| Cardiovascular disease was the leading cause for the death of urban and rural residents in China,of which 245 million Chinese people suffered from hypertention.The etiology of elevated blood pressure（BP）was quite complex,mainly developed in response to genetic and environmental factors,particularlly fine particulate matter(PM2.5,aerodynamic diameter ≤ 2.5 μm).Compared to adults,children were more susceptible to PM2.5 due to the special period of growth and development as well as their unique behavior and activity patterns.Previous studies showed that short-term exposure to PM2.5 was associated with increased BP and risk of hypertension in adults.However,only limited number of studies explored the acute effect of PM2.5 on BP in children,almost all of which were based on monitoring stations or fixed sites to collect the exposure level of PM2.5,and the results were inconsistent.Also,due to the different properties of PM2.5 and varied physiological parameters of children’s respiratory tract,the actual deposition dose of PM2.5 in the respiratory tract as well as their actual effects on BP would be unkonwn.Meanwhile,the chemical consitituents of PM2.5 were complex,and metal was one of important consitituents.Given the strong persistence,accumulation and potential toxicity of some metals,many countries have issued priority-controlled metals,including arsenic,cadmium,lead,antimony,thallium and other three metals.Priority-controlled metals were taken specific risk control measures according to the policy and regulations,including implementing the discharge permit system,restricting in use,encouraging alternatives and so on.Through digestive intake,inhalation,or dermal absorption,priority-controlled metals were mainly excreted in the urine,thus urinary metals would better reflect the internal exposure level.It’s reported that arsenic and lead were positively associated with adults’ BP.However,prior evidence avaiable on association between priority-controlled metals and children’s BP was insufficient.And almost all these limited reports were based on cross-sectional design with only once metal measurement among European or American children,but the results showed great heterogeneity.Moreover,it’s unknown whether there were dose-response relationships of PM2.5 and priority-controlled metals with children’s BP,and the time window for effect of PM2.5 and metals on outcomes,as well as the characteristics of children’s susceptibility,such as age,gender and lifestyles.Furthermore,the underlying mechanism behand PM2.5 and priority-controlled metals with children’s BP was unclear.Since exposure levels of PM2.5 and metal were affected by multiple factors,most previous studies based on cross-sectional design with once measurements of exposure and outcome were more likely to be biased.However,panel study could collect multiple repeated measurements among small sample population,and multiple self-controlled measurements could effectively control sampling error between individuals to improve the statistical power.Thus,panel study could provide more reliable evidence for acute effects of PM2.5 and metal on health outcomes based on personal exposure levels.Therefore,based on longitidinal panel studies in 3 cities of China,we explored the relations of PM2.5 and its respiratory tract depositions,urinary priority-controlled metals with children’s BP,as well as the role of cytokines in that associations.Part 1: Associations of ambient fine particulate matter and children’s BPObjective: We aimed to investigate the dose-response relationships of short-term exposure to personal PM2.5 and its respiratory tract depositions with children’s BP,recognize the major characteristics of children’s susceptibility,and explore the role of cytokines in relations between PM2.5 and BP.Method: We conducted panel studies with 3 surveys across 3 seasons in Wuhan（Central）,Guangzhou（Southern）and Weinan（Northern）,China from 2017 to 2019 among 421 children aged 413 years.In each survey of each city,72-h real-time personal PM2.5measurements and a series of health examinations were carried out on the morning of the4 th day,including meaurements of height,weight and BP,etc.The protocol was approved by the Medical Ethics Committee of Tongji Medical College,Huazhong University of Science and Technology,and we obtained written informed consents from all subjects’ guardians at enrollment.Multiple-Path Particle Dosimetry model simulated deposition fractions of PM2.5 in different respiratory tract regions,and 24 h deposition doses were calculated.48 serum cytokines were detected for children from Wuhan and significant cytokines were screened out.Combined with prior studies,10 cytokines were verified in children from Guangzhou.After excluding loss of follow-ups,missing blood drawing and BP measure,a total of 421 children with 1153 BP and 655 cytokines effective measurements were included for further analyses.We respectively performed linear mixed effects（LMEs）model and generalized estimating equations（GEEs）to explore the relations of PM2.5 at single lag day and cumulative lag day,and its respiratory tract depositions,with children’s BP and risk of hypertension,restricted cubic spline curve to fit dose-response relationships,and mediation analyses for the role of cytokines in associations of PM2.5 with BP.Result: After adjusting for potential confounders,personal PM2.5 was associated with elevated systolic BP（SBP）,diastolic BP（DBP）and mean arterial BP（MAP）within 3 days.Such relations were the strongest at Lag 1 h（The 1st h ahead of BP measurement）and declined over time.A-10 μg/m3 increase of PM2.5 at Lag 1 h was related to increment of0.25% [95% confidence interval（CI）: 0.14%,0.36%] in SBP,0.50%（95% CI: 0.33%,0.67%）in DBP,0.40%（95% CI: 0.27%,0.52%）in MAP.While,the positive relation of PM2.5 with risk of hypertension was consistently significant within 3 days,and PM2.5 at Lag2（The 2nd day ahead of BP measurement）was related to higher risk of prehypertension.A-10 μg/m3 increase of PM2.5 at Lag 2 was linked with odds ratio（OR）of prehypertension and hypertension with estimation of 1.081（95% CI: 1.033,1.130）and 1.058（95% CI: 1.023,1.094）,respectively.All above relationships showed in a dose-respondse manner.Notably,positive associations of PM2.5 with BP outcomes were still significant when PM2.5 below National Ambient Air Quality Standards（NAAQS）II（75 μg/m3）or NAAQS transition standard（50 μg/m3）,but not World Health Organization’s Itermia Target 4（25 μg/m3）.Also,compared to PM2.5,PM2.5 depositions in respiratory tracts displayed more evident effects on BP outcomes.For instance,each 10-μg increase in tracheobronchial and alveolar depositions were related to hypertension with OR of 1.111（95% CI: 1.043,1.184）and 1.063（95% CI: 1.026,1.103）,respectively.And,relations of PM2.5 deposited in tracheobronchial and alveolar regions with BP outcomes were stronger than deposition in extrathoracic/head region.Among 3 cities,the levels of PM2.5 and its depositions were the lowest while their effect on BP outcomes were the strongest in children from Guangzhou.In addition,age and daily extra-school activity modififed associations of PM2.5 and BP outcomes,which were more evident in school-age children and those with daily extra-school activity ≥ 1 h.As for the role of cytokines in the associations of PM2.5 with BP outcomes,among children from Wuhan,we found the positive relations of PM2.5 at Lag 1（The 1st day ahead of BP measurement）and Lag 2 with C-C motif chemokine ligand 27,hepatocyte growth factor,platelet derived growth factor,stem cell factor,Interleukin（IL）-1Ra,IL-2Rα,IL-16,and interferon-γ and macrophage-colony stimulating factor,which were the strongest at Lag 1.Meanwhile,the assocations of IL-2Rα,IL-16,stem cell factor,and macrophagecolony stimulating factor with BP were significant.Further,mediation analyses showed that IL-16 partly mediated the association of PM2.5 at Lag 0-1（Health examinations day and the1 st day ahead of BP measurement）and elevated BP with marginal effects,and its mediating proportion was 11.44%.However,none significant effect of cytokines on relations between PM2.5 and BP was found in children from Guangzhou.Conclusion: Personal exposure to PM2.5 was consistently and dose-responsive associated with children’s BP and risk of hypertension within 3 days.Such relationships were still significant when PM2.5 below NAAQS II and transition standard.Also,PM2.5 was related to multiple cytokines elevation,of which IL-16 might be partly involved in association between PM2.5 with BP.Part 2: Associations of urinary priority-controlled metals and children’s BPObjective: We aimed to assess the dose-response relationships of urinary prioritycontrolled metals,with children’s BP,recognize the major characteristics of children’s susceptibility,and explore the role of cytokines in relations between metals and BP.Method: We conducted panel studies in Guangzhou（Southern）and Weinan（Northern）,China as Part 1.In each survey of each city,urine samples were collected for 4 consecutive days and health examination was conducted on the morning of the 4th day.Urinary metals were detected by inductively coupled plasma-mass spectrometry.After excluding loss of follow-ups,missing blood drawing,urine collection and BP measure,a total of 283 children with 786 BP and 356 cytokines effective measurements were included for further analyses.And total 2735 urinary metals were obtained over 4 days.We respectively performed LMEs and GEEs to explore the relations of 5 detectably priority-controlled metals（arsenic,cadmium,lead,antimony and thallium）at single lag day [Lag 0（Health examinations day）,Lag 1,Lag 2 and Lag 3（The 3rd day ahead of BP measurement）] and cumulative lag day[Lag 0-3（4 days averaged）] with children’s BP and risk of hypertension,Bayesian Kernel Machine Regression to evaluate the relations of metals mixture at Lag 0-3 and BP outcomes,restricted cubic spline curve to fit dose-response relationships,and mediation analyses for the role of cytokines in relations between metals and BP outcomes.Result: After adjusting for potential confounders,antimony was positively and consistently related to SBP,MAP and risk of hypertension at Lag 0 Lag 3 and Lag 0-3,which were the strongest at Lag 0 and decline over time.And such relationships at Lag 0-3showed in a dose-response manner.A 1-fold increase of antimony at Lag 0 was related to increment of 0.56%（95% CI: 0.19%,0.94%）in SBP,0.53%（95% CI: 0.14%,0.92%）in MAP,hypertension with OR of 1.267（95% CI: 1.107,1.450）.Meanwhile,antimony was the only contributor to relations of mixture with SBP,MAP and risk of hypertension.Also,synergistic interactions between antimony and asenic showed significant,and relations of antimony and SBP was stronger when arsenic was at high level.Compared to Guangzhou,the level of antimony and its effect on BP in children from Weinan were larger.In addition,modification effect of passive smoking status on association of Sb and SBP was more evident in passive smokers than non-passive smokers.Moreover,the positive relations of arsenic with C-C motif chemokine ligand 3 and antimony and IL-1Ra were significant within 4 days,which were the strongest at Lag 0-3.Meawhile,we only observed the positive association of C-X-C motif chemokine ligand 1with risk of hypertension.However,we didn’t find the significant mediation of above cytokines in realtions of priority-controlled metals with children’s BP.Conclusion: Urinary antimony was positively and consistently associated with children’s BP and risk of hypertension within 4 days in a dose-repsonse manner.Meanwhile,links of metal mixture with BP and hypertension were mainly attributed to antimony.Above relations were not significantly mediated by cytokines.In summary,individual PM2.5 and urinary antimony were consistently associated with increased BP and hypertension within 4 days in dose-response manner among children.Multiple cytokines were related to PM2.5 and metals,only IL-16 might be partly involved in relation of PM2.5 and BP. |
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