk assessment. AOPs connect molecular initiating events (MIEs) to population-level adverse outcomes (AOs) via cellular, organ, and organism key events (KE) and KE relationships. As of yet, few AOPs describe the biology of AOs linked to air pollution exposure, particularly cardiovascular disease. Airway oxidative stress is implicated in the cardiovascular effects of air pollution but the exact mechanism is still elusive, making it difficult to identify MIEs and proximal KEs. The purpose of this work was to develop an AOP that could identify candidate MIEs for the transmission of oxidative stress from the lung to cardiovascular tissue. We hypothesized that red blood cells (RBCs, i.e. erythrocytes) could transmit free radicals from the lung into cardiovascular tissue because RBCs constantly pass through the lungs, transport electrophilic O2, and have finite antioxidant defenses. A systematic literature review was used to construct an AOP from a thrombolytic AO, i.e. stroke, heart attack, and death, through distal KEs atherosclerosis, plaque formation/growth, and foam cell formation/vascular injury. Another PubMed query was conducted using various combinations of the search terms red blood cell, erythrocyte, oxidative stress, hemoglobin, and free radical, etc. Search results were binned into 3 categories: [MIE] if publications supported potential RBC molecules prone to oxidation or free radical transport (29 references), e.g. changes to hemoglobin, the glutathione system, peroxiredoxin, Band-3, and membrane proteins/lipids, [KE1] if publications supported potential for phenotypic RBC changes that result from excessive oxidation (22 references), e.g. RBC free radical production, impaired antioxidant defenses, and membrane instability, and [KE2] if publications reported RBC capacity to oxidize extracellular targets, e.g. circulating lipids, monocytes, or endothelial cells (14 references). In conclusion, this new AOP focuses on MIE candidates for RBC transmission of oxidative stress into the cardiovascular system and may provide the ground work to expedite airway xenobiotic screening and air pollution risk assessments. [This work does not necessarily reflect the policies of the US EPA]
Record Details:Record Type: DOCUMENT (PRESENTATION/POSTER)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
ENVIRONMENTAL PUBLIC HEALTH DIVISION
CARDIOPULMONARY AND IMMUNOTOXICOLOGY BRANCH