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

> **NIH NIH R21** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2022 · $235,500

## Abstract

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.

## Key facts

- **NIH application ID:** 10527565
- **Project number:** 1R21ES033777-01A1
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** HOWARD M KIPEN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $235,500
- **Award type:** 1
- **Project period:** 2022-08-23 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10527565

## Citation

> US National Institutes of Health, RePORTER application 10527565, Acute Cognitive Impairments Following Exposure to Inhaled CO2: Translating Mouse Mechanisms to Humans (1R21ES033777-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10527565. Licensed CC0.

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