Yue Niu

Personal exposure to fine particulate matter and blood pressure: A role of angiotensin converting enzyme and its DNA methylation.

BACKGROUND The underlying intermediate mechanisms about the association between fine particulate matter (PM2.5) air pollution and blood pressure (BP) were unclear. Few epidemiological studies have explored the potential mediation effects of angiotensin-converting enzyme (ACE) and its DNA methylation. METHODS We designed a longitudinal panel study with 4 follow-ups among 36 healthy college students in Shanghai, China from December 17, 2014 to July 11, 2015. We measured personal real-time exposure to PM2.5, serum ACE level, and blood methylation of ACE gene and the repetitive elements. We applied linear mixed-effects models to examine the effects of PM2.5 on ACE protein, DNA methylation and BP markers. Furthermore, we conducted mediation analyses to evaluate the potential pathways. RESULTS An interquartile range increase (26.78μg/m(3)) in 24-h average exposure to PM2.5 was significantly associated with 1.12 decreases in ACE average methylation (%5mC), 13.27% increase in ACE protein, and increments of 1.13mmHg in systolic BP, 0.66mmHg in diastolic BP and 0.82mmHg in mean arterial pressure. ACE hypomethylation mediated 11.78% (P=0.03) of the elevated ACE protein by PM2.5. Increased ACE protein accounted for 3.90~13.44% (P=0.35~0.68) of the elevated BP by PM2.5. Repetitive-element methylation was also decreased but did not significantly mediate the association between PM2.5 and BP. CONCLUSIONS This investigation provided strong evidence that short-term exposure to PM2.5 was significantly associated with BP, ACE protein and ACE methylation. Our findings highlighted a possible involvement of ACE and ACE methylation in the effects of PM2.5 on elevating BP.

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.

Ambient carbon monoxide and cardiovascular mortality: a nationwide time-series analysis in 272 cities in China

BACKGROUND Evidence of the acute health effects of ambient carbon monoxide air pollution in developing countries is scarce and mixed. We aimed to evaluate short-term associations between carbon monoxide and daily cardiovascular disease mortality in China. METHODS We did a nationwide time-series analysis in 272 major cities in China from January, 2013, to December, 2015. We extracted daily cardiovascular disease mortality data from Chinas Disease Surveillance Points system. Data on daily carbon monoxide concentrations for each city were obtained from the National Urban Air Quality Real-time Publishing Platform. City-specific associations between carbon monoxide concentrations and daily mortality from cardiovascular disease, coronary heart disease, and stroke were estimated with over-dispersed generalised linear models. Bayesian hierarchical models were used to obtain national and regional average associations. Exposure-response association curves and potential effect modifiers were evaluated. Two-pollutant models were fit to evaluate the robustness of the effects of carbon monoxide on cardiovascular mortality. FINDINGS The average annual mean carbon monoxide concentration in these cities from 2013 to 2015 was 1·20 mg/m3, ranging from 0·43 mg/m3 to 2·45 mg/m3. For a 1 mg/m3 increase in average carbon monoxide concentrations on the present day and previous day (lag 0-1), we observed significant increments in mortality of 1·12% (95% posterior interval [PI] 0·42-1·83) from cardiovascular disease, 1·75% (0·85-2·66) from coronary heart disease, and 0·88% (0·07-1·69) from stroke. These associations did not vary substantially by city, region, and demographic characteristics (age, sex, and level of education), and the associations for cardiovascular disease and coronary heart disease were robust to the adjustment of criteria co-pollutants. We did not find a threshold below which carbon monoxide exposure had no effect on cardiovascular disease mortality. INTERPRETATION This analysis is, to our knowledge, the largest study done in a developing country, and provides robust evidence of the association between short-term exposure to ambient carbon monoxide and increased cardiovascular disease mortality, especially coronary heart disease mortality. FUNDING Public Welfare Research Program.

The association between ambient temperature and out-of-hospital cardiac arrest in Guangzhou, China.

Out-of-hospital cardiac arrest (OHCA) is becoming a considerable public health burden worldwide. The seasonal variation of OHCA has been observed, but the potential effects of ambient temperature on OHCA were rarely investigated. We, therefore, aimed to evaluate the association between ambient temperature and OHCA in Guangzhou, China. We collected daily emergency ambulance dispatches for OHCA from the Guangzhou Emergency Center from January 1, 2008 to December 31, 2012. We analyzed the associations using the time-series method. We applied the generalized linear model combined with the distributed lag non-linear model to estimate the potentially non-linear and lagged effects of temperature on OHCA. Time trends, day of the week, and air pollutants were controlled as covariates. We identified a total of 4369 cases of OHCD. The associations between daily mean temperature and OHCA were generally J-shaped. Both low and high temperatures could increase the risk of OHCA. The effects were strongest on the concurrent day (lag 0) and lasted for 6 or 7days. The cumulative risks of extreme cold (1st percentile of temperature) and extreme heat (99th percentile of temperature) over lags 0-21days were 3.75 (95% confidence interval [CI]: 1.63, 8.63) and 2.45 (95%CI: 1.15, 5.33), respectively, compared with the referent temperature (28°C)·This study suggested that both cold and hot temperatures could significantly increase the risk of OHCA in Guangzhou, China. Our results might have important public health implications for the prevention of OHCA.

Fine particulate matter constituents and blood pressure in patients with chronic obstructive pulmonary disease: A panel study in Shanghai, China.

Objective: The evidence is limited about the potentially different health effects of various chemical constituents of fine particulate matter (PM2.5). We thus assessed the acute effects of various chemical constituents of PM2.5 on blood pressure (BP). Methods: We performed a longitudinal panel study with six repeated visits in 28 urban residents with chronic obstructive pulmonary disease in Shanghai, China from May to July, 2014. Twelve (43%) of them took antihypertensive medications. We measured resting BP by using a mercury sphygmomanometer and monitored real‐time concentrations of PM2.5 constituents at a nearby site. Based on the linear mixed‐effects model, we evaluated the effects of 10 major constituents in PM2.5 on BP, using a single‐constituent model and a constituent‐residual model after accounting for the multicollinearity. Results: We obtained a total of 168 pairs of effective BP measurements during the study period. There are moderate or high correlations among various PM2.5 constituents. An interquartile range increase of PM2.5 (19.1 &mgr;g/m3) was associated with increments of 1.90 mmHg [95% confidence interval (CI): 0.66, 3.13] in systolic BP, 0.68 mmHg (95%CI: −0.02, 1.37) in diastolic BP and 1.23 mmHg (95%CI: 0.19, 2.29) in pulse pressure. Some constituents of PM2.5, including organic carbon, elemental carbon, nitrate and ammonium, were robustly associated with elevated BP after controlling for total PM2.5 mass and accounting for multi‐collinearity. Two constituents (magnesium and calcium) were associated with decreased BP. Conclusions: Organic carbon, elemental carbon, nitrate and ammonium may be mainly responsible for elevated BP from a short‐term exposure to PM2.5. Graphical abstract: Figure. No Caption available. HighlightsA short‐term exposure to PM2.5 was significantly associated with elevated BP levels.Most constituents of PM2.5 were associated with increased BP in single‐constituent model.OC, EC, NO3−, and NH4+ were robustly positively associated with the increased BP.The association between PM2.5 and BP was statistically significant only at lag 0 day.

Associations between short-term exposure to ambient sulfur dioxide and increased cause-specific mortality in 272 Chinese cities

BACKGROUND Ambient sulfur dioxide (SO2) remains a major air pollutant in developing countries, but epidemiological evidence about its health effects was not abundant and inconsistent. OBJECTIVES To evaluate the associations between short-term exposure to SO2 and cause-specific mortality in China. METHODS We conducted a nationwide time-series analysis in 272 major Chinese cities (2013-2015). We used the over-dispersed generalized linear model together with the Bayesian hierarchical model to analyze the data. Two-pollutant models were fitted to test the robustness of the associations. We conducted stratification analyses to examine potential effect modifications by age, sex and educational level. RESULTS On average, the annual-mean SO2 concentrations was 29.8 μg/m3 in 272 cities. We observed positive and associations of SO2 with total and cardiorespiratory mortality. A 10 μg/m3 increase in two-day average concentrations of SO2 was associated with increments of 0.59% in mortality from total non-accidental causes, 0.70% from total cardiovascular diseases, 0.55% from total respiratory diseases, 0.64% from hypertension disease, 0.65% from coronary heart disease, 0.58% from stroke, and 0.69% from chronic obstructive pulmonary disease. In two-pollutant models, there were no significant differences between single-pollutant model and two-pollutant model estimates with fine particulate matter, carbon monoxide and ozone, but the estimates decreased substantially after adjusting for nitrogen dioxide, especially in South China. The associations were stronger in warmer cities, in older people and in less-educated subgroups. CONCLUSIONS This nationwide study demonstrated associations of daily SO2 concentrations with increased total and cardiorespiratory mortality, but the associations might not be independent from NO2.

Estimation of personal ozone exposure using ambient concentrations and influencing factors

Evidence is limited regarding whether ambient monitoring can properly represent personal ozone exposure. We conducted a longitudinal panel study to measure personal exposure to ozone using real-time personal ozone monitors. Corresponding ambient ozone concentrations and possible influencing factors (meteorological conditions and activity patterns) were also collected. We used linear mixed-effect models to analyze personal-ambient ozone concentration associations and possible influencing factors. Ambient ozone concentrations were around two to three times higher than personal ozone (43.1 μg/m3 on average) and their correlations were weak with small slopes (0.35) and marginal R square (RM2) values (0.24). Larger RM2 values were found under high temperature (>29.5 °C), low humidity (<62.1%), good ventilation conditions (>4 h) and for individuals spent longer time outdoors (>0.6 h). In final model, personal ozone exposure was positively associated with ambient concentrations and ventilation conditions, but inversely correlated with ambient temperature and humidity. The models explained >50% of personal ozone concentration variabilities. Our results highlight that ambient ozone concentration alone is not a suitable surrogate for individual exposure assessment. Meteorological conditions (temperature and humidity) and activity patterns (windows opening and outdoor activities) that affecting personal ozone exposure should be taken into account.

Effects of Personal Short-Term Exposure to Ambient Ozone on Blood Pressure and Vascular Endothelial Function: A Mechanistic Study Based on DNA Methylation and Metabolomics

Short-term exposure to ambient ozone is associated with adverse cardiovascular effects, with inconsistent evidence on the molecular mechanisms. We conducted a longitudinal panel study among 43 college students in Shanghai to explore the effects of personal ozone exposure on blood pressure (BP), vascular endothelial function, and the potential molecular mechanisms. We measured real-time personal ozone exposure levels, serum angiotensin-converting enzyme (ACE) and endothelin-1 (ET-1), and locus-specific DNA methylation of ACE and EDN1 (coding ET-1). We used an untargeted metabolomic approach to explore potentially important metabolites. We applied linear mixed-effect models to examine the effects of ozone on the above biomarkers. An increase in 2 h-average ozone exposure was significantly associated with elevated levels of BP, ACE, and ET-1. ACE and EDN1 methylation decreased with ozone exposure, but the magnitude differed by genomic loci. Metabolomics analysis showed significant changes in serum lipid metabolites following ozone exposure that are involved in maintaining vascular endothelial function. Our findings suggested that acute exposure to ambient ozone can elevate serum levels of ACE and ET-1, decrease their DNA methylation, and alter the lipid metabolism, which may be partly responsible for the effects of ozone on BP and vascular endothelial function.

Personal ozone exposure and respiratory inflammatory response: the role of DNA methylation in the arginase–nitric oxide synthase pathway

Little is known regarding the molecular mechanisms behind respiratory inflammatory response induced by ozone. We performed a longitudinal panel study with four repeated measurements among 43 young adults in Shanghai, China from May to October in 2016. We collected buccal samples and measured the fractional exhaled nitric oxide (FeNO) after 3-day personal ozone monitoring. In buccal samples, we measured concentrations of inducible nitric oxide synthase (iNOS) and arginase (ARG), and DNA methylation of NOS2A and ARG2. We used linear mixed-effect models to analyze the effects of ozone on FeNO, two enzymes and their DNA methylation. A 10 ppb increase in ozone (lag 0-8 h) was significantly associated with a 3.89% increase in FeNO, a 36.33% increase in iNOS, and a decrease of 0.36 in the average methylation (%5mC) of NOS2A. Ozone was associated with decreased ARG and elevated ARG2 methylation, but the associations were not significant. These effects were more pronounced among allergic subjects than healthy subjects. The effects were much stronger when using personal exposure monitoring than fixed-site measurements. Our study demonstrated that personal short-term exposure to ozone may result in acute respiratory inflammation, which may be mainly modulated by NOS2A hypomethylation in the arginase-nitric oxide synthase pathway.

Fine particulate matter constituents and stress hormones in the hypothalamus–pituitary–adrenal axis

Fine particulate matter (PM2.5) has recently been associated with the activation of the hypothalamus-pituitary-adrenal (HPA) axis, increasing cardiometabolic risks. However, it is unknown which constituents of PM2.5 were mainly responsible for these associations. In a longitudinal panel study with 4 repeated measurements among 43 college students in Shanghai, China, we measured serum levels of corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol, as indicators of HPA axis activation. Then, we evaluated the associations of 22 constituents of PM2.5 with these stress hormones using linear mixed-effect models. During the study period, the average daily concentration of PM2.5 was 41.1 μg/m3. We found that short-term exposure to PM2.5 was associated with elevated levels of the 3 stress hormones. We observed that water-soluble inorganic ions, especially nitrate (NO3-) and ammonium, had stronger influences on 3 hormones. Six metallic elements, including Zn, Mn, Cu, Fe, Br, and Cr, had positive but generally instable associations with 3 hormones. The effects of organic carbon and elemental carbon on hormones were generally weak. When correcting for multiple comparisons using false discovery rate, NO3- was still significantly associated with CRH, but other important associations turned to be insignificant. An interquartile range increase in NO3- on the previous day were associated with 12.13% increase (95% confidence interval: 4.45%, 20.37%) in CRH. Our findings suggested that water-soluble inorganic constituents of PM2.5 (especially, NO3-) might have stronger influences on the activation of HPA axis than carbonaceous and elemental components.