Xiao-Wen Zeng

Air pollution associated hypertension and increased blood pressure may be reduced by breastfeeding in Chinese children: The Seven Northeastern Cities Chinese Children's Study

BACKGROUND Little is known about the association between air pollution and hypertension among children, and no studies report whether breastfeeding modifies this association in children. METHODS Nine thousand three hundred fifty-four Chinese children, ages 5-17 years old, from 24 elementary schools and 24 middle schools in the Seven Northeastern Cities during 2012-2013 were evaluated. The weight, height, and BP were measured. Four-year average concentrations of particles with an aerodynamic diameter of ≤10 μm (PM10), sulfur dioxide (SO2), nitrogen dioxides (NO2), ozone (O3), and carbon monoxide (CO) were calculated from monitoring stations. Two-level regression analysis was used to examine the effects, controlling for covariates. RESULTS The results showed that associations existed between hypertension and pollutants. The odds ratios for hypertension ranged from 1.12 per 46.3 μg/m3 increase for O3 (95% confidence interval [CI], 1.10-1.13) to 1.68 per 30.6 μg/m3 increase for PM10 (95% CI, 1.53-1.86). The increases in mean diastolic BP ranged from 0.58 mm Hg per 46.3 μg/m3 increase for O3 (95% CI, 0.52-0.63 mm Hg) to 2.89 mm Hg per 563.4 μg/m3 increase for CO (95% CI: 2.53-3.24 mm Hg). The increase in systolic BP ranged from 0.50 mm Hg per 46.3 μg/m3 increase for O3 (95% CI: 0.43-0.57 mm Hg) to 2.10 mm Hg per 30.6 μg/m3 increase for PM10 (95% CI, 1.73-2.47 mm Hg). Compared with children who had been breastfed, non-breastfed children exhibited consistently stronger effects. CONCLUSION Study findings indicate that high levels of PM10, SO2, NO2, O3, and CO are associated with increased arterial BP and hypertension among the children. Breastfeeding may reduce the risk.

Association of polyfluoroalkyl chemical exposure with serum lipids in children

Perfluoroalkyl and polyfluoroalkyl substances (PFASs), as well as polymers of PFASs, have been widely used in commercial applications and have been detected in humans and the environment. Previous epidemiological studies have shown associations between particular PFAS chemicals and serum lipid concentrations in adults, particularly perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). There exists, however, limited information concerning the effect of PFASs have on serum lipids among children. In the present cross-sectional study, 225 Taiwanese children (12-15 years of age) were recruited to determine the relationship between serum level PFASs and lipid concentration. Results showed that eight out of ten particular PFASs were detected in the serum of >94% of the participants. Serum PFOS and perfluorotetradecanoic acid (PFTA) levels were at an order of magnitude higher than the other PFASs, with arithmetical means of 32.4 and 30.7 ng/ml in boys and 34.2 and 27.4 ng/ml in girls, respectively. However, the variation in serum PFTA concentration was quite large. Following covariate adjustment, linear regression models revealed that PFOS, PFOA, and perfluorononanoic acid (PFNA) were positively associated with total cholesterol (TC), low-density lipoprotein (LDL) and triglycerides (TG), particularly for PFOS and PFTA. Quartile analysis, with the lowest exposure quartile as a reference, yielded associations between serum PFTA and elevations in TC (p=0.002) and LDL (p=0.004). Though not statistically significant, high-density lipoprotein (HDL) appeared to decrease linearly across quartiles for PFOS and PFOA exposure. In conclusion, a significant association was observed between serum PFASs and lipid level in Taiwanese children. These findings for PFTA are novel, and emphasize the need to investigate the exposure route and toxicological evidence of PFASs beyond PFOS and PFOA.

Interactions Between Air Pollution and Obesity on Blood Pressure and Hypertension in Chinese Children.

Background: Little information exists regarding the effect of interaction of obesity and long-term air pollution exposure on children’s blood pressure and hypertension in areas with high levels of air pollution. The aim of this study is to assess effect modification by obesity on the association between exposure and blood pressure in Chinese children. Methods: We studied 9,354 Chinese children, ages 5–17 years old, from 24 elementary schools and 24 middle schools in the Seven Northeastern Cities during 2012–2013. Four-year average concentrations of particles with an aerodynamic diameter ⩽10 µm (PM10), sulfur dioxide, nitrogen dioxides, and ozone (O3) were measured at the monitoring stations in the 24 districts. We used generalized additive models and two-level logistic regression models to examine the health effects. Results: Consistent interactions were found between exposure and obesity on blood pressure and hypertension. The association between exposure and hypertension was consistently larger for overweight/obese children than for children with normal-weight, with odds ratios for hypertension ranging from 1.16 per 46.3&mgr;g/m3 for O3 (95% confidence interval [CI] = 1.12, 1.20) to 2.91 per 30.6&mgr;g/m3 for PM10 (95% CI = 2.32, 3.64), and estimated increases in mean systolic and diastolic blood pressure ranging from 0.57 mmHg (95% CI = 0.36, 0.78) and 0.63 mmHg (95% CI = 0.46, 0.81) per 46.3 &mgr;g/m3 for O3 to 4.04 mmHg (95% CI = 3.00, 5.09) and 2.02 mmHg (95% CI = 1.14, 2.89) per 23.4 &mgr;g/m3 for sulfur dioxide. Conclusions: Obesity amplifies the association of long-term air pollution exposure with blood pressure and hypertension in Chinese children.

PP2A-AMPKα-HSF1 axis regulates the metal-inducible expression of HSPs and ROS clearance.

Metals such as cadmium and arsenic are ubiquitous toxicants that cause a variety of adverse health effects. Heat shock proteins (HSPs) response to metal-induced stress and protect cells from further damage. However, the intracellular signalling pathways responsible for activation of HSPs expression are not fully understood. Here, we demonstrate that protein phosphatase 2A (PP2A) regulates expression of HSP70 and HSP27 via dephosphorylation of an AMP-activated protein kinase α subunit (AMPKα) at Thr172. Dephosphorylated AMPKα phosphorylates heat shock factor 1 (HSF1) at Ser303, leading to significant transcriptional suppression of HSP70 and HSP27 in CdCl2- or NaAsO2-treated cells. Suppression of PP2A regulatory B56δ subunit resulted in the sustained phosphorylation of AMPKα upon CdCl2 treatment, subsequent reduction in expression of HSP70 and HSP27, and thereby dramatic reduction of reactive oxygen species (ROS) clearance. We further revealed that PP2A B56δ physically interacted with AMPKα, providing evidence that PP2A B56δ-AMPKα-HSF1 signalling pathway participated in regulating the inducible expression of HSPs and ROS clearance. Taken together, we identified a novel PP2A-dependent signalling pathway involved in regulation of HSPs expression in response to metal stress.

Specific histone modification responds to arsenic-induced oxidative stress

To explore whether specific histone modifications are associated with arsenic-induced oxidative damage, we recruited 138 arsenic-exposed and arsenicosis subjects from Jiaole Village, Xinren County of Guizhou province, China where the residents were exposed to arsenic from indoor coal burning. 77 villagers from Shang Batian Village that were not exposed to high arsenic coal served as the control group. The concentrations of urine and hair arsenic in the arsenic-exposure group were 2.4-fold and 2.1-fold (all P<0.001) higher, respectively, than those of the control group. Global histone modifications in human peripheral lymphocytes (PBLCs) were examined by ELISA. The results showed that altered global levels of H3K18ac, H3K9me2, and H3K36me3 correlated with both urinary and hair-arsenic levels of the subjects. Notably, H3K36me3 and H3K18ac modifications were associated with urinary 8-OHdG (H3K36me3: β=0.16; P=0.042, H3K18ac: β=-0.24; P=0.001). We also found that the modifications of H3K18ac and H3K36me3 were enriched in the promoters of oxidative stress response (OSR) genes in human embryonic kidney (HEK) cells and HaCaT cells, providing evidence that H3K18ac and H3K36me3 modifications mediate transcriptional regulation of OSR genes in response to NaAsO2 treatment. Particularly, we found that reduced H3K18ac modification correlated with suppressed expression of OSR genes in HEK cells with long term arsenic treatment and in PBLCs of all the subjects. Taken together, we reveal a critical role for specific histone modification in response to arsenic-induced oxidative damage.

Heavy Metal-Induced Metallothionein Expression is Regulated by Specific Protein Phosphatase 2A Complexes

Background: The molecular mechanism and key signaling pathways underlying MT expression in response to metal stress remains elusive. Results: Upon metal stress, PP2A PR110 complexes bind to and dephosphorylate MTF-1 at Thr-254, leading to the transactivation of MTs. Conclusion: Specific PP2A complexes regulate metal-induced MTs expression. Significance: Delineate a novel pathway regulating metal-induced cytotoxicity and clarify the role of PP2A in cellular stress response. Induction of metallothionein (MT) expression is involved in metal homeostasis and detoxification. To identify the key pathways that regulate metal-induced cytotoxicity, we investigate how phosphorylated metal-responsive transcription factor-1 (MTF-1) contributed to induction of MT expression. Immortal human embryonic kidney cells (HEK cells) were treated with seven kinds of metals including cadmium chloride (CdCl2), zinc sulfate (ZnSO4), copper sulfate(CuSO4), lead acetate (PbAc), nickel sulfate (NiSO4), sodium arsenite (NaAsO2), and potassium bichromate (K2Cr2O7). The MT expression was induced in a dose-response and time-dependent manner upon various metal treatments. A cycle of phosphorylation and dephosphorylation was required for translocation of MTF-1 from cytoplasm to nucleus, leading to the up-regulation of MTs expression. Protein phosphatase 2A (PP2A) participated in regulating MT expression through dephosphorylation of MTF-1. A loss-of-function screen revealed that the specific PP2A complexes containing PR110 were involved in metal-induced MT expression. Suppression of PP2A PR110 in HEK cells resulted in the persistent MTF-1 phosphorylation and the disturbance of MTF-1 nuclear translocation, which was concomitant with a significant decrease of MT expression and enhanced cytotoxicity in HEK cells. Notably, MTF-1 was found in complex with specific PP2A complexes containing the PR110 subunit upon metal exposure. Furthermore, we identify that the dephosphorylation of MTF-1 at residue Thr-254 is directly regulated by PP2A PR110 complexes and responsible for MTF-1 activation. Taken together, these findings delineate a novel pathway that determines cytotoxicity in response to metal treatments and provide new insight into the role of PP2A in cellular stress response.

Specific long non-coding RNAs response to occupational PAHs exposure in coke oven workers

Highlights • HOTAIR and MALAT1 were upregulated in PBLCs of PAHs-exposed workers.• HOTAIR and MALAT1 expression was positively associated with the degree of DNA damage induced by PAHs.• H3K27me3 modification was positively correlated with the degree of genetic damage and the increase of HOTAIR expression.

Upregulation of miR-34a-5p antagonizes AFB1-induced genotoxicity in F344 rat liver.

Aflatoxin B1 (AFB1) is a well-known human hepatotoxicant and genotoxicant. Recent studies demonstrated that aberrant miRNA expression patterns were correlated with the cellular and genetic lesions induced by chemicals. To explore the role of miRNAs in AFB1-induced hepatotoxicity and genotoxicity, we examined alterations in miRNA expression patterns in F334 rat livers after exposure to 100 μg/kg or 200 μg/kg AFB1 for 28 days. Using high-throughput sequencing, we discovered that rno-miR-34a-5p, rno-miR-200b-3p, and rno-miR-429 were up-regulated and that rno-miR-130a-3p was down-regulated in liver tissue from rats that received 200 μg/kg of AFB1; this finding was validated by real-time PCR. AFB1 treatment resulted in the upregulation of rno-miR-34a-5p and rno-miR-200b-3p in the rat H-4-II-E cell line similar to our in vivo observations. Moreover, rno-miR-34a-5p was transcriptionally elevated via p53 activation after AFB1 exposure. Upregulation of rno-miR-34a-5p suppressed the expression of the cell cycle-related genes CCND1, CCNE2 and MET and led to cell cycle arrest in the G0-G1 phase. The CBMN assay indicated that inhibition of rno-miR-34a-5p and p53 expression aggravated the DNA damage induced by AFB1, which might be associated with shortening of the DNA damage repair period. Circulating miR-34a-5p in rat sera preceded a significant increase in ALT activity and other miRNAs in the 100 μg/kg AFB1 group. These observations demonstrated that rno-miR-34a-5p responded sensitively to AFB1 exposure and facilitated p53 repair of DNA damage by impacting the cell cycle. Thus, circulating rno-miR-34a-5p may be a sensitive indicator for the induction of hepatic genotoxicity by AFB1 in rats.

Long-term exposure to ambient air pollution (including PM 1 ) and metabolic syndrome: The 33 Communities Chinese Health Study (33CCHS)

&NA; Little evidence exists about the effects of long‐term exposure to ambient air pollution on metabolic syndrome (MetS). This study aimed to determine the association between long‐term ambient air pollution and MetS in China. A total of 15,477 adults who participated in the 33 Communities Chinese Health Study (33CCHS) in 2009 were evaluated. MetS was defined based on the recommendation by the Joint Interim Societies. Exposure to air pollutants was assessed using data from monitoring stations and a spatial statistical model (including particles with diameters ≤ 1.0 &mgr;m (PM1), ≤ 2.5 &mgr;m (PM2.5), and ≤ 10 &mgr;m (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), and ozone (O3)). Two‐level logistic regression analyses were utilized to assess the associations between air pollutants and MetS. The prevalence of MetS was 30.37%. The adjusted odds ratio of MetS per 10 &mgr;g/m3 increase in PM1, PM2.5, PM10, SO2, NO2, and O3 were 1.12 (95% CI = 1.00–1.24), 1.09 (95% CI = 1.00–1.18), 1.13 (95% CI = 1.08–1.19), 1.10 (95% CI = 1.02–1.18), 1.33 (95% CI = 1.12–1.57), and 1.10 (95% CI = 1.01–1.18), respectively. Stratified analyses indicated that the above associations were stronger in participants with the demographic variables of males, < 50 years of age, and higher income, as well as with the behavioral characteristics of smoking, drinking, and consuming sugar‐sweetened soft drinks frequently. This study indicates that long‐term exposure to ambient air pollutants may increase the risk of MetS, especially among males, the young to middle aged, those of low income, and those with unhealthy lifestyles. HighlightsAssociations of ambient air pollution with metabolic syndrome were scarcely studied.Data from 15,477 Chinese adults were analyzed.Long‐term exposure to air pollution was associated with metabolic syndrome.Demographic and lifestyle factors modified the association between metabolic syndrome and air pollution.

Effects of in utero and Postnatal Exposure to Secondhand Smoke on Lung Function by Gender and Asthma Status: The Seven Northeastern Cities (SNEC) Study

Background: Little information exists on whether gender or asthma status modifies the effects of secondhand smoke (SHS) exposure on lung function. Objective: To evaluate whether gender or asthma status modifies the association of SHS exposure with lung function. Methods: A total of 6,740 children (average 11.6 years) were recruited from 24 districts of 7 cities in northeast China in 2012. SHS exposure included exposure to environmental and maternal smoking both in utero and during early childhood (postnatal). Lung function was measured using electronic spirometers. Two-step regressions were used to analyze the association between SHS and lung function. Results: In utero and postnatal exposure to SHS was independently associated with decreased lung function in both genders; however, this association was greater among males. For example, when exposed to maternal smoking during pregnancy, the adjusted odds ratio (aOR) for decreased forced vital capacity (FVC) was 6.46 (95% confidence interval [CI]: 2.58-16.17) among males, while only 2.16 (95% CI: 0.96-4.88) among females. More positive associations between SHS exposure and decreased lung function were detected among nonasthmatic compared with asthmatic children. Nonasthmatics had significantly larger deficits from in utero exposure to maternal smoking, which concerned decreased lung FVC function (aOR = 2.58, 95% CI: 1.28-5.21) and decreased lung forced expiratory volume in 1 s (FEV1) function (aOR = 2.32, 95% CI: 1.01-5.33). A similar pattern was also observed for the associations between SHS exposure and continuous pulmonary function test measurements. Conclusions: SHS exposure was associated with decreased lung function. Males and nonasthmatics seem to be more susceptible than their respective counterparts.