Long-term exposure to air pollutants and new-onset migraine: A large prospective cohort study.

BACKGROUNDS: Short-term exposure to air pollutants increases the risk of migraine, but the long-term impacts of exposure to multiple pollutants on migraine have not been established. The aim of this large prospective cohort study was to explore these links. METHODS: A total of 458,664 participants who were free of migraine at baseline from the UK Biobank were studied. Cox proportional hazards models were used to estimate the risk of new-onset migraine from combined long-term exposure to four pollutants, quantified as an air pollution score using principal component analysis. RESULTS: During a median (IQR) follow-up of 12.5 (11.8, 13.2) years, a total of 5417 new-onset migraine cases were documented. Long-term exposure to multiple air pollutants was associated with an increased risk of new-onset migraine, as indicated by an increased in the SDs of PM2.5 (hazard ratio (HR): 1.04, 95% CI: 1.01-1.06, P = 0.009), PM10 (HR: 1.07, 95% CI: 1.04-1.10, P < 0.001), NO2 (HR: 1.10, 95% CI: 1.07-1.13, P < 0.001) and NOx (HR: 1.04, 95% CI: 1.01-1.07, P = 0.005) in the main model. The air pollution score showed a doseresponse association with an increased risk of new-onset migraine. Similarly, compared with those of the lowest tertile, the HRs (95% CI) of new-onset migraine were 1.11 (95% CI: 1.04-1.19, P = 0.002) and 1.17 (95% CI: 1.09-1.26, P < 0.001) in tertiles 2 and 3, respectively, according to the main model (P trend < 0.001). CONCLUSION: Long-term individual and joint exposure to multiple air pollutants is associated with an increased risk of new-onset migraine.

Triclosan in paired-maternal and cord blood, and their relationships with congenital heart disease of baby.

Prenatal triclosan (TCS) exposure has been reported to be associated with various birth outcomes and thyroid function, while the study of TCS exposure for congenital heart disease (CHD) patients is limited. In the present study, paired mother-fetus blood samples from CHD and healthy participants were collected to measure TCS exposure levels, and then check their relationship. Coupled with the concentrations of thyroid function biomarkers [free thyroxine (FT4), free triiodothyronine (FT3), thyroid-stimulating hormone (TSH), and thyroid antibodies (TgAb)] in maternal blood, we aimed to investigate whether the hormone-disrupting properties of TCS will affect its association with CHD. Our results indicated that the maternal TCS concentrations in the CHD group (median 0.31 ng/mL) were significantly lower than those in the control group (0.48 ng/mL, Mann Whitney U test, p = 0.01). Higher interquartile of TCS levels in maternal blood was associated with decrease odds of CHD (adjusted OR = 0.61, 95%CI: 0.41-0.91, p = 0.02). Maternal blood TCS higher than the cut-off value (25th quantile, 0.17 ng/mL) was significantly negatively associated with CHD risk (adjusted OR = 0.24, 95%CI: 0.09-0.62, p < 0.01). Besides, none of the thyroid biomarkers were significantly associated with maternal TCS exposure. However, maternal FT4 concentrations were positively correlated with TCS transplacental transfer rate and cord blood TCS levels (general linear regression, both p < 0.01). The results of molecular docking and dynamics simulation suggested that these correlations might be related to the transthyretin, a thyroid hormone-binding protein involved in the placental thyroid hormone transport system. Overall, our findings indicated that at normal exposure levels, the increase of maternal blood TCS concentration may have an inverse association with CHD, which merits further investigation.

Co-exposure to perfluoroalkyl acids and heavy metals mixtures associated with impaired kidney function in adults: A community-based population study in China.

BACKGROUND: Previous studies have separately linked either perfluoroalkyl acid (PFAA) or heavy metal exposure with kidney dysfunction. However, the relationships of co-exposure to PFAAs and heavy metals with kidney function are still unclear. OBJECTIVES: To explore the associations between exposure to PFAAs and heavy metals mixtures and kidney function in adults. METHODS: We conducted a cross-sectional community-based population study in Guangzhou, China, enrolling 1312 adults from November 2018 to August 2019. We quantified 13 PFAAs in serum and 14 heavy metals in plasma. We chose estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD) as outcomes of interest. Distributed lag non-linear models (DLNMs) were used to check nonlinearity of individual pollutant with kidney function. Joint associations of pollutant mixtures on kidney function were assessed by Bayesian Kernel Machine Regression (BKMR) models. We further explored modification effects of gender. RESULTS: Most individual PFAA and heavy metal were associated with declined kidney function in single-pollutant models. We also observed significant dose-response relationships of pollutant mixtures with reduced eGFR levels and increased odds of CKD in BKMR models. Perfluoroheptanesulfonic acid (PFHpS), arsenic (As) and strontium (Sr) were the predominant contributors among pollutant mixtures. A change in log PFHpS, As and Sr concentrations from the 25th to the 75th percentile were associated with a decrease in eGFR of -5.42 (95% confidence interval (CI): -6.86, -3.98), -2.14 (95% CI: -3.70, -0.58) and -1.87 (95% CI: -3.03, -0.72) mL/min/1.73 m2, respectively, when other pollutants were at their median values. In addition, the observed associations were more obvious in females. CONCLUSIONS: We provided new evidence that co-exposure to PFAAs and heavy metals mixtures was associated with reduced kidney function in adults and PFHpS, As and Sr appeared to be the major contributors. Further studies are warranted to confirm our findings and elucidate the underlying mechanisms.

Per- and perfluoroalkyl substances alternatives, mixtures and liver function in adults: A community-based population study in China.

Experimental evidence has shown that per- and polyfluoroalkyl substances (PFAS) alternatives and mixtures may exert hepatotoxic effects in animals. However, epidemiological evidence is limited. This research aimed to explore associations of PFAS and the alternatives with liver function in a general adult population. The study participants consisted of 1,303 adults from a community-based cross-sectional investigation in Guangzhou, China, from November 2018 to August 2019. We selected 13 PFAS with detection rates > 85% in serum samples and focused on perfluorooctane-sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and their alternatives [6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA), 8:2 Cl-PFESA, and perfluorohexanoic acid (PFHxA)] as predictors of outcome. Six liver function biomarkers (ALB, ALT, AST, GGT, ALP, and DBIL) were chosen as outcomes. We applied regression models with restricted cubic spline function to explore correlations between single PFAS and liver function and inspected the combined effect of PFAS mixtures on liver by applying Bayesian kernel machine regression (BKMR). We discovered positive associations among PFAS and liver function biomarkers except for ALP. For example, compared with the 25th percentile of PFAS concentration, the level of ALT increased by 12.36% (95% CI: 7.91%, 16.98%) for ln-6:2 Cl-PFESA, 5.59% (95% CI: 2.35%, 8.92%) for ln-8:2 Cl-PFESA, 3.56% (95% CI: -0.39%, 7.68%) for ln-PFHxA, 13.91% (95% CI: 8.93%, 19.13%) for ln-PFOA, and 14.25% (95% CI: 9.91%, 18.77%) for ln-PFOS at their 75th percentile. In addition, higher exposed serum PFAS was found to be correlated with greater odds of abnormal liver function. Analysis from BKMR models also showed an adverse association between PFAS mixtures and liver function. The combined effect of the PFAS mixture appeared to be non-interactive, in which PFOS was the main contributor to the overall effect. Our findings provide evidence of associations between PFAS alternatives, PFAS mixtures, and liver function in the general adult population.

Associations between both legacy and alternative per- and polyfluoroalkyl substances and glucose-homeostasis: The Isomers of C8 health project in China.

BACKGROUND: Epidemiological studies on the associations of legacy per- and polyfluoroalkyl substances (PFASs) and glucose homeostasis remain discordant. Understanding of PFAS alternatives is limited, and few studies have reported joint associations of PFASs and PFAS alternatives. OBJECTIVES: To investigate associations of novel PFAS alternatives (chlorinated perfluoroalkyl ether sulfonic acids, Cl-PFESAs and perfluorobutanoic acid, PFBA) and two legacy PFASs (Perfluorooctanoic acid, PFOA and perfluorooctane sulfonate, PFOS) with glucose-homeostasis markers and explore joint associations of 13 legacy and alternative PFASs with the selected outcomes. METHODS: We used cross-sectional data of 1,038 adults from the Isomers of C8 Health Project in China. Associations of PFASs and PFAS alternatives with glucose-homeostasis were explored in single-pollutant models using generalized linear models with natural cubic splines for PFASs. Bayesian Kernel Machine Regression (BKMR) models were applied to assess joint associations of exposures and outcomes. Sex-specific analyses were also conducted to evaluate effect modification. RESULTS: After adjusting for confounders, both legacy (PFOA, PFOS) and alternative (Cl-PFESAs and PFBA) PFASs were positively associated with glucose-homeostasis markers in single-pollutant models. For example, in the total study population, estimated changes with 95% confidence intervals (CI) of fasting glucose at the 95th percentile of 6:2Cl-PFESA and PFOS against the thresholds were 0.90 (95% CI: 0.59, 1.21) and 0.44 (95% CI: 0.26, 0.62). Positive joint associations were found in BKMR models with 6:2Cl-PFESA contributing most. Sex-specific associations existed in both single- and multi-pollutant models. CONCLUSIONS: Legacy and alternative PFASs were positively associated with glucose-homeostasis markers. 6:2Cl-PFESA was the primary contributor. Sex-specific associations were also identified. These results indicate that joint associations and effect modification should be considered in risk assessment. However, further studies are recommended to strengthen our findings and to elucidate the mechanisms of action of legacy and alternative PFASs.

Perfluorooctane sulfonate alternatives and metabolic syndrome in adults: New evidence from the Isomers of C8 Health Project in China.

Chlorinated polyfluoroalkyl ether sulfonates (Cl-PFESAs), are ubiquitous alternatives to perfluorooctane sulfonate (PFOS), a widely used poly- and perfluoroalkyl substance (PFAS). Despite in vivo and in vitro evidence of metabolic toxicity, no study has explored associations of Cl-PFESAs concentrations with metabolic syndrome (MetS) in a human population. To help address this data gap, we quantified 32 PFAS, including 2 PFOS alternative Cl-PFESAs (6:2 and 8:2 Cl-PFESAs) in serum from 1228 adults participating in the cross-sectional Isomers of C8 Health Project in China study. The odds ratios (ORs) and 95% confidence intervals (CIs) of MetS and its various components were estimated using individual PFAS as a continuous or categorical predictor in multivariate regression models. The association between the overall mixture of PFAS and MetS was examined using probit Bayesian Kernel Machine Regression (BKMR-P). Greater serum PFAS concentrations were associated with higher odds of MetS and demonstrated a statistically significant dose-response trend (P for trend < 0.001). For example, each ln-unit (ng/mL) increase in serum 6:2 Cl-PFESA was associated with a higher prevalence of MetS (OR = 1.52, 95% CI: 1.25, 1.85). MetS was also 2.26 (95% CI: 1.59, 3.23) times more common in the highest quartile of serum 6:2 Cl-PFESA concentration than the lowest, and particularly high among women (OR = 6.41, 95% CI: 3.65, 11.24). The BKMR-P analysis showed a positive association between the overall mixture of measured PFAS and the odds of MetS, but was only limited to women. While our results suggest that exposure to Cl-PFESAs was associated with MetS, additional longitudinal studies are needed to more definitively address the potential health concerns of these PFOS alternatives.

[Analysis of environmental risk factors in congenital heart defects].

OBJECTIVE: To explore the environmental risk factors of different categories of congenital heart defects (CHD) and provide evidence for further risk factors and prevention research of CHD phenotypes. METHODS: Data of Guangdong CHD Register Study from 2004 to 2012 were used. In the study, 3 038 CHD cases and 3 038 paired controls from 34 hospitals distributed in 17 cities were registered and related information were collected using uniform, and structured questionnaires. All the CHD phenotypes were coded according to the International Classification of Diseases 10th Revision (ICD-10) and classified into 6 categories according to their pathological features. Univariate analyses were adopted to filter potential risk factors for each category of CHD. Then multivariate conditional Logistic regression was used to calculate the odds ratios of the risk factors for each category of CHD. RESULTS: The risk factors for left-to-right shunt CHD included low (OR=2.63, 95%CI:2.04-3.39) or over birth weight (OR=2.21, 95%CI: 1.47-3.32), premature delivery (OR=1.95, 95%CI: 1.53-2.49), polyembryony (OR=1.99, 95%CI: 1.22-3.26), maternal low education, mother as factory worker (OR=1.62, 95%CI: 1.32-1.98), parity≥2 (OR=1.38, 95%CI: 1.13-1.69), maternal abnormal reproduction history (OR=2.29, 95%CI: 1.75-3.01), fever (OR=2.38, 95%CI: 1.26-4.48), virus infection (OR=1.80, 95%CI: 1.29-2.51), medicine usage (OR=1.73, 95%CI: 1.11-2.69), passive smoking (OR=1.69, 95%CI: 1.26-2.29), chemical agent contact (OR=8.71, 95%CI: 2.33-32.58), living in newly decorated houses (OR=2.56, 95%CI: 1.60-4.09) or room close to the main road (OR=1.40, 95%CI: 1.14-1.72) in the first 3 months of pregnancy and father as factory worker (OR=1.46, 95%CI: 1.23-1.73). The risk factors for pulmonary outflow tract obstruction CHD included low (OR=5.98, 95%CI: 2.88-12.44) or over birth weight (OR=6.56, 95%CI:1.19-36.26), maternal low education, parity≥2 (OR=2.08, 95%CI: 1.03-4.22), virus infection in the first 3 months of pregnancy (OR=4.30, 95%CI: 1.27-13.45). The risk factors for left ventricular outflow tract obstruction CHD included father as factory worker (OR=6.01, 95%CI:1.05-34.59). The risk factors for transposition of the great arteries included low birth weight (OR=12.93, 95%CI:1.14-146.26), maternal low education, mother as factory worker (OR=3.69, 95%CI:1.53-8.91). The risk factors for conditions with intra cardiac mixing of oxygenated and deoxygenated blood included parity=2 (OR=3.45, 95%CI: 1.42-8.38). The risk factors for other CHD included over birth weight (OR=4.87, 95%CI: 1.19-19.94), maternal abnormal reproduction history (OR=2.96, 95%CI: 1.14-7.68), virus infection (OR=4.92, 95%CI: 1.56-15.47), medicine usage (OR=4.90, 95%CI: 1.22-19.77) or passive smoking (OR=10.31, 95%CI: 1.25-85.05) in the first 3 months of pregnancy. CONCLUSION: The environmental risk factors were discrepant among different categories of CHD. Further risk factors study of CHD phenotypes should be performed specially. To prevent CHD, attention should be paid to the risk factors which are related to multi or complex categories of CHD.

Characterization of a Synthetic Steroid 24-keto-cholest-5-en-3ß, 19-diol as a Neuroprotectant.

BACKGROUND: Neuroactive steroids represent promising candidates for the treatment of neurological disorders. Our previous studies identified an endogenous steroid cholestane-3ß, 5α, 6ß-triol (Triol) as a novel neuroprotectant. AIM: We aimed to identify a potent candidate for stroke treatment through a screening of Triol analogs. METHODS: Hypoxia- and glutamate-induced neuronal injury models in vitro, middle cerebral artery occlusion (MCAO)-induced cerebral ischemia model in vivo, fluorescein diacetate (FDA) for alive and propidium iodide (PI) for dead staining, LDH assay, and calcium imaging techniques were used. RESULTS: 24-keto-cholest-5-en-3ß, 19-diol (Diol) showed the most potent neuroprotective effect among the screened structurally related compounds. FDA and PI staining showed that Diol concentration dependently increased the survival rate of cerebellar granule neurons (CGNs) challenged with glutamate or hypoxia, with an effective threshold concentration of 2.5 µM. Consistently, the quantitative LDH release assay showed the same concentration-dependent protection in both models. Diol, at 10 µM, potently decreased glutamate- and hypoxia-induced LDH release from 51.6 to 18.2% and 62.1 to 21.7%, respectively, which values are close to the normal LDH release (~16-18%). Moreover, we found Diol effectively decreased MCAO-induced infarction volume in mice from ~23% to 7%, at a dose of 6 mg/kg. We further explored the underlying mechanism and found that Diol attenuated NMDA-induced intracellular calcium ([Ca(2+) ]i ) increase in cortical neurons, suggesting a negative modulatory effect on NMDA receptor. CONCLUSION: Taken together, we identified Diol as a potent neuroprotectant. It may represent a novel and promising neuroprotectant for stroke intervention.

[Study on the differences of risk factors regarding congenital heart defects between floating population and permanent residents in Guangdong].

OBJECTIVE: To analyze the differences of risk factors on congenital heart defect (CHD)between floating population and permanent residents in Guangdong. METHODS: A multicenter case-control study was carried out to investigate the risk factors of CHD in floating population and in permanent residents. Data was from 34 Guangdong CHD Monitoring Network centers during the year of 2004 to 2011. Exposed information related to the parents at pre-pregnancy and early pregnancy periods, was collected, using the same questionnaire survey methodology in the two populations. Possible risk factors were analyzed by univariate analysis and multivariate non-conditional logistic regression(ENTER method)methods. Risk factors were compared between the two populations. RESULTS: Totally, 855 CHD cases and their controls from the floating population, as well as 1673 cases and their controls from the permanent residents were included in this study. Age of the children under study was defined from 28th week of gestation to 1 year old postnatal. In the floating population, specific risk factor for CHD appeared as:maternal passive smoking in early pregnancy, while the specific protective factor as high family income. However, the specific risk factors would include: having diseases as maternal diabetes mellitus or syphilis, living in a newly (within half a year) decorated house or with fetal macrosomia in the permanent residents. High education level showed as a risk factor in floating population, however contrarily, as protective factor to the permanent residents. Except for the factors related to having fever of the mother and infant with low birth weight, factors as having history of deliveries more than two, with maternal virus infection, exposure to chemical agent and negative bearing history etc., have higher OR values in floating population than in the permanent residents. CONCLUSION: Significant differences of risk factors for CHD were noticed between floating population and the permanent residents, which have their individual specific risk factors. Most of the ORs appeared higher in floating population than in the permanent residents.

[Risk factors of congenital heart defects in fetal and infants born from 2004 to 2011 in Guangdong].

OBJECTIVE: To analyze the risk factors of congenital heart defects (CHD) in fetal and infants born from 2004 to 2011 in Guangdong province. METHODS: Babies with CHD aged from 28th week of gestation to 1 year old postnatal from July 1 2004 to December 31 2011 were registered in Guangdong CHD monitoring network with 34 participating units. Totally 2568 CHD cases were included, and 1: 1 matched with a normal control cohort by gender, living district and birth date (time span within 3 months).Exposed information of mother and father at pre-pregnancy and early pregnancy was collected. Post collinearity diagnostics analysis, univariate analysis results were included in a multivariate analysis model with forward stepwise conditional logistic regression. RESULTS: Multivariate conditional logistic regression analysis showed that high risk factors for CHD included low birth weight infant (OR = 5.34, P < 0.01), macrosomia (OR = 1.67, P < 0.05), low per capita income (0-1200 yuan, OR = 1.68, P < 0.01), exposure to chemical agent at early pregnancy (OR = 19.72, P < 0.01), floating population (OR = 2.13, P < 0.01), abnormal reproductive history (OR = 3.18, P < 0.01), exposure to passive smoking (OR = 2.59, P < 0.01), suffering from fever (OR = 3.74, P < 0.01), equal to or more than twice parity (OR = 1.45, P < 0.01), living in a newly (within six months)-decorated-apartment (OR = 2.74, P < 0.01), suffering from virus infection (OR = 2.08, P < 0.01), rural residence (OR = 1.33, P < 0.01), living in an apartment within 50 meters of major traffic road (OR = 1.52, P < 0.01), syphilis infection at early pregnancy (OR = 13.06, P < 0.05) and father's drinking habit at pre-pregnancy (OR = 1.57, P < 0.05). CONCLUSION: Numerous risk factors for CHD in fetal and infants of Guangdong province are indicated by our results, comprehensive intervention should be considered in pre-pregnancy and early pregnancy to reduce the risk of CHD.

[Current prevalence rate of congenital heart disease in 12 month-old and younger infants among four regions of Guangdong province].

OBJECTIVE: To summarize prevalence rate and region distribution of congenital heart disease (CHD) in 12-month-old and younger infants among four regions of Guangdong province, China. METHODS: Data from Guangdong CHD monitoring network including 34 monitoring units covering different geographic regions were analyzed. Professional training on screening and diagnosing CHD was provided to each work group member to improve the diagnosis level. CHD infants under or aged 12 months detected in the monitoring unit were included. CHD was diagnosed by fetus and infants echocardiography. RESULTS: From July 2004 to December 2010, 383 281 perinatal were registered and 3263 cases of CHD were detected in the 34 member units of Guangdong CHD monitoring network [total prevalence rate of CHD: 0.851% (3263/383 281), male prevalence rate: 0.868% (1799/207 347), female prevalence rate:0.828% (1456/175 843)].Stillbirth CHD prevalence rate was significantly higher than livebirth CHD prevalence rate [10.627% (676/6361) vs. 0.686% (2587/376 920), P < 0.01]. The total prevalence of CHD was significantly higher in Pearl River Delta region [0.906% (2826/311 823)] than in other regions [0.611% (437/71 458), P < 0.01]. Ventricular septal defect [39.93% (1033/2587) in livebirth] was the most dominant CHD, followed by patent ductus arteriosus [29.84% (772/2587)] and secundum atrial septal defect [13.76% (356/2587)]. CONCLUSIONS: The present data indicate that the prevalence of CHD in Guangdong is at the medium-upper level of the country associated with high stillbirth rate. The dominant type of CHD is ventricular septal defect. CHD prevalence is higher in the Pearl River Delta region than in other regions.

Aspirin inhibits proliferation of gemcitabine-resistant human pancreatic cancer cells and augments gemcitabine-induced cytotoxicity.

AIM: To investigate whether aspirin is able to augment gemcitabine-induced cytotoxicity in human pancreatic cancer cells. METHODS: Two gemcitabine-insensitive human pancreatic cancer cell lines, PANC-1 and Capan-1, were used. Cells were treated with either aspirin or gemcitabine alone or both of them. Cell growth and apoptosis were determined by MTT assay, Annexin V or Hoechest 33258 staining. Cell cycle distribution was examined by flow cytometry. Western blot with specific phosphorylated protein antibodies was used to detect the activation of protein kinase. RT-PCR and Western blot were applied to assess the transcription and protein level for cyclin D1 and Bcl-2. RESULTS: Aspirin alone significantly inhibits the proliferation of PANC-1 cells by causing cell cycle arrest at G(1) phase. Aspirin potentiates the anti-survival effect of gemcitabine as well as its pro-apoptotic effect in PANC-1 cells, although aspirin per se does not trigger apoptosis. Aspirin inhibits GSK-3beta activation and suppresses the expression of its downstream gene products (cyclin D1 and Bcl-2), which are implicated in proliferation, survival and chemoresistance of pancreatic cancer. The effects of aspirin on Capan-1, were similar to that on PANC-1. CONCLUSION: Our results suggest that aspirin inhibits the proliferation of gemcitabine-resistant pancreatic cancer cells and augments the antisurvival effect of gemcitabine, probably by suppressing the activity of GSK-3beta and its downstream gene products.