Sex differences in the redox response to fine particulate matter (<scp>PM</scp>_2.5) air pollution protects female mice against metabolic and cardiac injury

Fine particulate matter (PM_2.5) exposure increases the cardiometabolic disease risk. While there is extensive research on how PM_2.5 impairs cardiometabolic health in male mice, its health impact is largely unexplored in females. To examine PM_2.5-induced cardiometabolic effects in females, female and male mice (n = 10/group) on a regular (12 h:12 h, RLC) or disturbed (18 h:6 h, DLC) light-dark cycle were exposed to concentrated ambient PM_2.5 (CAP) for 30 days. In females, CAP exposure neither impacted glucose tolerance nor skeletal muscle or liver insulin sensitivity. Western blot analysis of cardiac insulin signaling in females and males showed that CAP impaired insulin-stimulated phospho-Akt in the heart of male mice but did not impair cardiac insulin signaling in females. While CAP exposure increased circulating malondialdehyde (MDA) and decreased plasma nitrite (NO_x) in male mice, females were protected against CAP-induced systemic oxidative/nitrosative stress. Similarly, CAP exposure increased thiobarbituric acid reactive substances (TBARS) and depleted glutathione only in the male lungs. Interestingly, in females, CAP increased pulmonary oxidized-glutathione (GSSG) without decreasing reduced glutathione (GSH) indicating advanced pulmonary antioxidant defense in female mice also supported by higher pulmonary antioxidant enzymes mRNA abundance. Our results show that female mice are protected against cardiometabolic PM_2.5 toxicity possibly by preventing PM_2.5-induced pulmonary oxidative stress.