Sex modifies the pulmonary and inflammatory responses to ozone and nitrogen dioxide: results from a controlled human exposure trial
Citation:
Pulczinski, J., A. Rappold, R. Devlin, M. Case, A. Ghio, AND S. McCullough. Sex modifies the pulmonary and inflammatory responses to ozone and nitrogen dioxide: results from a controlled human exposure trial. Society of Toxicology 63rd Annual Meting and ToxExp, Salt Lake City, UT, March 10 - 14, 2024.
Impact/Purpose:
Ozone (O3) and nitrogen dioxide (NO2) are two highly reactive gases and common air pollutants. In epidemiologic studies, sex has been shown to modify the associations between NO2 and O3 exposure and disease, however the direction and magnitude of this effect are unclear. In this study, participants were exposed to clean air, O3, or NO2, and their lung function and blood markers of inflammation were measured. Results from this study demonstrate that males experience great losses in lung function after O3 exposure compared to females. They also show that blood markers of inflammation are modified by O3 and NO2 exposure, and further modified by sex. These data provide evidence of sex specific responses to O3 and NO2 and may help explain sex differences in disease rates and health outcomes seen in air pollution epidemiologic studies. Program partners and the scientific community can apply and further these results to investigate how sex modifies the response to air pollution and if these differences are associated with the development of disease.
Description:
Ozone (O3) and nitrogen dioxide (NO2) are common air pollutants and highly reactive gases that can induce airway irritation and inflammation. O3 exposure is associated with COPD, type II diabetes, cardiovascular disease, NO2 exposure is associated with asthma and COPD exacerbation and hospitalization, both pollutants are associated with all cause-mortality. There is growing evidence that the risk from O3 and NO2 exposure is modified by sex. Long term exposure to O3 is more strongly associated with declines in pulmonary function in males than females, but females have been shown to be at greater risk from NO2 exposure, via increased risk of cardiovascular disease, loss of lung function, and mortality. In a single blind, randomized crossover, controlled exposure study, healthy adult participants (n=22) underwent separate two-hour exposures to clean air, 300 ppb O3, and 500 ppb NO2 exposures. Outcomes were measured before and after each exposure and 24 hours after exposure and are presented as percent change. Outcomes include Forced Expiratory Volume 1 (FEV1) and Forced Vital Capacity (FVC), acute phase proteins and makers of coagulation in plasma assayed via ELISA. Associations between exposure and sex were assessed using a mixed-effects model. All study participants gave informed consent and received monetary compensation for their participation. This study was approved by the Institutional Review Board of the University of North Carolina at Chapel Hill and the U.S. EPA (ClinicalTrials.gov Identifier: NCT02133586). O3 exposure significantly decreased FEV1 by an average of 4.6% (p<0.0001) and decreased FVC by an average of 3.6% (p<0.0001) immediately post exposure. O3 exposure significantly elevated IL-6 (mean = 19.5%, p<.01), C-Reactive Protein (CRP) (mean = 41.9%, p<0.0001), and Serum amyloid A (SAA) (mean = 36.0%, p<0.01). NO2 exposure did not modify PFTs but significantly elevated D-dimer (mean = 5.2%, p<0.05). When stratified by sex, males displayed significantly greater decrements in FEV1 after O3 exposure, decreasing by an average of 6.7% compared to a decrease of 2.5% in females (p<0.05). Of the acute phase proteins modified by O3, CRP showed significant differences by sex, with males averaging an increase of 82.8% compared to an increase of 7.9% in female (p<0.01). O3 elevated IL-1β by an average of 9.5% in females compared to a decrease of 20.4% in males (p<0.01) and elevated TNFα by an average of 13.1% among females compared to a 2.9% decrease in males (p<0.01). Sex was further associated with changes in inflammatory markers after NO2 exposure, D-dimer trended up in females by an average of 9.1% compared to an increase of 0.45% in males (p=0.06). TNFα was also significantly reduced in females after NO2 exposure, by an average of 12.9% compared to a decrease of 4.7% in males (p<0.05). Acute O3 exposure induced decrements in pulmonary function and increased acute phase proteins in plasma. Acute NO2 exposure did not alter pulmonary function but increased D-Dimer in plasma. Sex modified these associations, with males showing greater declines in pulmonary function after O3 exposure when compared to females. Acute phase protein expression after O3 and NO2 exposure was also modified by sex. These data suggest that sex modifies the pulmonary response to O3 and the inflammatory response to O3 and NO2. The views expressed in this abstract are those of the author(s) and do not necessarily represent the views or the policies of the U.S. Environmental Protection Agency.