Sex modifies response to ozone and nitrogen dioxide: a controlled human exposure study

Ozone (O₃) and nitrogen dioxide (NO₂) are highly reactive gases associated with all cause-mortality. Epidemiology studies suggest that the risk from O₃ and NO₂ exposure is modified by sex. O₃ is more strongly associated with declines in pulmonary function in males, but females show stronger associations with cardiovascular disease (CVD). For NO₂ exposure, females show stronger associations for increased risk of CVD, loss of lung function, and mortality. It remains unclear if these differences stem from social constructs or underlying biologic responses.

To investigate sex differences after pollutant exposure, we used a single blind, randomized crossover, controlled exposure study to examine the pulmonary, inflammatory, and clotting/fibrinolysis response after exposure to O₃ and NO₂ relative to clean air. Healthy adult participants (n = 22 male = 10, female = 12) underwent separate two-hour exposures to clean air, 300 ppb O₃, and 500 ppb NO₂ exposures while exercising intermittently.

Compared to air, exposure to O₃ resulted in a mean percent change in FEV₁ (-5.74%, 95%CI: -7.83, -3.65, p < 0.001), FVC (-3.94%, 95%CI: -5.59, -2.30, p < 0.001), and FEV₁/FVC (-1.90%, 95%CI: -3.54, -0.25, p < 0.01), and elevated IL-6 (16.3%, 95%CI: 0.51, 32.14, p < 0.01), C-Reactive Protein (CRP) (44.54%; 95%CI: 15.44, 73.65, p < 0.001), and Serum amyloid A (SAA) (33.6%; 95%CI: 7.30, 60.0, p < 0.01). NO₂ exposure resulted in a mean percent change of D-dimer (10.9%, 95%CI: -0.23, 21.93, p < 0.05). When stratified by sex, after O₃ exposure, males displayed greater decrements in FEV₁ (males; -7.81% (95%CI: -11.45, -4.19) females: -4.00% (95%CI: -6.20, -1.80; p < 0.05)) and CRP increased in males by 78.50% (95%CI: 27.50, 129.50) compared to 16.20% (95%CI: -10.43, 42.84) in females (p < 0.01) and SAA increased in males by 60.25% (95%CI: 12.02, 108.48) compared to 15.18% (95%CI: -14.53, 44.90) in females (p = 0.051). TNFα was elevated in females by an average of 10.9% (95%CI: 0.75, 21.23) compared to males (-2.29%, 95%CI: -12.32, 7.75) (p < 0.05). After NO₂, D-dimer was elevated in females by 18.98% (95%CI: 4.69, 33.26) compared to males (1.52%, 95%CI: -16.12,19.16) (p = 0.062).

Sex modified the pulmonary and inflammatory response to O₃ and NO₂, a finding consistent with epidemiological observations of sex differences after O3 and NO2 exposure.