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Background/Aim: Melatonin is a free radical scavenger and an anti-inflammatory molecule. Air pollution exposure has been associated with increased inflammatory responses. We hypothesize that endogenous melatonin plays a role in inflammatory responses to air pollution exposure. Methods: We tested this hypothesis in a cohort of 53 healthy adults (22-52 years old, 16 women), none of whom were on melatonin supplementation. Early morning urine and blood were collected from each participant for up to three times. We analyzed urinary 6-sulfatoxymelatonin (aMT6s), as a surrogate of circulating melatonin, and pro- and anti-inflammatory cytokines in plasma. Indoor and outdoor air pollutants were measured and combined with participants’ time-activity pattern to calculate personal exposure to O₃, PM_2.5, NO₂, and SO₂ averaged over 12-hour, 24-hour, 1-week, and 2-week prior to biospecimen collection, respectively. Linear mixed effects models were used to examine the relationships of urinary aMT6s with personal pollution exposure and plasma cytokines controlling for covariates including temperature, humidity, sex, age, and respiratory infection & smoking status. Mediation analysis was conducted to test whether aMT6s is a mediator for the relationships between pollution exposure and inflammatory cytokines. Results: A one interquartile range (4.2 ppb) increase in 2-week O₃ exposure was associated with a -29.4% (95% CI: -50.0%, -0.50%) decrease in aMT6s, while the relationships of aMT6s with other pollutant exposures were nonsignificant. Within the range of endogenous aMT6s concentration (0.5-53.0 ng/ng creatinine), increasing aMT6s level was associated with decreasing levels of pro-inflammatory cytokines, including IL-1β, IL-6, IL-8, IL-17A, IFN-γ, and TNF-α. The mediation analysis showed that 5.2%, 7.7%, 8.2%, 10.5%, 16.1%, and 8.3% of the total effects of 2-week O₃ exposure on IL-1β, IL-6, IL-8, IL-17A, IFN-γ, and TNF-α were mediated by urinary aMT6s, respectively. Conclusions: Our findings suggest that air pollution exposure may decrease endogenous melatonin, which may further contribute to enhanced pro-inflammatory responses.