Associations of Short-Term Ozone Exposure With Hypoxia and Arterial Stiffness.

Abstract

Epidemiological studies reported associations between ozone (O₃) exposure and cardiovascular diseases, yet the biological mechanisms remain underexplored. Hypoxia is a shared pathogenesis of O₃-associated diseases; therefore, we hypothesized that O₃ exposure may induce changes in hypoxia-related markers, leading to adverse cardiovascular effects. This study aimed to investigate associations of short-term O₃ exposure with hypoxic biomarkers and arterial stiffness. We conducted a panel study involving 210 young healthy residents in 2 cities at different altitudes on the Qinghai-Tibetan Plateau in China, where O₃ concentrations are high and particulate pollution is low. Participants underwent 4 repeated visits to assess ambient O₃ exposure levels, hypoxic biomarkers, and arterial stiffness. We applied linear mixed-effects models to assess the associations of O₃ exposure (lag1 to lag1-7 days) with hypoxic biomarkers and arterial stiffness, adjusted for confounders. Mediation analyses explored the hypoxia's role in O₃-related arterial stiffness changes. We further examined effect modification by residence altitude and the robustness of results by including PM_2.5 (particulate matter ≤2.5 μm in aerodynamic diameter) or NO₂ in 2-pollutant models. O₃ exposure 1 to 7 days before visits was significantly associated with changes in multiple hypoxic biomarkers. A 10-ppb increase in O₃ exposure was linked to significant decreases in oxygen saturation (SpO₂) and increases in red blood cell count (RBC), hemoglobin concentration, and hematocrit, with maximum changes by -0.42%, 0.92%, 0.97%, and 1.92%, respectively. Laboratory analysis of mRNA and protein markers consistently indicated that O₃ exposure activated the hypoxia-inducible factor 1 (HIF-1) signaling pathway. Additionally, a 10-ppb increase in O₃ corresponded to a 1.04% to 1.33% increase in carotid-femoral pulse wave velocity (cfPWV), indicating increased arterial stiffness. RBC, hemoglobin concentration, and hematocrit increases significantly mediated the O₃-cfPWV association, whereas the SpO₂ reduction had an insignificant mediating effect. Associations of O₃ with hypoxic biomarkers varied by altitude. The higher altitude group showed delayed associations with SpO₂ and HIF-1 expression but stronger associations with RBC indices. These associations remained robust after adjusting for copollutants. O₃ exposure may reduce oxygen availability, prompting compensatory increases in red blood cells and hemoglobin, which exacerbate arterial stiffening. These findings provide new insights into the mechanisms underlying O₃-induced cardiovascular injury.