Acute Cognitive Impairments Following Exposure to Inhaled CO2: Translating Mouse Mechanisms to Humans

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Project Summary/Abstract Humans in developed countries spend 80% of their time indoors. Carbon dioxide (CO2) is a product of respiration, expired at a concentration of 40,000 ppm, leading to higher levels indoors than outdoors. CO2 is widely regarded as nontoxic. However, three human experimental studies using highly sensitive tests of cognitive function including an airline flight simulator, reported concentration-related decrements in higher cognitive function during 2 hr. exposures to elevated, but real-world CO2 concentrations (<2,500 ppm). Additionally, in vitro and animal studies demonstrated that CO2 at the same concentrations caused enhanced neutrophil (PMN) activation and accompanying brain vascular leak. CO2 can interact with a variety of reactive oxygen and nitrogen species (RONS), altering their subsequent reactivity with biological targets. We speculate that CO2 inhalation redirects RONS towards a novel subset of biomolecules in PMN and that this leads to PMN activation and oxidative stress; this causes brain vascular leak, and consequently cognitive dysfunction. We hypothesize that exposure of humans to inhaled CO2 at environmental levels will lead to human cognitive decrements as a consequence of CO2-mediated nitrosation and nitration of intracellular biomolecules in PMN, leading to cellular activation. This novel high-risk high-reward mechanistic model integrates experimental, in vitro, and in vivo data with human studies on cognitive effects of CO2. To test this hypothesis, we will: (1) analyze the effects of CO2 ion cognitive function in volunteers stratified on GSTM1 genotype; and (2) determine whether CO2 inhalation results in nitrosative and nitrative modification of target proteins in PMN, and if this is correlated with PMN activation and oxidative stress. A double-blind, randomized order, cross-over study will be performed. Healthy subjects (n=24) will breathe in random order 600 ppm (control), and 2,500 ppm (exposed) CO2 for 2 hrs. in our controlled environmental facility. The Strategic Management Systems cognitive assessment test will be administered. PMNs will be collected from subjects’ peripheral blood immediately and 4 hr. after each exposure and measurements made of activation (oxidative burst, NLRP3 inflammasome activation) and mitochondrial oxidative stress. Oxidation, nitrosation, and nitration of intracellular proteins in PMN will be assessed as potential mediators of CO2 induced alterations in cellular function; release of microparticles will also be assessed. Changes in cognitive function, PMN oxidative stress and nitrosative and nitrative modification of target proteins will be stratified on GSTM1 status, predicted to influence responsiveness to CO2 inhalation. Positive results will provide important mechanistic data on CO2 and impaired cognitive function that will inform consideration of acceptable CO2 levels in indoor environments.