The Role of Melatonin in Pathophysiologic Responses to Air Pollution Exposure

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2020

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AbstractIt is widely accepted that the pathophysiologic pathways linking air pollution exposure and adverse health effects are via the augmentation of oxidative stress and inflammation in the respiratory tract and the circulatory system. Melatonin is a potent antioxidant and anti-inflammatory molecule and may thereby affect individuals’ biological responses to air pollution exposure. This dissertation aims to investigate the role of melatonin in pathophysiological responses to air pollution exposure. In Aim 1 of this dissertation research, a method was developed to simultaneously measure urinary concentrations of 6-sulfatoxymelatonin (aMT6s) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). As a major metabolite of melatonin excreted in the urine, aMT6s has been widely used as a surrogate of circulating melatonin. Urinary 8-OHdG, a stable product of DNA oxidative damage, has been used as an oxidative stress biomarker. This new method is expected to have important applications in biomedical and environmental health studies involving the oxidative stress pathophysiological pathway. In Aim 2 of this dissertation research, the role of melatonin in oxidative stress responses to air pollution exposure was examined. Stored urine samples collected from 159 healthy adults, and their personal air pollution exposure data were used. These urine samples were analyzed for aMT6s and 8-OHdG; and statistical analyses were conducted to examine the relationships among aMT6s, 8-OHdG and another previously measured urinary oxidative stress biomarker, malondialdehyde (MDA), and pollutant exposures. The results of this analysis suggest the need for controlling for aMT6s as a confounder in using urinary 8-OHdG and MDA as biomarkers of oxidative stress related to short-term air pollution exposure. In Aim 3 of this dissertation research, the role of melatonin in inflammatory responses to air pollution exposure was examined. Blood inflammatory cytokines and urinary aMT6s were measured in 53 healthy adults three times within 2 consecutive months. Personal air pollution exposure was calculated prior to biospecimen collections. The study found that concentrations of proinflammatory cytokines were significantly and negatively associated with O3 exposures averaged over the preceding 12 hours while significantly but positively associated with O3 exposures averaged over the preceding 2 weeks. These findings suggest that exposure to O3 for different time durations may affect systemic inflammatory responses in different ways. In addition, the study found that pro-inflammatory responses to O3 exposure in the preceding 2 weeks may partly result from the depletion of endogenous melatonin by O3. In Aim 4 of this dissertation research, the role of melatonin in pathophysiologic and oxidative stress responses to air pollution exposure in asthmatic children was examined. Urine, nasal fluid, and pulmonary physiology data were obtained from 43 asthmatic children four times with a 2-week interval between the consecutive clinic visits. At each visit, pulmonary physiology indicators, comprised of airway mechanics, lung function, airway inflammation, and asthma symptom scores were measured. Stored urine samples were analyzed for aMT6s, 8-OHdG, and MDA; stored nasal fluid samples were analyzed for MDA. Personal exposures to PM2.5 and O3 prior to a health outcome measurement were calculated. Three major analyses were conducted in the Aim 4 study. First, the associations of personal air pollutant exposures with the indicators of pulmonary physiology were examined. The results show that daily changes in personal exposure to PM2.5 were associated with significantly increased small airway resistance, total airway resistance, and airway inflammation (fractional exhaled nitric oxide, FeNO). The findings suggest the importance of reducing personal exposure to PM2.5 as part of the asthma management plan to improve airflow limitation. Second, statistical analyses were conducted to examine the relationships among personal pollutant exposures, nasal fluid MDA, urinary 8-OHdG, urinary MDA, FeNO, and asthma symptom scores. The results showed that increased personal exposures to PM2.5 and O3 exposure were both associated with increased nasal MDA concentrations and worsened asthma symptom scores. Increased nasal MDA concentration was associated with decreased asthma symptom scores indicating worsening of asthma symptoms. These findings support that MDA in the nasal fluid may serve as a useful biomarker for monitoring asthma status, especially in relation to PM2.5 and O3 exposure, two known risk factors of asthma exacerbation. Third, statistical analyses were conducted to investigate the relationship of urinary aMT6s with personal air pollutant exposures, biomarkers of oxidative stress, and indicators of pulmonary physiology. The results showed that increasing urinary MDA or 8-OHdG concentration and personal exposures to PM2.5 and O3 were associated with increased urinary aMT6s concentrations in asthmatic children. We also found that increased concentration of urinary aMT6s was associated with improved pulmonary inflammation and airway resilience. The results suggest a potential biological mechanism that increased systemic oxidative stress may stimulate the excretion of melatonin as a defense mechanism to alleviate the adverse effects of air pollution exposure. In summary, the findings from this dissertation research support that endogenously generated melatonin can modulate oxidative, inflammatory, and physiological responses to air pollution exposure in a beneficial way. This dissertation research supports the need for future trials to assess the efficacy or effectiveness of using melatonin supplementation to mitigate the adverse health effects of air pollution exposure at the individual level. This is particularly important for susceptible populations living in highly polluted areas (e.g., developing countries and regions subject to frequent wildfires), people with melatonin deficiency, and those using dirty household fuels.

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He, Linchen (2020). The Role of Melatonin in Pathophysiologic Responses to Air Pollution Exposure. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/22167.

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