Caspase-8 promotes NLRP3 inflammasome activation mediates eye development defects in zebrafish larvae exposed to perfulorooctane sulfonate (PFOS).

Epidemiological evidence showed that serum high perfluorooctane sulfonate (PFOS) levels are associated with multiple eye related diseases, but the potential underlying molecular mechanisms remain poorly understood. Zebrafish and photoreceptor cell (661w) models were used to investigate the molecular mechanism of PFOS induced eye development defects. Our results showed a novel molecular mechanism of PFOS-induced inflammation response-mediated photoreceptor cell death associated with eye development defects. Inhibition of Caspase-8 activation significantly decreased photoreceptor cell death in PFOS exposure. Mechanistically, Toll-like receptor 4 (TLR4) mediates activation of Caspase-8 promote activation of NLR family pyrin domain-containing 3 (NLRP3) inflammasome to elicit maturation of interleukin-1 beta (IL-1ß) via Caspase-1 activation, facilitating photoreceptor cell inflammation damage in PFOS exposure. In addition, we also made a novel finding that Caspase-3 activation was increased via Caspase-8 activation and directly intensified cell death. Our results show the important role of Caspase-8 activation in PFOS induced eye development defects and highlight Caspase-8 mediated activation of the NLRP3 inflammation triggers activation of Caspase-1 and promote the maturation of IL-1ß in retinal inflammatory injury.

Relationship of single and co-exposure of per-and polyfluoroalkyl substances and their alternatives with uric acid: A community-based study in China.

Numerous studies have suggested per-and polyfluoroalkyl substances (PFASs) are related to uric acid levels, but evidence related to PFAS alternatives is limited. Moreover, the effect of the combined exposure to PFASs and their alternatives on uric acid has not been reported. Hence, we conducted a cross-sectional study involving 1312 adults in Guangzhou, China. Generalized linear regression model was adopted to explore the effect of single PFAS exposure on serum uric acid levels. Further, multi-pollutant models such as Bayesian kernel machine regression, weighted quantile sum, and quantile G-computation were employed to investigate the combined association of PFASs and alternatives with serum uric acid levels. We performed molecular docking to understand the potential interaction of PFAS with Organic Anion Transporters (OATs), involved in the secretion of uric acid. Per log serum 6:2 Cl-PFESA and PFOA increases were accompanied with an increase of serum uric acid with statistical significance (for 6:2 Cl-PFESA: beta: 0.19 ng/mL, 95% CI 0.11-0.26 and for PFOA: beta: 0.43 ng/mL, 95% CI 0.34-0.52). The associations were strongest among overweight and elderly. Multi-pollutant models also revealed a positive association. These positive associations may be PFASs can competitively combine with OAT1 and OAT3, leading to the increase of serum uric acid.

Influence of Air Pollution Exposures on Cardiometabolic Risk Factors: a Review.

PURPOSE OF REVIEW: The increasing prevalence of cardiometabolic risk factors (CRFs) contributes to the rise in cardiovascular disease. Previous research has established a connection between air pollution and both the development and severity of CRFs. Given the ongoing impact of air pollution on human health, this review aims to summarize the latest research findings and provide an overview of the relationship between different types of air pollutants and CRFs. RECENT FINDINGS: CRFs include health conditions like diabetes, obesity, hypertension etc. Air pollution poses significant health risks and encompasses a wide range of pollutant types, air pollutants, such as particulate matter (PM), nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone (O2). More and more population epidemiological studies have shown a positive correlation between air pollution and CRFs. Although various pollutants have diverse effects on specific cellular molecular pathways, their main influence is on oxidative stress, inflammation response, and impairment of endothelial function. More and more studies have proved that air pollution can promote the occurrence and development of cardiovascular and metabolic risk factors, and the research on the relationship between air pollution and CRFs has grown intensively. An increasing number of studies are using new biological monitoring indicators to assess the occurrence and development of CRFs resulting from exposure to air pollution. Abnormalities in some important biomarkers in the population (such as homocysteine, uric acid, and C-reactive protein) caused by air pollution deserve more attention. Further research is warranted to more fully understand the link between air pollution and novel CRF biomarkers and to investigate potential prevention and interventions that leverage the mechanistic link between air pollution and CRFs.

Early life exposure to F-53B induces neurobehavioral changes in developing children and disturbs dopamine-dependent synaptic signaling in weaning mice.

BACKGROUND: Previous studies have shown that F-53B exposure may be neurotoxic to animals, but there is a lack of epidemiological evidence, and its mechanism needs further investigation. METHODS: Serum F-53B concentrations and Wisconsin Card Sorting Test (WCST) were evaluated in 314 growing children from Guangzhou, China, and the association between them were analyzed. To study the developmental neurotoxicity of F-53B, experiments on sucking mice exposed via placental transfer and breast milk was performed. Maternal mice were orally exposed to 4, 40, and 400 µg/L of F-53B from postnatal day 0 (GD0) to postnatal day 21 (PND 21). Several genes and proteins related to neurodevelopment, dopamine anabolism, and synaptic plasticity were examined by qPCR and western blot, respectively, while dopamine contents were detected by ELISA kit in weaning mice. RESULTS: The result showed that F-53B was positively associated with poor WCST performance. For example, with an interquartile range increase in F-53B, the change with 95 % confidence interval (CI) of correct response (CR), and non-perseverative errors (NPE) was -2.47 (95 % CI: -3.89, -1.05, P = 0.001), 2.78 (95 % CI: 0.79, 4.76, P = 0.007), respectively. Compared with the control group, the highest exposure group of weaning mice had a longer escape latency (35.24 s vs. 51.18 s, P = 0.034) and a lesser distance movement (34.81 % vs. 21.02 %, P < 0.001) in the target quadrant, as observed from morris water maze (MWM) test. The protein expression of brain-derived neurotrophic factor (BDNF) and growth associated protein-43 (GAP-43) levels were decreased, as compared to control (0.367-fold, P < 0.001; 0.366-fold, P < 0.001; respectively). We also observed the upregulation of dopamine transporter (DAT) (2.940-fold, P < 0.001) consistent with the trend of dopamine content (1.313-fold, P < 0.001) in the hippocampus. CONCLUSION: Early life exposure to F-53B is associated with adverse neurobehavioral changes in developing children and weaning mice which may be modulated by dopamine-dependent synaptic plasticity.

Toward esthetically and biomechanically reliable anterior resin composite restorations: Current clinical experiences among dental practitioners in Saudi Arabia.

Background: Esthetic anterior composite restorations are very challenging. They constitute a main part of the clinical practice of restoring teeth with resin composites. Distinctive variations in composite material selection and technique of application in anterior teeth exist when compared to the practice of restoring posterior teeth with resin composites. In a continuation of a previous assessment of class II resin composite practice,  a cross-sectional survey study was performed to determine the awareness of general dental practitioners in Saudi Arabia about resin composite restorations in anterior teeth and to provide evidence-based recommendations to improve their practice. Methods: A total of 500 dental practitioners from different provinces in Saudi Arabia were invited to participate in an online questionnaire which comprised four domains and included a total of sixteen questions addressing aspects regarding the selection of resin composites, cavity configuration, etching protocol, light-curing technique, liner application, application of poly-chromatic composite, as well as finishing and polishing procedures. Chi square testing and descriptive statistics were used to analyze the attained data. Results: From 250 respondents, the greatest participation was from the Eastern and Middle provinces of Saudi Arabia. Female dentists participated less than males. There was no general agreement between participants regarding the resin composite material or the employed technique of application in restoring anterior tooth defects. Respondents indicated that discoloration and hypersensitivity were the most common reasons for patient's dissatisfaction with resin composites in anterior teeth. Conclusions: Dental practitioners are highly encouraged to improve their clinical practice of restoring anterior teeth using resin composites with the focus upon continuous education programs, online webinars, and workshops.

Per- and polyfluoroalkyl substances in ambient fine particulate matter in the Pearl River Delta, China: Levels, distribution and health implications.

Per- and polyfluoroalkyl substances (PFAS) have attracted worldwide attention as one of persistent organic pollutants; however, there is limited knowledge about the exposure concentrations of PFAS-contained ambient particulate matter and the related health risks. This study investigated the abundance and distribution of 32 PFAS in fine particulate matter (PM2.5) collected from 93 primary or secondary schools across the Pearl River Delta region (PRD), China. These chemicals comprise four PFAS categories which includes perfluoroalkyl carboxylic acids (PFCAs), perfluoroalkyl sulfonic acids (PFSAs), perfluoroalkyl acid (PFAA) precursors and PFAS alternatives. In general, concentrations of target PFAS ranged from 11.52 to 419.72 pg/m3 (median: 57.29 pg/m3) across sites. By categories, concentrations of PFSAs (median: 26.05 pg/m3) were the dominant PFAS categories, followed by PFCAs (14.25 pg/m3), PFAS alternatives (2.75 pg/m3) and PFAA precursors (1.10 pg/m3). By individual PFAS, PFOS and PFOA were the dominant PFAS, which average concentration were 24.18 pg/m3 and 6.05 pg/m3, respectively. Seasonal variation showed that the concentrations of PFCAs and PFSAs were higher in winter than in summer, whereas opposite seasonal trends were observed in PFAA precursors and PFAS alternatives. Estimated daily intake (EDI) and hazard quotient (HQ) were used to assess human inhalation-based exposure risks to PFAS. Although the health risks of PFAS via inhalation were insignificant (HQ far less than one), sufficient attention should be levied to ascertain the human exposure risks through inhalation, given that exposure to PFAS through air inhalation is a long term and cumulative process.

An integrative analysis of lipidomics and transcriptomics in various mouse brain regions in response to real-ambient PM2.5 exposure.

Exposure to Fine particulate matter (PM2.5) has been associated with various neurological disorders. However, the underlying mechanisms of PM2.5-induced adverse effects on the brain are still not fully defined. Multi-omics analyses could offer novel insights into the mechanisms of PM2.5-induced brain dysfunction. In this study, a real-ambient PM2.5 exposure system was applied to male C57BL/6 mice for 16 weeks, and lipidomics and transcriptomics analysis were performed in four brain regions. The findings revealed that PM2.5 exposure led to 548, 283, 304, and 174 differentially expressed genes (DEGs), as well as 184, 89, 228, and 49 distinctive lipids in the hippocampus, striatum, cerebellum, and olfactory bulb, respectively. Additionally, in most brain regions, PM2.5-induced DEGs were mainly involved in neuroactive ligand-receptor interaction, cytokine-cytokine receptor interaction, and calcium signaling pathway, while PM2.5-altered lipidomic profile were primarily enriched in retrograde endocannabinoid signaling and biosynthesis of unsaturated fatty acids. Importantly, mRNA-lipid correlation networks revealed that PM2.5-altered lipids and DEGs were obviously enriched in pathways involving in bile acid biosynthesis, De novo fatty acid biosynthesis, and saturated fatty acids beta-oxidation in brain regions. Furthermore, multi-omics analyses revealed that the hippocampus was the most sensitive part to PM2.5 exposure. Specifically, dysregulation of Pla2g1b, Pla2g, Alox12, Alox15, and Gpx4 induced by PM2.5 were closely correlated to the disruption of alpha-linolenic acid, arachidonic acid and linoleic acid metabolism in the hippocampus. In summary, our findings highlight differential lipidomic and transcriptional signatures of various brain regions by real-ambient PM2.5 exposure, which will advance our understanding of potential mechanisms of PM2.5-induecd neurotoxicity.

Maternal transfer of F-53B inhibited neurobehavior in zebrafish offspring larvae and potential mechanisms: Dopaminergic dysfunction, eye development defects and disrupted calcium homeostasis.

Maternal exposure to environment toxicants is an important risk factor for neurobehavioral health in their offspring. In our study, we investigated the impact of maternal exposure to chlorinated polyfluoroalkyl ether sulfonic acids (Cl-PFESAs, commercial name: F-53B) on behavioral changes and the potential mechanism in the offspring larvae of zebrafish. Adult zebrafish exposed to Cl-PFESAs (0, 0.2, 2, 20 and 200 µg/L) for 21 days were subsequently mated their embryos were cultured for 5 days. Higher concentrations of Cl-PFESAs in zebrafish embryos were observed, along with, reduced swimming speed and distance travelled in the offspring larvae. Molecular docking analysis revealed that Cl-PFESAs can form hydrogen bonds with brain-derived neurotropic factor (BDNF), protein kinase C, alpha, (PKCα), Ca2+-ATPase and Na, K - ATPase. Molecular and biochemical studies evidenced Cl-PFESAs induce dopaminergic dysfunction, eye developmental defects and disrupted Ca2+ homeostasis. Together, our results showed that maternal exposure to Cl-PFESAs lead to behavioral alteration in offspring mediated by disruption in Ca2+ homeostasis, dopaminergic dysfunction and eye developmental defects.

Effects of exposure to chlorinated paraffins on human health: A scoping review.

Chlorinated paraffins (CPs) belong to an emerging class of persistent organic pollutants (POPs) widely detected in environmental matrices and human samples. The potential health risks of CPs on humans have initiated intense concerns but there have been few studies focusing on the said topic. Addressing the gap, we make a scoping review on the current global body of evidence from epidemiological and toxicological studies. Furthermore, the management strategies and regulations related to CPs are presented and discussed. There were 70 articles among 11,280 records, including four epidemiological studies, one case report, another twenty-nine studies reporting human body burden, and thirty-six toxicological studies, finally included in this review. Additionally, twenty-three management regulation relevant documents/websites were included. CPs exist in human blood, breast milk, placenta, and other tissues. Population-based and laboratory studies suggest that CPs may cause liver and kidney toxicity, developmental toxicity, neurotoxicity, endocrine disorder, immune dysfunction, and reproductive toxicity. CPs with shorter carbon chains and higher chlorine content may be more harmful. In particular, the combined effect of CPs with other pollutants is of great concern. Population-based studies are far from sufficient at present, and most of them are conducted in China or developed countries. Besides, the toxicity assessment studies of CPs are inadequate. In addition, most studies focus on short-chain CPs (SCCPs) while few studies explored the effect of long-chain CPs (LCCPs). Thus, conducting more epidemiological studies in larger populations and toxicological studies combined with new technology methods are of great significance for better understanding the adverse health effects of CPs, which may promote CPs management regulations.

Prenatal Exposure to Legacy and Alternative Per- and Polyfluoroalkyl Substances and Neuropsychological Development Trajectories over the First 3 Years of Life.

The neurotoxic effects of prenatal exposure to per- and polyfluoroalkyl substances (PFAS) on offspring animals are well-documented. However, epidemiological evidence for legacy PFAS is inconclusive, and for alternative PFAS, it is little known. In this investigation, we selected 718 mother-child pairs from the Chinese Maoming Birth Cohort Study and measured 17 legacy and alternative PFAS in the third-trimester serum. Neuropsychological developments (communication, gross motor function, fine motor function, problem solving ability, and personal-social skills) were assessed at 3, 6, 12, 18, 24, and 36 months using the Ages and Stages Questionnaires 3rd edition. Trajectories of each subscale were classified into persistently low and persistently high groups via group-based trajectory modeling. Logistic regression and grouped weighted quantile sum were fitted to assess the potential effects of individual PFAS and their mixtures, respectively. Higher linear PFHxS levels were associated with elevated odds for the persistently low trajectories of communication (OR = 1.73; 95% CI: 1.12, 2.66) and problem solving ability (OR = 2.11; 95% CI: 1.14, 3.90). Similar findings were observed for linear PFOS, 1m-PFOS, PFDA, PFDoDA, PFUnDA, and legacy PFAS mixture. However, no association was observed for alternative PFAS and their mixture. We provided insights into the longitudinal links between prenatal legacy/alternative PFAS exposure and neuropsychological development trajectories over the first 3 years of life.

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.

Environmentally relevant concentrations of F-53B induce eye development disorders-mediated locomotor behavior in zebrafish larvae.

The perfluorooctane sulfonate alternative, F-53B, induces multiple physiological defects but whether it can disrupt eye development is unknown. We exposed zebrafish to F-53B at four different concentrations (0, 0.15, 1.5, and 15 µg/L) for 120 h post-fertilization (hpf). Locomotor behavior, neurotransmitters content, histopathological alterations, morphological changes, cell apoptosis, and retinoic acid signaling were studied. Histology and morphological analyses showed that F-53B induced pathological changes in lens and retina of larvae and eye size were significantly reduced as compared to control. Acridine orange (AO) staining revealed a dose-dependent increase in early apoptosis, accompanied by upregulation of p53, casp-9 and casp-3 genes. Genes related to retinoic acid signaling (aldh1a2), lens developmental (cryaa, crybb, crygn, and mipa) and retinal development (pax6, rx1, gant1, rho, opn1sw and opn1lw) were significantly downregulated. In addition, behavioral responses (swimming speed) were significantly increased, while no significant changes in the neurotransmitters (dopamine and acetylcholine) level were observed. Therefore, in this study we observed that exposure to F-53B inflicted histological and morphological changes in zebrafish larvae eye, induced visual motor dysfunctions, perturbed retinoid signaling and retinal development and ultimately triggering apoptosis.

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.

Perfluorooctane sulfonates induces neurobehavioral changes and increases dopamine neurotransmitter levels in zebrafish larvae.

It has been reported that exposure to perfluorooctane sulfonates (PFOS) causes behavioral abnormalities in zebrafish larvae, but the possible mechanisms underlying these changes remain unexplored. In this study, zebrafish embryos (2 h postfertilization, 2-hpf) were exposed to PFOS at different concentrations (0, 0.032, 0.32 and 3.2 mg/L) for 120 h. Developmental endpoints and the locomotion behavior of larvae were evaluated. Reactive oxygen species (ROS) levels, dopamine contents, several genes and proteins related to neurodevelopment and dopamine signaling were examined. Our results indicate that increased ROS levels in the zebrafish larvae heads may be causally associated with neurodevelopment damage. Meanwhile, brain-derived neurotrophic factor (BDNF) and alpha1-Tubulin (α1-Tubulin) protein contents were significantly increased, which may be a compensatory mechanism for the impaired central nervous system. PFOS-induced locomotor hyperactivity was observed in the first light phase and dark phase at the 0.32 and 3.2 mg/L of PFOS. Upregulation of dopamine-related genes tyrosine hydroxylase (th) and dopamine transporter (dat) associated with increased dopamine contents in the 3.2 mg/L of PFOS. In addition, protein expression of TH and DAT were noted at the 0.32 and 3.2 mg/L of PFOS concentrations. Our results suggested that PFOS induces neurobehavioral changes in zebrafish larvae, possibly by perturbing a dopamine signaling pathway. In addition, PFOS induced development damage, such as increased malformation rate and shorter body length.

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.

Exposure to isomers of per- and polyfluoroalkyl substances increases the risk of diabetes and impairs glucose-homeostasis in Chinese adults: Isomers of C8 health project.

Per- and polyfluoroalkyl substances (PFAS) exposure has been linked to diabetes, but evidence on the association of isomers of PFAS with type 2 diabetes (T2D) remains scant. This population based cross-sectional study aimed to investigate associations between serum PFAS isomers, glucose-homeostasis markers and T2D, adjusted for multiple potential confounders. We used data from "Isomers of C8 Health Project in China" from July 2015 to October 2016. A total of 10 PFAS including isomers of PFOS and PFOA were measured in serum of 1045 Chinese adults. Fasting blood glucose, fasting insulin, homeostasis model of insulin (HOMA-IR) and beta cell function (HOMA-ß) were considered as markers of glucose-homeostasis. We found significant positive associations between serum PFAS isomers and glucose-homeostasis markers, namely, fasting blood glucose, fasting insulin and HOMA-IR. Per log-unit increase in branched (br)-PFOS concentration was associated with increased fasting blood glucose (ß = 0.25, 95% CI: 0.18, 0.33), fasting insulin (ß = 2.19, 95% CI: 1.44, 2.93) and HOMA-IR (ß = 0.69, 95% CI: 0.50, 0.89). As compared to br-PFOS, linear (n)-PFOS and -PFOA showed lesser significant associations with glucose-homeostasis makers. Further, exposure to all PFAS including isomeric PFOS, PFOA and PFHxS increased the risk of T2D with br-PFOS exhibiting the highest risk (OR = 5.41, 95% CI: 3.68-7.96). The associations were stronger among women than men. In conclusion, chronic exposure to PFAS isomers was associated with impaired glucose-homeostasis and may increase the prevalence of T2D in Chinese adults. Given the ubiquity of PFAS in the environment and the public health burden of T2D, future studies are warranted to corroborate the findings.

Associations of perfluorooctane sulfonate alternatives and serum lipids in Chinese adults.

BACKGROUND: Chlorinated polyfluorinated ether sulfonic acids (Cl-PFESAs), a group of perfluorooctane sulfonate (PFOS) alternatives, can be widely observed in humans and environmental matrices. However, associations between exposure to Cl-PFESAs and serum lipid levels in adults are unknown. OBJECTIVE: To explore the relationships between Cl-PFESA levels and serum lipid levels in adults. METHODS: We analyzed 1238 adults from the Isomers of C8 Health Project, a cross-sectional study conducted in China from July 2015 to October 2016. The average age of the participants was 61.98 ± 14.40 years. We quantified two select legacy per- and perfluoroalkyl substances [perfluorooctanoic acid (PFOA) and PFOS] and their alternatives (6:2 and 8:2 Cl-PFESAs). We also measured four serum lipids: low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG). We used generalized linear models to estimate the associations between PFASs and serum lipids, with PFASs defined as either a categorical variable divided into quartiles or as a continuous variable. RESULTS: We found that 6:2 Cl-PFESA was positively associated with serum TC and LDL-C. For instance, LDL-C levels in the highest quartile of 6:2 Cl-PFESA exposure (Q4) were significantly higher than those in the lowest quartile (Q1) [ß: 0.19, 95% confidence interval (CI): 0.08, 0.30]. Further analysis showed that one ln-ng/mL increase in 6:2 Cl-PFESA exposure corresponded to a 0.10 mmol/L (95% CI: 0.05, 0.16) LDL-C increase, and that exposure to 8:2 Cl-PFESA was negatively correlated with HDL-C (ß: -0.03, 95% CI: -0.05, -0.01). TC had a similar relationship with both 6:2 Cl-PFESA and legacy PFASs. Participants with a BMI ≥ 25 kg/m2 exhibited a stronger association between 6:2 Cl-PFESA and TC. CONCLUSIONS: Our findings make the novel suggestion that exposure to Cl-PFESAs are adversely associated with serum lipid levels, and that such associations are also observed in legacy PFASs. Increased investigation into the effects of Cl-PFESAs exposure on human health is warranted.

Association Between Residential Greenness, Cardiometabolic Disorders, and Cardiovascular Disease Among Adults in China.

Importance: Living in areas with more vegetation (referred to as residential greenness) may be associated with cardiovascular disease (CVD), but little data are available from low- and middle-income countries. In addition, it remains unclear whether the presence of cardiometabolic disorders modifies or mediates the association between residential greenness and CVD. Objective: To evaluate the associations between residential greenness, cardiometabolic disorders, and CVD prevalence among adults in China. Design, Setting, and Participants: This analysis was performed as part of the 33 Communities Chinese Health Study, a large population-based cross-sectional study that was conducted in 33 communities (ranging from 0.25-0.64 km2) in 3 cities within the Liaoning province of northeastern China between April 1 and December 31, 2009. Participants included adults aged 18 to 74 years who had resided in the study area for 5 years or more. Greenness levels surrounding each participant's residential community were assessed using the normalized difference vegetation index and the soil-adjusted vegetation index from 2010. Lifetime CVD status (including myocardial infarction, heart failure, coronary heart disease, cerebral thrombosis, cerebral hemorrhage, cerebral embolism, and subarachnoid hemorrhage) was defined as a self-report of a physician diagnosis of CVD at the time of the survey. Cardiometabolic disorders, including hypertension, diabetes, dyslipidemia, and overweight or obese status, were measured and defined clinically. Generalized linear mixed models were used to evaluate the association between residential greenness levels and CVD prevalence. A 3-way decomposition method was used to explore whether the presence of cardiometabolic disorders mediated or modified the association between residential greenness and CVD. Data were analyzed from October 10 to May 30, 2020. Main Outcomes and Measures: Lifetime CVD status, the presence of cardiometabolic disorders, and residential greenness level. Results: Among 24 845 participants, the mean (SD) age was 45.6 (13.3) years, and 12 661 participants (51.0%) were men. A total of 1006 participants (4.1%) reported having a diagnosis of CVD. An interquartile range (1-IQR) increase in the normalized difference vegetation index within 500 m of a community was associated with a 27% lower likelihood (odds ratio [OR], 0.73; 95% CI, 0.65-0.83; P < .001) of CVD prevalence, and an IQR increase in the soil-adjusted vegetation index within 500 m of a community was associated with a 26% lower likelihood (OR, 0.74; 95% CI, 0.66-0.84; P < .001) of CVD prevalence. The presence of cardiometabolic disorders was found to mediate the association between residential greenness and CVD, with mediation effects of 4.5% for hypertension, 4.1% for type 2 diabetes, 3.1% for overweight or obese status, 12.7% for hypercholesterolemia, 8.7% for hypertriglyceridemia, and 11.1% for high low-density lipoprotein cholesterol levels. Conclusions and Relevance: In this cross-sectional study, higher residential greenness levels were associated with lower CVD prevalence, and this association may be partially mediated by the presence of cardiometabolic disorders. Further studies, preferably longitudinal, are warranted to confirm these findings.

Serum levels of per- and polyfluoroalkyl substances alternatives and blood pressure by sex status: Isomers of C8 health project in China.

Several in vitro and in vivo studies have demonstrated the toxicity of perfluoroalkyl and polyfluoroalkyl substances (PFASs) alternatives, however, relevant epidemiological findings remain to be performed. In addition, the association between PFASs alternatives and blood pressure has not been explored. To address this gap, we quantified serum levels of alternatives and legacy PFAS in 1273 healthy Chinese, aged 34-94 years, from "isomers of C8 health project". Our results showed that an increase of serum PFASs levels was correlated with elevated blood pressure and higher prevalence of hypertension: per natural log unit (ng/mL) increase of 6:2 chlorinated polyfluorinated ether sulfonic acids (Cl-PFESA) elevated 1.31 (95%CI: 0.13, 2.50) mmHg of diastolic pressure (DBP). Adjusted odds ratios (aORs) for hypertension with per natural log increase of 6:2 and 8:2 Cl-PFESA were 2.57 (95%CI: 1.86, 3.56) and 1.18 (95%CI: 1.06, 1.32), respectively. When stratified by sex, the effects of PFASs alternatives on increased blood pressure and hypertension were stronger in women. Meanwhile, the association between 6:2 Cl-PFESA (aOR = 6.81; 95%CI: 3.54, 13.09) and hypertension was stronger than perfluorooctanoic acid (PFOA) (aOR = 2.32, 95%CI: 1.38, 3.91) in women. In conclusion, our pilot study demonstrates that serum concentrations of PFASs alternatives are positively associated with blood pressure. Moreover, women seem to be more susceptible, and alternatives exhibited stronger effects than legacy PFASs.