Overall and individual associations between per- and polyfluoroalkyl substances and liver function indices and the metabolic mechanism.

Per- and polyfluoroalkyl substances (PFAS) can disrupt liver homeostasis. Studies have shown that a single exposure to PFAS may provoke abnormal liver function; however, few studies have investigated the overall effect of PFAS mixtures. We aimed to investigate associations between exposure to PFAS mixtures and liver function indices and explore the relevant mechanisms. This study included 278 adult males from Guangzhou, China. Serum metabolite profiles were analyzed using untargeted metabolomics. We applied weighted quantile sum (WQS) regression as well as Bayesian kernel machine regression (BKMR) to analyze the association of nine PFAS mixtures with 14 liver function indices. PFAS mixtures were positively associated with apolipoprotein B (APOB) and gamma-glutamyltransferase (GGT) and negatively associated with direct bilirubin (DBIL) and total bilirubin (TBIL) in both the WQS and BKMR analyses. In addition, Spearman's correlation test showed individual PFAS correlated with APOB, GGT, TBIL, and DBIL, while there's little correlation between individual PFAS and other liver function indices. In linear regression analysis, PFHxS, PFOS, PFHpS, PFNA, PFDA, and PFUdA were associated with APOB; PFOA, PFDA, PFOS, PFNA, and PFUdA were associated with GGT. Subsequently, a metabolome-wide association study and mediation analysis were combined to explore metabolites that mediate these associations. The mechanisms linking PFAS to APOB and GGT are mainly related with amino acid and glycerophospholipid metabolism. High-dimensional mediation analysis showed that glycerophospholipids are the main markers of the association between PFAS and APOB, and that (R)-dihydromaleimide, Ile Leu, (R)-(+)-2-pyrrolidone-5-carboxylic acid, and L-glutamate are the main markers of the association between PFAS and GGT. In summary, overall associations between PFAS and specific indices of liver function were found using two statistical methods; the metabolic pathways and markers identified here may serve to prompt more detailed study in animal-based systems, as well as a similar detailed analysis in other populations.

Metabolome-wide association study of four groups of persistent organic pollutants and abnormal blood lipids.

Environmental exposure increases the risk of dyslipidemia, which affects human health. Research has shown that persistent organic pollutants (POPs), including per- and polyfluoroalkyl substances (PFASs), polychlorinated biphenyls, polybrominated diphenyl ethers, and phthalate metabolites, are associated with a higher risk of abnormal blood lipid levels in humans. However, the key molecules involved in dyslipidemia and the mechanisms are not fully understood. This study aims to investigate the biomarkers that mediate the relationships between blood lipids and four groups of POPs and revealed their potential mechanisms. Specifically, in 278 male blood samples, blood lipid and POPs levels were measured and metabolites were detected using untargeted metabolomics. Spearman's correlation analysis and binary logistic regression were employed to assess the relationship between POPs and lipid indexes. We observed that PFASs were associated with a higher risk of abnormal total cholesterol (TC) and low-density lipoprotein (LDL), while other POPs displayed little association with abnormal lipid indexes. Among all the PFASs, 6:2Cl-PFESA was associated with the fewest metabolites. A metabolome-wide association study combined with a meet-in-the-middle approach was used to identify potential biomarkers that mediate the association between POPs and abnormal blood lipids. The mediation analysis pointed to 105 significant mediators as potential biomarkers mediating the association between PFASs and TC, and 82 significant mediators were potential biomarkers that mediated the association between PFASs and LDL. 24-Hydroxycholesterol, 3alpha,7alpha-dihydroxy-5beta-cholestan-26-al, PC(18:0/0:0), PC(22:5/0:0), GPCho(18:1/18:1), LysoPC(22:2(13Z,16Z)), LysoPC(16:0), 9(S)-HODE, 9,10-DHOME, l-glutamate, 4-hydroxybutyric acid, cytosine, PC(14:1(9Z)/18:0), sphinganine, and (S)-beta-aminoisobutyrate were identified as important biomarkers. The mechanism may mainly involves glycerophospholipid metabolism, primary bile acid biosynthesis, and linoleic acid metabolism. PPARγ likely plays a role in the associations between PFASs and abnormal cholesterol metabolism. Overall, our study provides clues for the early detection of PFAS-induced dyslipidemia and brings forth a theoretical framework for further research into this mechanism.

Implantation underneath the abdominal anterior rectus sheath enables effective and functional engraftment of stem-cell-derived islets.

Human pluripotent stem cell-derived islets (hPSC islets) are a promising alternative to primary human islets for the treatment of insulin-deficient diabetes. We previously demonstrated the feasibility of this approach in nonhuman primates; however, the therapeutic effects of hPSC islets can be limited by the maladaptive processes at the transplantation site. Here, we demonstrate successful implantation of hPSC-derived islets in a new transplantation site in the abdomen, the subanterior rectus sheath, in eight nonhuman primates (five male and three female). In this proof-of-principle study, we find that hPSC islets survive and gradually mature after transplantation, leading to improved glycemic control in diabetic primates. Notably, C-peptide secretion responds to meal challenge from 6 weeks post-transplantation (wpt), with stimulation indices comparable to those of native islets. The average post-prandial C-peptide level reaches approximately 2.0 ng ml-1 from 8 wpt, which is five times higher than the peak value we previously obtained after portal vein infusion of hPSC islets and was associated with a decrease of glycated hemoglobin levels by 44% at 12 wpt. Although additional studies in larger cohorts involving long-term follow-up of transplants are needed, our results indicate that the subanterior rectus sheath supports functional maturation and maintenance of hPSC islets, suggesting that it warrants further exploration as a transplantation target site in the context of for hPSC-based cell-replacement therapies.

Joint effects of per- and polyfluoroalkyl substance alternatives and heavy metals on renal health: A community-based population study in China.

BACKGROUND: Previous studies have indicated that chlorinated polyfluorinated ether sulfonic acids (Cl-PFESAs), when used as an alternative to per- and polyfluoroalkyl substances (PFASs), result in kidney toxicity. However, their co-exposure with heavy metals, has not yet been described. OBJECTIVES: To explore the joint effects of Cl-PFESAs and heavy metal exposure on renal health in Chinese adults, and identify specific pollutants driving the associations. METHODS: Our sample consists of 1312 adults from a cross-sectional survey of general communities in Guangzhou, China. We measured Cl-PFESAs, legacy PFASs (perfluorooctanoic acid [PFOA] and perfluorooctane sulfonated [PFOS]), and heavy metals (arsenic, cadmium, and lead). The relationship between single pollutant and glomerular filtration rate (eGFR) and the odds ratio (OR) of chronic kidney disease (CKD) was studied using Generalized additive models (GAMs). Bayesian Kernel Machine Regression (BKMR) models were applied to assess joint effects of Cl-PFESAs and heavy metals. Additionally, we conducted a sex-specific analysis to determine the modification effect of this variable. RESULTS: In single pollutant models, CI-PFESAs, PFOA, PFOS and arsenic were negatively associated with eGFR. Additionally, PFOA and heavy metals were positively correlated with the OR of CKD. For example, the estimated change with 95% confidence intervals (CI) of eGFR at from the highest quantile of 6:2 Cl-PFESA versus the lowest quantile was -5.65 ng/mL (95% CI: -8.21, -3.10). Sex played a role in modifying the association between 8:2 Cl-PFESA, PFOS and eGFR. In BKMR models, pollutant mixtures had a negative joint association with eGFR and a positive joint effect on CKD, especially in women. Arsenic appeared to be the primary contributing pollutant. CONCLUSION: We provide epidemiological evidence that Cl-PFESAs independently and jointly with heavy metals impaired kidney health. More population-based human and animal studies are needed to confirm our results.

Associations of per- and polyfluoroalkyl substances and their alternatives with bone mineral density levels and osteoporosis prevalence: A community-based population study in Guangzhou, Southern China.

BACKGROUND: Evidence concerning associations of per- and polyfluoroalkyl substances (PFASs) exposure with bone mineral density (BMD) and osteoporosis is scarce. Additionally, no study has examined the effects of PFAS isomers and alternatives on bone health. OBJECTIVES: To evaluate the associations of PFASs and PFAS alternatives with BMD levels and osteoporosis prevalence. METHODS: A total of 1260 healthy adults from southern China were enrolled. Serum concentrations of 32 legacy PFASs, PFAS isomers, and alternatives were measured using modified liquid chromatography-tandem mass spectrometry. Logistic and linear regression models were applied to evaluate the associations of PFASs with osteoporosis prevalence and BMD levels, respectively, adjusting for confounding factors. We performed stratified analyses to assess potential effect modifications of age and sex. We further used sensitivity analyses to testify the robustness of the main findings. RESULTS: There were 204 (16.2 %) participants diagnosed with osteoporosis. Eleven of the studied PFASs (i.e., PFHpA, PFOA, PFBS, PFHpS, total-PFHxS, n-PFHxS, br-PFHxS, br-PFOS, 1m-PFOS, Σ3 + 4 + 5m-PFOS, and 6:2 Cl-PFESA) showed significant and inverse associations with BMD levels (mean differences ranged from -6.47 to -26.07 per one ln-unit increase in the PFASs). Additionally, we observed that each one ln-unit increase in PFHpA was significantly associated a 23 % (OR = 1.23, 95 % CI = 1.04, 1.45) greater odds of osteoporosis. The above associations were consistent in several sensitivity analyses we performed. Stratified analyses showed stronger associations among women and younger compared to their counterparts. CONCLUSIONS: Our findings suggested that greater PFAS exposure is associated with poorer bone health, especially in women and younger people.

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.

Beyond the mean: Quantile regression to differentiate the distributional effects of ambient PM2.5 constituents on sperm quality among men.

Ambient PM2.5 (particulate matter ≤ 2.5 µm in aerodynamic diameter) constituents have been related to mean changes in semen quality, but focusing on the mean response may not well capture distributional and heterogeneous effects of PM2.5 constituents on semen quality. In this study, 2314 semen samples of 622 men between Jan 1, 2019 and Dec 31, 2019 from Guangdong Human Sperm Bank were subjected to semen quality analysis. Daily average concentrations of PM2.5 constituents including 4 water-soluble ions and 15 metals/metalloid were measured for 7 days per month at 3 fixed atmospheric pollutant monitoring stations. We used quantile regression for longitudinal data to examine whether the associations between PM2.5 constituents and quality indicators of semen varied across quantiles of outcome distribution. Heterogeneous associations were found between PM2.5 constituents and sperm quality across different quantiles. An interquartile range (14.0 µg/m3) increase in PM2.5 mass was negatively associated with lower tails of sperm concentration and upper tails of sperm count distribution. PM2.5 vanadium exposure was significantly related to the 90th percentile of sperm count distribution, but not to the lower quantiles. In addition, those subjects with relatively high sperm motility were more susceptible to sulfate, chromium, and manganese constituents in PM2.5. Our results indicate that PM2.5 and certain constituents were associated with sperm quality, especially sperm motility, and the associations are more pronounced in men with relatively high or low sperm motility.

Characteristics of and variation in airborne ARGs among urban hospitals and adjacent urban and suburban communities: A metagenomic approach.

Environmental antibiotic resistance genes (ARGs) have received much attention, while the characteristics of ARGs carried by particulate matter (PM) as a function of urban functional region are almost unknown. In this study, ARGs carried by PM2.5 and PM10 in an urban hospital, a nearby urban community and the nearest suburban community were detected using metagenomics. In total, 643 ARG subtypes belonging to 22 different ARG types were identified. The chloramphenicol exporter gene, sul1, bacA, and lnuA were the most abundant ARG subtypes in all air samples. The hospital exhibited higher ARG abundance and richness than the nearby communities. ARG profiles depended on functional region: hospital and suburban samples clustered separately, and samples from the nearby urban community interspersed among them. The representation of multidrug and quinolone resistance genes decayed with distance from the hospital to the urban community to the suburban community, indicating that hospital PM may be a hotspot for ARGs encoding proteins conferring multidrug and quinolone resistance. Airborne ARGs carried by PM in the hospital environment were more closely associated with clinically important pathogens than were those in nearby communities. In particular, carbapenemase genes, including blaNDM,blaKPC,blaIMP,blaVIM,and blaOXA-48, were discovered in hospital PM. In the suburban community, crAssphage, a human host-specific bacteriophage, was applied to predict ARG abundance and found to be enriched due to anthropogenic pollution but showed no clear evidence for ARG selection. In the hospital and the nearby urban community, the drivers of ARGs were complex. Our results highlighted that PM ARGs were closely related to human activities and revealed a potential hotspot, which could provide new evidence for further research and consequently mitigate the formation of airborne ARGs and transfer risks.

Interactions between ambient air pollutants and temperature on emergency department visits: Analysis of varying-coefficient model in Guangzhou, China.

BACKGROUND: At present, there are few studies on the effect of short-term interactions between ambient air pollutants and temperature on cause-specific emergency department visits in China. This study aimed to explore their short-term interactions on cause-specific emergency department visits using data collected from a total of 65 public hospitals in Guangzhou city, south China. MATERIAL AND METHODS: We included a total of 226,443 emergency department visits which were diagnosed as neurological, respiratory and circulatory disease in Guangzhou from January 1, 2014 to December 31, 2017. Average daily concentrations of air pollutants including carbon monoxide (CO), particulate matter having a median diameter of 2.5 µm or less (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2) and ozone (O3) were collected from the Guangzhou Environmental Protection Bureau. We employed quasi-Poisson varying coefficient regression models to assess the interaction effects between air pollutants and daily temperature levels (DTLs) on emergency department visits for neurological, respiratory and circulatory diseases, respectively. RESULTS: Average number of emergency department visits for neurological, respiratory and circulatory diseases were 92, 26 and 38, respectively. After controlling for other pollutants, meteorological factors and other time-varying confounders, we found the interactions between NO2 and the 1st DTL (3.4-17.1 °C), NO2 and the 2nd DTL (17.1-23.5 °C) for neurological emergency department visits were statistically significant, displaying a nonlinear relationship. Additionally, we found that the interactions between SO2 and the 4th DTL (27.4-31.1 °C) also had a significantly adverse effect on respiratory emergency department visits. CONCLUSIONS: Our findings provide novel evidence on SO2-by-temperature interactions, and NO2-by-temperature interactions for emergency department visits of cause-specific diseases.

Short-term associations of ambient air pollution and cause-specific emergency department visits in Guangzhou, China.

BACKGROUND: Evidence of association of ambient air pollution with cause-specific emergency department visits in China is still limited. This study aimed to investigate short-term associations between exposures to air pollutants and daily cause-specific emergency department visits using a large-scale multicenter database involving a total of 65 sentinel hospitals in Guangzhou, the most densely-populated city in south China, during 2013-2015. MATERIAL AND METHODS: We obtained data on 162,771 emergency department visits from 65 hospitals from the Emergency Medical Command Center in Guangzhou between January 1, 2013 and December 31, 2015. Daily air pollution data on particulate matter (PM) of aerodynamic diameter<10 and 2.5µm (PM10, and PM2.5, respectively), sulfur dioxide (SO2), nitrogen dioxide (NO2) and ozone (O3) were collected from the Daily Quality Report of the Guangzhou Environmental Protection Bureau during the study period. Visits for neurologic, respiratory and circulatory diseases were assessed in relation to air pollutants using Poisson generalized additive models. RESULTS: Mean daily number of emergency department visits for neurologic, respiratory and circulatory diseases was 89, 24 and 35, respectively. After adjustment for other pollutants (PM2.5, PM10, NO2 and O3), meteorological factors and time-varying confounders, a 7.98-µg/m3 (interquartile range) increment in 2-day moving average of same-day and previous-day SO2 concentrations was associated with the statistically significant increase of 4.89% (95% confidence interval: 2.86, 6.95) in neurologic emergency department visits; elevation in SO2 level (per 7.98µg/m3) was linked to a 5.19% (95% confidence interval: 2.03, 8.44) increase in circulatory emergency department visits. Most positive links were seen during the cold season. CONCLUSIONS: The results of this study contribute to the evidence of the significant associations between SO2 and specific neurologic and circulatory conditions, and also provide insight into the planning of clinical services and emergency contingency response for air pollution exposures in Guangzhou.

Seasonal influenza vaccine effectiveness among children, 2010-2012.

BACKGROUND: The annual differences in the seasonal influenza vaccine and the circulating strains make it necessary to assess influenza vaccine effectiveness (VE) yearly. We assessed the effectiveness of the trivalent inactivated influenza vaccine for the 2010-2011 and 2011-2012 influenza seasons among children in Guangzhou, China. METHODS: We conducted a 1:2 matched case-control study based on date of birth (±7 days), gender, and area of residence. The influenza cases from surveillance sites in Guangzhou were laboratory-confirmed during the 2010-2012 seasons. The controls were randomly selected from children aged 6-59 months in the Children's Expanded Programmed Immunization Administrative Computerized System. The influenza vaccination information for both cases and controls was retrieved from this system. RESULTS: We analyzed the vaccination information for 1255 influenza cases and 2510 matched controls in 2 influenza seasons in Guangzhou, China. We found that the VE for vaccination during the 2010-2011 and 2011-2012 seasons of virus circulation was 73·2% (95% confidence interval (CI), 52·2-85·0%) and 52·9% (95% CI, 42·1-61·7%), respectively. The VE decreased from 68·9% (95% CI, 57·5-77·2%) in the period between January and March to 48·4% (95% CI, 33·8-59·7%) in the period between April and June. CONCLUSIONS: This post-licensing study of VE found moderate protection against influenza for vaccinated children aged 6-59 months. Although the influenza vaccine strains for the 2010-2011 and the 2011-2012 seasons were the same, our study indicated that annual vaccination is recommended even for those who received the vaccine during the previous season.

Effectiveness of seasonal influenza vaccine against clinically diagnosed influenza over 2 consecutive seasons in children in Guangzhou, China: a matched case-control study.

Influenza vaccine has to be reformulated each year due to the ever-changing antigenicity of the influenza virus. However, few post-licensure studies of influenza vaccine are available in China. We aimed to measure the effectiveness of seasonal influenza vaccine during 2 consecutive seasons. Among children in Guangzhou aged 6 to 59 mo in 2010-2012, we matched each child with clinically diagnosed influenza to 3 healthy children. Cases with clinically diagnosed influenza were identified from surveillance system. Healthy controls were randomly sampled from the Children's Expanded Programmed Immunization Administrative Computerized System. Conditional logistic regression was used to calculate vaccine effectiveness (VE). A total of 275 matched sets of subjects were included. VE levels against clinically diagnosed influenza for both seasons combined was 47.4% [95% confidence interval (CI), 8.5-69.8%] for full vaccination for children aged 6-35 mo, 33.6% (95% CI, 5.4-53.5%) for any vaccination for children aged 6-59 mo, respectively. VE by time since vaccination for any vaccination was 34.6% (95% CI, 4.7-55.2%) in 0-5 mo, and no protection was observed in 6-11 mo. Annual, full and timely vaccination should be encouraged for children.