Irregular Cycles, Ovulatory Disorders, and Cardiometabolic Conditions in a US-Based Digital Cohort.

Importance: Polycystic ovary syndrome (PCOS), characterized by irregular menstrual cycles and hyperandrogenism, is a common ovulatory disorder. Having an irregular cycle is a potential marker for cardiometabolic conditions, but data are limited on whether the associations differ by PCOS status or potential interventions. Objective: To evaluate the association of PCOS, time to regularity since menarche (adolescence), and irregular cycles (adulthood) with cardiometabolic conditions. Design, Setting, and Participants: This cross-sectional study used a large, US-based digital cohort of users of the Apple Research application on their iPhone. Eligibility criteria were having ever menstruated, living in the US, being at age of consent of at least 18 years (or 19 years in Alabama and Nebraska or 21 years in Puerto Rico), and being able to communicate in English. Participants were enrolled between November 14, 2019, and December 13, 2022, and completed relevant surveys. Exposures: Self-reported PCOS diagnosis, prolonged time to regularity (not spontaneously establishing regularity within 5 years of menarche), and irregular cycles. Main Outcomes and Measures: The primary outcome was self-reported cardiometabolic conditions, including obesity, prediabetes, type 1 and 2 diabetes, high cholesterol, hypertension, metabolic syndrome, arrhythmia, congestive heart failure, coronary artery disease, heart attack, heart valve disease, stroke, transient ischemic attack (TIA), deep vein thrombosis, and pulmonary embolism measured using descriptive statistics and logistic regression to estimate prevalence odds ratios (PORs) and 95% CIs. Effect modification by lifestyle factors was also estimated. Results: The study sample (N = 60 789) had a mean (SD) age of 34.5 (11.1) years, with 12.3% having PCOS and 26.3% having prolonged time to regularity. Among a subset of 25 399 participants who completed the hormonal symptoms survey, 25.6% reported irregular cycles. In covariate-adjusted logistic regression models, PCOS was associated with a higher prevalence of all metabolic and several cardiovascular conditions, eg, arrhythmia (POR, 1.37; 95% CI, 1.20-1.55), coronary artery disease (POR, 2.92; 95% CI, 1.95-4.29), heart attack (POR, 1.79; 95% CI, 1.23-2.54), and stroke (POR, 1.66; 95% CI, 1.21-2.24). Among participants without PCOS, prolonged time to regularity was associated with type 2 diabetes (POR, 1.24; 95% CI, 1.05-1.46), hypertension (POR, 1.09; 95% CI, 1.01-1.19), arrhythmia (POR, 1.20; 95% CI, 1.06-1.35), and TIA (POR, 1.33; 95% CI, 1.01-1.73), and having irregular cycles was associated with type 2 diabetes (POR, 1.36; 95% CI, 1.08-1.69), high cholesterol (POR, 1.17; 95% CI, 1.05-1.30), arrhythmia (POR, 1.21; 95% CI, 1.02-1.43), and TIA (POR, 1.56; 95% CI, 1.06-2.26). Some of these associations were modified by high vs low body mass index or low vs high physical activity. Conclusions and Relevance: These findings suggest that PCOS and irregular cycles may be independent markers for cardiometabolic conditions. Early screening and intervention among individuals with irregular menstrual cycles may be beneficial.

Evaluation of Menstrual Cycle Tracking Behaviors in the Ovulation and Menstruation Health Pilot Study: Cross-Sectional Study.

BACKGROUND: Menstrual cycle tracking apps (MCTAs) have potential in epidemiological studies of women's health, facilitating real-time tracking of bleeding days and menstrual-associated signs and symptoms. However, information regarding the characteristics of MCTA users versus cycle nontrackers is limited, which may inform generalizability. OBJECTIVE: We compared characteristics among individuals using MCTAs (app users), individuals who do not track their cycles (nontrackers), and those who used other forms of menstrual tracking (other trackers). METHODS: The Ovulation and Menstruation Health Pilot Study tested the feasibility of a digitally enabled evaluation of menstrual health. Recruitment occurred between September 2017 and March 2018. Menstrual cycle tracking behavior, demographic, and general and reproductive health history data were collected from eligible individuals (females aged 18-45 years, comfortable communicating in English). Menstrual cycle tracking behavior was categorized in 3 ways: menstrual cycle tracking via app usage, that via other methods, and nontracking. Demographic factors, health conditions, and menstrual cycle characteristics were compared across the menstrual tracking method (app users vs nontrackers, app users vs other trackers, and other trackers vs nontrackers) were assessed using chi-square or Fisher exact tests. RESULTS: In total, 263 participants met the eligibility criteria and completed the digital survey. Most of the cohort (n=191, 72.6%) was 18-29 years old, predominantly White (n=170, 64.6%), had attained 4 years of college education or higher (n= 209, 79.5%), and had a household income below US $50,000 (n=123, 46.8%). Among all participants, 103 (39%) were MCTA users (app users), 97 (37%) did not engage in any tracking (nontrackers), and 63 (24%) used other forms of tracking (other trackers). Across all groups, no meaningful differences existed in race and ethnicity, household income, and education level. The proportion of ever-use of hormonal contraceptives was lower (n=74, 71.8% vs n=87, 90%, P=.001), lifetime smoking status was lower (n=6, 6% vs n=15, 17%, P=.04), and diagnosis rate of gastrointestinal reflux disease (GERD) was higher (n=25, 24.3% vs n=12, 12.4%, P=.04) in app users than in nontrackers. The proportions of hormonal contraceptives ever used and lifetime smoking status were both lower (n=74, 71.8% vs n=56, 88.9%, P=.01; n=6, 6% vs n=11, 17.5%, P=.02) in app users than in other trackers. Other trackers had lower proportions of ever-use of hormonal contraceptives (n=130, 78.3% vs n=87, 89.7%, P=.02) and higher diagnostic rates of heartburn or GERD (n=39, 23.5% vs n=12, 12.4%, P.03) and anxiety or panic disorder (n=64, 38.6% vs n=25, 25.8%, P=.04) than nontrackers. Menstrual cycle characteristics did not differ across all groups. CONCLUSIONS: Our results suggest that app users, other trackers, and nontrackers are largely comparable in demographic and menstrual cycle characteristics. Future studies should determine reasons for tracking and tracking-related behaviors to further understand whether individuals who use MCTAs are comparable to nontrackers.

Associations between air pollution, residential greenness, and glycated hemoglobin (HbA1c) in three prospective cohorts of U.S. adults.

BACKGROUND: While studies suggest impacts of individual environmental exposures on type 2 diabetes (T2D) risk, mechanisms remain poorly characterized. Glycated hemoglobin (HbA1c) is a biomarker of glycemia and diagnostic criterion for prediabetes and T2D. We explored associations between multiple environmental exposures and HbA1c in non-diabetic adults. METHODS: HbA1c was assessed once in 12,315 women and men in three U.S.-based prospective cohorts: the Nurses' Health Study (NHS), Nurses' Health Study II (NHSII), and Health Professionals Follow-up Study (HPFS). Residential greenness within 270 m and 1,230 m (normalized difference vegetation index, NDVI) was obtained from Landsat. Fine particulate matter (PM2.5) and nitrogen dioxide (NO2) were estimated from nationwide spatiotemporal models. Three-month and one-year averages prior to blood draw were assigned to participants' addresses. We assessed associations between single exposure, multi-exposure, and component scores from Principal Components Analysis (PCA) and HbA1c. Fully-adjusted models built on basic models of age and year at blood draw, BMI, alcohol use, and neighborhood socioeconomic status (nSES) to include diet quality, race, family history, smoking status, postmenopausal hormone use, population density, and season. We assessed interactions between environmental exposures, and effect modification by population density, nSES, and sex. RESULTS: Based on HbA1c, 19% of participants had prediabetes. In single exposure fully-adjusted models, an IQR (0.14) higher 1-year 1,230 m NDVI was associated with a 0.27% (95% CI: 0.05%, 0.49%) lower HbA1c. In basic component score models, a SD increase in Component 1 (high loadings for 1-year NDVI) was associated with a 0.19% (95% CI: 0.04%, 0.34%) lower HbA1c. CI's crossed the null in multi-exposure and fully-adjusted component score models. There was little evidence of associations between air pollution and HbA1c, and no evidence of effect modification. CONCLUSIONS: Among non-diabetic adults, environmental exposures were not consistently associated with HbA1c. More work is needed to elucidate biological pathways between the environment and prediabetes.

Respiratory Effects of Traffic-Related Air Pollution: A Randomized, Crossover Analysis of Lung Function, Airway Metabolome, and Biomarkers of Airway Injury.

BACKGROUND: Exposure to traffic-related air pollution (TRAP) has been associated with increased risks of respiratory diseases, but the biological mechanisms are not yet fully elucidated. OBJECTIVES: Our aim was to evaluate the respiratory responses and explore potential biological mechanisms of TRAP exposure in a randomized crossover trial. METHODS: We conducted a randomized crossover trial in 56 healthy adults. Each participant was exposed to high- and low-TRAP exposure sessions by walking in a park and down a road with high traffic volume for 4 h in random order. Respiratory symptoms and lung function, including forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), the ratio of FEV1 to FVC, and maximal mid-expiratory flow (MMEF), were measured before and after each exposure session. Markers of 8-isoprostane, tumor necrosis factor-α (TNF-α), and ezrin in exhaled breath condensate (EBC), and surfactant proteins D (SP-D) in serum were also measured. We used linear mixed-effects models to estimate the associations, adjusted for age, sex, body mass index, meteorological condition, and batch (only for biomarkers). Liquid chromatography-mass spectrometry was used to profile the EBC metabolome. Untargeted metabolome-wide association study (MWAS) analysis and pathway enrichment analysis using mummichog were performed to identify critical metabolomic features and pathways associated with TRAP exposure. RESULTS: Participants had two to three times higher exposure to traffic-related air pollutants except for fine particulate matter while walking along the road compared with in the park. Compared with the low-TRAP exposure at the park, high-TRAP exposure at the road was associated with a higher score of respiratory symptoms [2.615 (95% CI: 0.605, 4.626), p=1.2×10-2] and relatively lower lung function indicators [-0.075L (95% CI: -0.138, -0.012), p=2.1×10-2] for FEV1 and -0.190L/s (95% CI: -0.351, -0.029; p=2.4×10-2) for MMEF]. Exposure to TRAP was significantly associated with changes in some, but not all, biomarkers, particularly with a 0.494-ng/mL (95% CI: 0.297, 0.691; p=9.5×10-6) increase for serum SP-D and a 0.123-ng/mL (95% CI: -0.208, -0.037; p=7.2×10-3) decrease for EBC ezrin. Untargeted MWAS analysis revealed that elevated TRAP exposure was significantly associated with perturbations in 23 and 32 metabolic pathways under positive- and negative-ion modes, respectively. These pathways were most related to inflammatory response, oxidative stress, and energy use metabolism. CONCLUSIONS: This study suggests that TRAP exposure might lead to lung function impairment and respiratory symptoms. Possible underlying mechanisms include lung epithelial injury, inflammation, oxidative stress, and energy metabolism disorders. https://doi.org/10.1289/EHP11139.

Abnormal uterine bleeding patterns determined through menstrual tracking among participants in the Apple Women's Health Study.

BACKGROUND: Use of menstrual tracking data to understand abnormal bleeding patterns has been limited because of lack of incorporation of key demographic and health characteristics and confirmation of menstrual tracking accuracy. OBJECTIVE: This study aimed to identify abnormal uterine bleeding patterns and their prevalence and confirm existing and expected associations between abnormal uterine bleeding patterns, demographics, and medical conditions. STUDY DESIGN: Apple Women's Health Study participants from November 2019 through July 2021 who contributed menstrual tracking data and did not report pregnancy, lactation, use of hormones, or menopause were included in the analysis. Four abnormal uterine bleeding patterns were evaluated: irregular menses, infrequent menses, prolonged menses, and irregular intermenstrual bleeding (spotting). Monthly tracking confirmation using survey responses was used to exclude inaccurate or incomplete digital records. We investigated the prevalence of abnormal uterine bleeding stratified by demographic characteristics and used logistic regression to evaluate the relationship of abnormal uterine bleeding to a number of self-reported medical conditions. RESULTS: There were 18,875 participants who met inclusion criteria, with a mean age of 33 (standard deviation, 8.2) years, mean body mass index of 29.3 (standard deviation, 8.0), and with 68.9% (95% confidence interval, 68.2-69.5) identifying as White, non-Hispanic. Abnormal uterine bleeding was found in 16.4% of participants (n=3103; 95% confidence interval, 15.9-17.0) after accurate tracking was confirmed; 2.9% had irregular menses (95% confidence interval, 2.7-3.1), 8.4% had infrequent menses (95% confidence interval, 8.0-8.8), 2.3% had prolonged menses (95% confidence interval, 2.1-2.5), and 6.1% had spotting (95% confidence interval, 5.7-6.4). Black participants had 33% higher prevalence (prevalence ratio, 1.33; 95% confidence interval, 1.09-1.61) of infrequent menses compared with White, non-Hispanic participants after controlling for age and body mass index. The prevalence of infrequent menses was increased in class 1, 2, and 3 obesity (class 1: body mass index, 30-34.9; prevalence ratio, 1.31; 95% confidence interval, 1.13-1.52; class 2: body mass index, 35-39.9; prevalence ratio, 1.25; 95% confidence interval, 1.05-1.49; class 3: body mass index, >40; prevalence ratio, 1.51; 95% confidence interval, 1.21-1.88) after controlling for age and race/ethnicity. Those with class 3 obesity had 18% higher prevalence of abnormal uterine bleeding compared with healthy-weight participants (prevalence ratio, 1.18; 95% confidence interval, 1.02-1.38). Participants with polycystic ovary syndrome had 19% higher prevalence of abnormal uterine bleeding compared with participants without this condition (prevalence ratio, 1.19; 95% confidence interval, 1.08-1.31). Participants with hyperthyroidism (prevalence ratio, 1.34; 95% confidence interval, 1.13-1.59) and hypothyroidism (prevalence ratio, 1.17; 95% confidence interval, 1.05-1.31) had a higher prevalence of abnormal uterine bleeding, as did those reporting endometriosis (prevalence ratio, 1.28; 95% confidence interval, 1.12-1.45), cervical dysplasia (prevalence ratio, 1.20; 95% confidence interval, 1.03-1.39), and fibroids (prevalence ratio, 1.14; 95% confidence interval, 1.00-1.30). CONCLUSION: In this cohort, abnormal uterine bleeding was present in 16.4% of those with confirmed menstrual tracking. Black or obese participants had increased prevalence of abnormal uterine bleeding. Participants reporting conditions such as polycystic ovary syndrome, thyroid disease, endometriosis, and cervical dysplasia had a higher prevalence of abnormal uterine bleeding.

Ultraviolet radiation and age at natural menopause in a nationwide, prospective US cohort.

BACKGROUND: Solar ultraviolet radiation (UV) is a critical environmental factor for dermal conversion of vitamin D, which is suggested to support reproductive health. However, current epidemiological studies have reported conflicting results on the associations between vitamin D levels and ovarian reserve. Further, few studies have considered UV exposure and reproductive aging, which is closely related to declined ovarian reserve. OBJECTIVES: We sought to examine the associations of long-term UV exposure and age at natural menopause in a large, nationwide, prospective cohort. METHODS: Participants in the Nurses' Health Study II (NHS II) who were premenopausal at age 40 were included and followed through 2015. Erythemal UV radiation from a high-resolution geospatial model was linked to the participants' residential histories. Early-life UV was estimated using the reported state of residence at birth, age 15, and age 30. We used time-varying Cox proportional hazards models to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) for natural menopause, adjusting for potential confounders and predictors of menopause. RESULTS: A total of 63,801 women reported natural menopause across the 1,051,185 person-years of follow-up among 105,631 eligible participants. We found very modest associations with delayed menopause for long-term UV exposure (adjusted HR comparing highest to lowest quartile of cumulative average UV: 0.96, 95% CI: 0.94, 0.99). There was a suggestive inverse association between UV at age 30 with menopause (adjusted HR comparing highest to lowest quartile: 0.97, 95% CI: 0.95, 1.00) but not with UV at birth and age 15. CONCLUSIONS: Solar UV exposure in adulthood was modestly associated with later onset of menopause. Although consistent with previous findings on vitamin D intake and menopause in the same population, these weak associations found in this study may not be of clinical relevance.

Hourly concentrations of fine and coarse particulate matter and dynamic pulmonary function measurements among 4992 adult asthmatic patients in 25 Chinese cities.

The short-term associations of fine particulate matter (PM2.5) and coarse particulate matter (PM2.5-10) with pulmonary function were inconsistent and rarely evaluated by dynamic measurements. Our study aimed to investigate the associations of PM2.5 and PM2.5-10 with real-time pulmonary function. We conducted a longitudinal study based on dynamic pulmonary function measurements among adult asthmatic patients in 25 cities of 19 provincial regions of China from 2017 to 2020. Linear mixed-effects models combined with polynomial distributed lag models were used for statistical analysis. A total of 298,396 records among 4,992 asthmatic patients were evaluated. We found generally inverse associations of PM2.5 and PM2.5-10 with 16 pulmonary function indicators that were independent of gaseous pollutants. The associations occurred at lag 1 d, became the strongest at lag 4 d, and vanished a week later. PM2.5-10 had stronger associations than PM2.5, especially in southern China. Nationally, an interquartile increase in PM2.5-10 (28.0 µg/m3) was significantly associated with decreases in forced expiratory volume in 1 s (FEV1, 41.6 mL), the ratio of FEV1 in forced vital capacity (1.1%), peak expiratory flow (136.9 mL/s), and forced expiratory flow at 25-75% of forced vital capacity (54.3 mL/s). We observed stronger associations in patients of male, BMI ≥ 25 kg/m2, age ≥ 45 years old, and during warm seasons. In conclusion, this study provided robust evidence for impaired pulmonary function by short-term exposure to PM2.5 and PM2.5-10 in asthmatic patients using the largest dataset of dynamic monitoring. The associations can last for one week and PM2.5-10 may be more hazardous.

Associations of long-term exposure to environmental noise and outdoor light at night with age at natural menopause in a US women cohort.

Previous studies have suggested noise, especially at night time, and light at night (LAN) could cause neuroendocrine disturbance and circadian disruption, which may lead to ovarian follicle atresia and earlier onset of menopause. However, no study to date has directly investigated the associations of exposure to these factors and menopausal age. METHODS: Premenopausal women from the Nurses' Health Study II (NHS II) were followed from age 40 through 2015. Median daytime and nighttime anthropogenic noise and outdoor LAN exposure were measured from a geospatial prediction model and satellite images, respectively, at residential addresses throughout the follow-up. Time-varying Cox proportional hazard models were used to calculate the hazard ratios and 95% confidence intervals, adjusting for individual lifestyle, reproductive history, and neighborhood socioeconomic factors. Possible effect modification by region, smoking status, body mass index, race/ethnicity, history of rotating shift work, and census tract population density and median income was examined. RESULTS: A total of 63,380 of 105,326 women self-reported natural menopause during 1,043,298 person-years of follow-up. No associations were found for noise (both daytime and nighttime) and outdoor LAN exposure with age at natural menopause (hazard ratios = 0.99-1.00) in the fully adjusted models. Sensitivity analyses showed similar null associations. No meaningful effect modification was found for region, smoking status, body mass index, race/ethnicity, history of rotating shift work, and census tract socioeconomic measures in stratified analyses. CONCLUSION: No associations were found between environmental noise and outdoor LAN exposure in mid-adulthood and menopausal age in this cohort of US women.

The prospective effects of long-term exposure to ambient PM2.5 and constituents on mortality in rural East China.

Few cohort studies explored the associations of long-term exposure to ambient fine particulate matter with an aerodynamic diameter of 2.5 µm or less (PM2.5) and its chemical constituents with mortality risk in rural China. We conducted a 12-year prospective study of 28,793 adults in rural Deqing, China from 2006 to 2018. Annual mean PM2.5 and its constituents, including black carbon (BC), organic carbon (OC), ammonium (NH4+), nitrate (NO3-), sulfate (SO42-), and soil dust were measured at participants' addresses at enrollment from a satellite-based exposure predicting model. Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs) of long-term exposure to PM2.5 for mortality. A total of 1960 deaths were identified during the follow-up. We found PM2.5, BC, OC, NH4+, NO3-, and SO42- were significantly associated with an increased risk of non-accidental mortality. The HR for non-accidental mortality was 1.17 (95%CI: 1.07, 1.28) for each 10 µg/m3 increase in PM2.5. As for constituents, the strongest association was found for BC (HR = 1.21, 95%CI: 1.11, 1.33), followed by NO3-, NH4+, SO42-, and OC (HR = 1.14-1.17 per interquartile range). A non-linear relationship was found between PM2.5 and non-accidental mortality. Similar associations were found for cardio-cerebrovascular and cancer mortality. Associations were stronger among men and ever smokers. Conclusively, we found long-term exposure to ambient PM2.5 and its chemical constituents (especially BC and NO3-) increased mortality risk. Our results suggested the importance of adopting effective targeted emission control to improve air quality for health protection in rural East China.

Associations of fine particulate matter and its constituents with airway inflammation, lung function, and buccal mucosa microbiota in children.

BACKGROUND: Previous studies have suggested acute effects of ambient fine particulate matter (PM2.5) air pollution on respiratory health among children, but evidence for PM2.5 constituents and respiratory health were still limited. OBJECTIVES: To investigate associations of short-term exposure to PM2.5 and its constituents with airway inflammation, lung function, and airway microbiota in children. METHODS: We conducted a longitudinal panel study with 3 repeated health measurements among 62 children in Shanghai, China from November 2018 to June 2019. Respiratory health was measured by fractional exhaled nitric oxide (FeNO), saliva tumor necrosis factor-α (TNF-α), lung function (forced vital capacity and forced exhaled volume in 1 s), and microbiota diversity in buccal mucosa samples. Based on the linear mixed-effect models, we applied the single-constituent models and the constituent-PM2.5 adjustment models to examine the associations between PM2.5 constituents and health outcomes. RESULT: Short-term exposure to PM2.5 was associated with higher TNF-α, FeNO levels and reduced lung function. Among all constituents, organic carbon, elemental carbon, NO3- and NH4+ had the consistent and strongest associations with airway inflammation biomarkers and lung function parameters, followed by metallic elements. We also found short-term PM2.5 exposure was associated with decreased diversity in buccal mucosa bacterial community and two bacterial phyla, Fusobacteria and Proteobacteria, were identified as differential microbes with PM2.5 exposure. CONCLUSION: Short-term exposure to PM2.5 may impair children's respiratory health represented by higher airway inflammation, lower lung function and altered buccal mucosa microbial colonization. Organic carbon, elemental carbon, NO3- and NH4+ may dominate these effects.

Exposure to ultrafine particles and oral flora, respiratory function, and biomarkers of inflammation: A panel study in children.

Particulate matter (PM) is the most important air pollution problem that leads to substantial health effects. However, very few studies focused on the effects of ultrafine particles (UFPs, particles< 0.1 µm) on children respiratory health. We performed a panel study with 3 rounds of follow-up among 65 pupils at the Elementary School Affiliated to Shanghai Normal University in China from November 2018 to June 2019. Real-time concentrations of UFPs were measured in the campus. In each visit, we detected biomarkers in saliva and microflora in buccal mucosa, fractional exhaled nitric oxide (FeNO) and lung function. We applied a linear mixed-effect (LME) model to examine the associations of UFPs and each health outcome. We found increased levels of FeNO and tumor necrosis factor-α (TNF-α) and reduced lung function in association with higher UFP exposure. For each interquartile range increase of UFPs, the largest changes were found in lag 0-72 h for forced vital capacity [-69.02 ml (95% CI: -114.20, -23.84)], TNF-α [13.41 pg/ml (95% CI: 7.08, 19.73)], and FeNO [26.85% (95% CI: 11.84%, 43.88%)]. UFP exposure was associated with reduced diversity in buccal microflora with largest reduction in lag 0-72 h [12.24 (95% CI: 7.76, 16.71) for Ace index; 8.78 (95% CI: 2.96, 14.60) for Chao1 index]. UFP exposure was also associated with increased Streptococcus, Gemella, and decreased Actinomyces. Short-term UFP exposures may impair the respiratory system by inducing inflammation, decreasing lung function and attenuating buccal microbe diversity in children.

Long-term exposure to particulate matter and roadway proximity with age at natural menopause in the Nurses' Health Study II Cohort.

Evidence has shown associations between air pollution and traffic-related exposure with accelerated aging, but no study to date has linked the exposure with age at natural menopause, an important indicator of reproductive aging. In this study, we sought to examine the associations of residential exposure to ambient particulate matter (PM) and distance to major roadways with age at natural menopause in the Nurses' Health Study II (NHS II), a large, prospective female cohort in US. A total of 105,996 premenopausal participants in NHS II were included at age 40 and followed through 2015. Time-varying residential exposures to PM10, PM2.5-10, and PM2.5 and distance to roads was estimated. We calculated hazard ratios (HR) and 95% confidence intervals (CIs) for natural menopause using Cox proportional hazard models adjusting for potential confounders and predictors of age at menopause. We also examined effect modification by region, smoking, body mass, physical activity, menstrual cycle length, and population density. There were 64,340 reports of natural menopause throughout 1,059,229 person-years of follow-up. In fully adjusted models, a 10 µg/m3 increase in the cumulative average exposure to PM10 (HR: 1.02, 95% CI: 1.00, 1.04), PM2.5-10 (HR: 1.03, 95% CI: 1.00, 1.05), and PM2.5 (HR: 1.03, 95% CI: 1.00, 1.06) and living within 50 m to a major road at age 40 (HR: 1.03, 95%CI: 1.00, 1.06) were associated with slightly earlier menopause. No statistically significant effect modification was found, although the associations of PM were slightly stronger for women who lived in the West and for never smokers. To conclude, we found exposure to ambient PM and traffic in midlife was associated with slightly earlier onset of natural menopause. Our results support previous evidence that exposure to air pollution and traffic may accelerate reproductive aging.

Fine Particulate Air Pollution and the Expression of microRNAs and Circulating Cytokines Relevant to Inflammation, Coagulation, and Vasoconstriction.

BACKGROUND: MicroRNAs (miRNAs) are a key factor in epigenetic regulation of gene expression, but miRNA responses to fine particulate matter (PM2.5) air pollution and their potential contribution to cardiovascular effects of PM2.5 are unknown. OBJECTIVE: We explored the potential influence of PM2.5 on the expression of selected cytokines relevant to systemic inflammation, coagulation, and vasoconstriction, and on miRNAs that may regulate their expression. METHODS: We designed a double-blind, randomized crossover study in which true and sham air purifiers were used to expose 55 healthy young adult students in Shanghai, China, to reduced or ambient levels of indoor PM2.5 during two-week periods, and we measured the expression (mRNA and protein) of 10 serum cytokines, and miRNAs that target them, after each intervention period. We used linear mixed-effect models to estimate associations of the intervention, and time-weighted personal PM2.5 exposures, with the cytokines, mRNA, and miRNAs; we also explored potential mediation by miRNAs. RESULTS: The findings were generally consistent for associations with the intervention and for associations with an interquartile range increase in time-weighted PM2.5. Specifically, higher PM2.5 exposure was positively associated with the expression (mRNA, protein, or both) of interleukin-1 (encoded by IL1), IL6, tumor necrosis factor (encoded by TNF), toll-like receptor 2 (encoded by TLR2), coagulation factor 3 (encoded by F3), and endothelin 1 (encoded by EDN1), and was negatively associated with miRNAs (miR-21-5p, miR-187-3p, miR-146a-5p, miR-1-3p, and miR-199a-5p) predicted to target mRNAs of IL1, TNF, TLR2, and EDN1. CONCLUSIONS: Our findings require confirmation but suggest that effects of PM2.5 on cardiovascular diseases may be related to acute effects on cytokine expression, which may be partly mediated through effects of PM2.5 on miRNAs that regulate cytokine expression. https://doi.org/10.1289/EHP1447.

Possible Mediation by Methylation in Acute Inflammation Following Personal Exposure to Fine Particulate Air Pollution.

Air pollution may increase cardiovascular and respiratory risk through inflammatory pathways, but evidence for acute effects has been weak and indirect. Between December 2014 and July 2015, we enrolled 36 healthy, nonsmoking college students for a panel study in Shanghai, China, a city with highly variable levels of air pollution. We measured personal exposure to particulate matter with an aerodynamic diameter less than or equal to 2.5 µm (PM2.5) continuously for 72 hours preceding each of 4 clinical visits that included phlebotomy. We measured 4 inflammation proteins and DNA methylation at nearby regulatory cytosine-phosphate-guanine (CpG) loci. We applied linear mixed-effect models to examine associations over various lag times. When results suggested mediation, we evaluated methylation as mediator. Increased PM2.5 concentration was positively associated with all 4 inflammation proteins and negatively associated with DNA methylation at regulatory loci for tumor necrosis factor alpha (TNF-α) and soluble intercellular adhesion molecule-1. A 10-µg/m3 increase in average PM2.5 during the 24 hours preceding blood draw corresponded to a 4.4% increase in TNF-α and a statistically significant decrease in methylation at one of the two studied candidate CpG loci for TNF-α. Epigenetics may play an important role in mediating effects of PM2.5 on inflammatory pathways.

The Acute Effects of Fine Particulate Matter Constituents on Blood Inflammation and Coagulation.

Limited evidence is available on the effects of various fine particulate matter (PM2.5) constituents on blood inflammation and coagulation. We examined the associations between 10 constituents and 10 circulating biomarkers in a panel of 28 urban residents with four repeated measurements in Shanghai, China. Based on the linear mixed-effect models, we fitted the single-constituent models, the constituent-PM2.5 joint models, and the constituent-residual models to evaluate the associations between PM2.5 constituents and eight inflammatory biomarkers (fibrinogen, C-reactive protein, monocyte chemoattractant protein-1, tumor necrosis factor-α, interleukin-1b, intercellular adhesion molecule-1, P-selectin, vascular cell adhesion molecule-1) and two coagulation biomarkers (plasminogen activator inhibitor-1 and soluble CD40 ligand). We found robust associations of organic carbon (OC), elemental carbon (EC), nitrate (NO3-), and ammonium (NH4+) with at least 1 of 8 inflammatory markers. On average, an interquartile range increase in the four constituents corresponded to increments of 50%, 37%, 25%, and 26% in inflammatory biomarkers, respectively. Only sulfate (SO42-) or NH4+ was robustly associated with coagulation markers (corresponding increments: 23% and 20%). Our results provided evidence that some constituents in PM2.5 (OC, EC, NO3-, SO42-, and NH4+) might play crucial roles in inducing systematic inflammation and coagulation, but their roles varied by the selected biomarkers.

Associations Between Air Quality Changes and Biomarkers of Systemic Inflammation During the 2014 Nanjing Youth Olympics: A Quasi-Experimental Study.

There is increasing interest in quasi-experimental research to evaluate whether actions taken to improve air quality will benefit public health. We conducted a quasi-experimental study to evaluate inflammatory response to changes in air quality during the 2014 Nanjing Youth Olympics in China. We repeatedly measured 8 biomarkers of systemic inflammation in 31 healthy adults and obtained hourly air pollutant concentrations from a nearby fixed-site monitoring station. We used linear mixed-effect models to examine the associations between air quality changes and blood biomarkers. Air pollutant concentrations decreased apparently during the Youth Olympics. Concomitantly, we observed significant decreases in levels of soluble cluster of differentiation 40 (CD40) ligand and interleukin 1ß (geometric means ratios were 0.45 and 0.24, respectively) from the pre-Olympic period to the intra-Olympic period. Afterwards, levels of C-reactive protein and vascular cell adhesion molecule 1 increased significantly (geometric means ratios were 2.22 and 1.29, respectively) in the post-Olympic period. Fine particulate matter and ozone were significantly associated with soluble CD40 ligand, P-selectin, interleukin 1ß, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1. Other pollutants showed positive but nonsignificant associations. Our study indicated that reduced air pollution, especially fine particulate matter and ozone, during the 2014 Nanjing Youth Olympics was associated with alleviated systemic inflammation in healthy adults.