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Background: Estrogens play a critical role in parturition, and poly- and perfluoroalkyl substances (PFAS), which have estrogenic effects, have been associated with preterm birth. However, the impact of estrogens on the association between PFAS and preterm birth is unknown., Objective: The objective of this study is to investigate if estrogens modified the association between PFAS and preterm birth, using a nested case-control study design., Methods: A total of 371 preterm births and 508 controls were selected from a birth cohort study in China between 2016 and 2018. Perfluorobutanoic acid (PFBA), perfluorohexanesulfonic acid (PFHxS) and its branched isomer, perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS) and its branched isomer, and perfluorononanoic acid (PFNA) were quantified in maternal serum (mean gestational age of 32 wk). Estradiol and estriol were quantified in cord serum. Preterm birth was defined as live delivery at < 37 gestational weeks. Causal mediation analysis was used to estimate the mediation and interaction effects of estrogen on the association between PFAS and preterm birth. Latent profile analysis was used to identify important estrogen profiles. Multiple linear regression was used to estimate associations between PFAS and preterm birth and interactions between PFAS and estrogens on preterm birth., Results: Overall, higher odds ratios (ORs) of preterm birth were associated with each 1 ln-unit PFAS increase: PFBA [1.20, 95% confidence interval (CI): 1.14, 1.26], PFNA (1.30, 95% CI: 1.21, 1.39), PFOA (1.98, 95% CI: 1.54, 2.55), and PFOS (1.91, 95% CI: 1.76, 2.07) and its branched isomer (1.91, 95% CI: 1.90, 1.92). We detected statistically significant interactions between cord estradiol and PFAS on preterm birth, while no mediation effects of cord estrogen were observed. The ORs of PFOS (4.29, 95% CI: 1.31, 8.25), its branched isomer (6.71, 95% CI: 1.06, 11.91), and preterm birth were greater for participants with high cord estrogen levels than for participants with low cord estrogen levels., Discussion: Our findings suggest that estrogen modified the association between maternal PFAS exposure and preterm birth. Further studies on maternal PFAS exposure and preterm birth, taking interaction effects of cord estrogens into account, are warranted. https://doi.org/10.1289/EHP11377.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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 (PM 2.5 ) 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/m 3 (median: 57.29 pg/m 3 ) across sites. By categories, concentrations of PFSAs (median: 26.05 pg/m 3 ) were the dominant PFAS categories, followed by PFCAs (14.25 pg/m 3 ), PFAS alternatives (2.75 pg/m 3 ) and PFAA precursors (1.10 pg/m 3 ). By individual PFAS, PFOS and PFOA were the dominant PFAS, which average concentration were 24.18 pg/m 3 and 6.05 pg/m 3 , 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Glucocorticoid plays a key role in the growth and organ maturation of fetus. However, the effect of glucocorticoid on the association between per- and polyfluoroalkyl substance (PFAS) exposure and fetal growth is still unknown. We detected cord cortisol (active glucocorticoid in human) and 34 PFAS concentrations in the maternal serum samples, which were collected from 202 mother-fetus pairs in the Maoming Birth Cohort from 2015 to 2018. The mediation effect of cord cortisol on the association between maternal PFAS and the neonatal growth index (NGI) was estimated. We found that higher PFAS concentrations were associated with lower NGI in terms of ponderal index, birth weight (BW), head circumference (HC), and its z-scores (BWZ and HCZ) ( P < 0.05). Fetal cortisol could mediate 12.6-27.3% of the associations between PFAS and NGI. Specifically, cord cortisol mediated the association between branched perfluorooctane sulfonate (branched PFOS) and HCZ by 20.4% and between perfluorooctanoate (PFOA) and HCZ by 27.3%. Our findings provide the first epidemiological data evincing that fetal cortisol could mediate the association between prenatal PFAS exposure and fetal growth. Further investigations are recommended to elucidate the interactions among cord cortisol, PFAS, and fetal growth.

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.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Perfluoroalkyl acids (PFAA) have been measured in ovarian follicular fluid from women using in vitro fertilization (IVF), although associations between follicular fluid PFAA and IVF outcomes have been inconsistent., Objectives: We investigated the association between follicular fluid PFAA and embryo quality in women undergoing IVF., Methods: We prospectively enrolled 729 women undergoing IVF treatment in Guangxi province, China, from July 2018 to December 2018. We measured 32 PFAA, including branched isomers, in follicular fluid using ultra-performance liquid chromatography coupled to tandem mass spectrometry. We applied restricted cubic splines, linear regression, and log-binominal regression models to investigate associations between follicular fluid PFAA and embryo quality, adjusting for confounding variables and investigated oocyte maturity as an intervening variable using causal mediation analysis. We further estimated the overall effect of the PFAA mixture on outcomes using Bayesian kernel machine regression (BKMR)., Results: We detected 8 of 32 measured PFAA in > 85 % of follicular fluid samples. Higher PFAA concentrations were associated with fewer high-quality embryos from IVF. The high-quality embryo rates at the 50th percentile of linear perfluoro-1-octanesulfonate acid (n-PFOS), all branched PFOS isomers (Br-PFOS) and linear perfluoro- n -octanoic acid (n-PFOA) were - 6.34 % [95% confidence interval (CI): - 9.45 , - 3.32 % ], - 16.78 % (95% CI: - 21.98 , - 11.58 % ) and - 8.66 % (95% CI: - 11.88 , - 5.43 % ) lower, respectively, than the high quality embryo rates at the reference 10th percentile of PFAA. Oocyte maturity mediated 11.76% (95% CI: 3.18, 31.80%) and 14.28% (95% CI: 2.95, 31.27%) of the n-PFOS and n-PFOA associations, respectively. The results of the BKMR models showed a negative association between the PFAA mixture and the probability of high-quality embryos, with branched PFOS isomers having posterior inclusion probabilities of 1 and accounting for the majority of the association., Discussion: Exposure to higher PFAA concentrations in follicular fluid was associated with poorer embryo quality during IVF. Branched PFOS isomers may have a stronger effect than linear PFOS isomers. More studies are needed to confirm these findings and to directly estimate the effects on pregnancy and live-birth outcomes. https://doi.org/10.1289/EHP10857.

Studies have investigated associations between maternal exposure to PFAS and preterm birth, but the impact of paternal and overall family exposure to PFAS mixtures on preterm birth remains unknown. To address this knowledge gap, a total of 355 preterm births and 481 controls were selected for a family-based birth cohort study in a coastal area of China, between 2016 and 2018. Seven PFAS, including perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA), were quantified in maternal, paternal and neonatal sera. Preterm birth was defined as live delivery at <37 completed gestational weeks. Bayesian kernel machine regression (BKMR) model was used to inspect the combined effect of family PFAS mixtures. Latent class analysis was used to identify family-level PFAS exposure profiles. Multiple linear regression analysis showed higher odds of preterm birth in association with higher maternal PFBA (OR = 1.16, 95%CI:1.09, 1.25), PFOA (OR = 1.51, 95%CI:1.27, 1.80), PFOS (OR = 2.07, 95%CI:1.70, 2.52) and PFNA (OR = 1.36, 95%CI: 1.01, 1.83), and neonatal PFBA (OR = 1.16, 95%CI:1.05,1.29), PFHxA (OR = 1.46, 95%CI:1.32, 1.62), PFHxS (OR = 1.15, 95%CI:1.05, 1.26) and PFNA (OR = 1.30, 95%CI:1.09,1.56). The associations were reversed between individual paternal PFAS exposures and preterm birth. At the family level, higher PFAS mixture concentration was associated with higher odds of preterm birth. In particular, higher PFNA and PFDA exposure was associated with greater preterm birth risk (OR = 2.55, 95%CI:1.45, 4.50). The PFAS-preterm association was modified by family-level seafood consumption. Our results suggest that higher family-level PFNA and PFDA exposure was associated with greater preterm birth risk, although the results for individual paternal, maternal and neonatal PFAS exposures were contradictory. If replicated in other coastal areas, these findings highlight a need to focus on the family triad and to consider seafood consumption when assessing the reproductive toxicity of PFAS exposure., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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 m 2 , 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Chlorinated polyfluorinated ether sulfonates (Cl-PFESAs) are one kind of replacement chemistry for perfluorooctanesulfonate (PFOS). Recent studies have shown that Cl-PFESAs could interfere with thyroid function in animal models. However, epidemiological evidence on the link between Cl-PFESAs and thyroid function remains scarce. In this study, we focused on two representative legacy perfluoroalkyl substances (PFAS), including PFOS and perfluorooctanoic acid (PFOA), and two PFOS alternatives (6:2 and 8:2 Cl-PFESAs) in the general adult population from a cross-sectional study, the "Isomers of C8 Health Project in China". Three serum thyroid hormones (THs), thyroid stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4), were measured. We fitted generalized linear regression, restricted cubic spline regression, and Bayesian kernel machine regression models to assess associations of individual Cl-PFESAs, legacy PFAS, and PFAS mixtures with THs, respectively. We found individual PFAS and their mixtures were nonlinearly associated with THs. The estimated changes of the TSH level (μIU/mL) at the 95th percentile of 6:2 Cl-PFESA and PFOS against the 5th percentile were -0.74 (95% CI: -0.94, -0.54) and -1.18 (95% CI: -1.37, -0.98), respectively. The present study provided epidemiological evidence for the association of 6:2 Cl-PFESA with thyroid hormone levels in the general adult population.

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., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Numerous epidemiological studies have investigated the lipid interference effects of legacy PFASs, however, no studies on PFAS alternatives and blood lipids have been published. In this study, we explored the association between Cl-PFESAs, a typical PFASs alternative in China, and blood lipid profiles in 1336 Guangzhou community residents using linear and non-linear regression models. The results showed a deleterious effect of Cl-PFESAs and blood lipids: adjusted estimates (β) for TC, TG, LDL-C and HDL-C per natural log unit increase of 6:2 Cl-PFESA were 0.029 (95% CI: 0.020, 0.038), 0.075 (95% CI: 0.049, 0.101), 0.035 (95% CI: 0.021, 0.049) and -0.071 (95% CI: -0.084, -0.058), respectively. The association between Cl-PFESAs and dyslipidemia was also positively significant (P < 0.05). Furthermore, a non-linear relationship was observed in Cl-PFESAs and serum lipid levels using a restricted cubic splines (RCS) model. In summary, our research suggested a negative impact of Cl-PFESAs on blood lipid patterns and a possible non-linear association., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier B.V.)

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., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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) [β: 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 (β: -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/m 2 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., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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-β) 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 (β = 0.25, 95% CI: 0.18, 0.33), fasting insulin (β = 2.19, 95% CI: 1.44, 2.93) and HOMA-IR (β = 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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Exposure to perfluoroalkyl acids (PFAAs) is known to be associated with metabolic disorders. However, whether PFAAs isomers are associated with metabolic syndrome (MetS) still remains unknown., Objectives: To explore the associations between serum PFAAs isomers and MetS., Methods: We recruited 1,501 adults from a cross-sectional study, the "Isomers of C8 Health Project in China" to investigate the associations between PFAAs isomers and MetS. A total of 20 PFAAs including the isomers of PFOS and PFOA were detected. Logistic regression models and restricted cubic spline models were used to evaluate the relationship of serum PFAAs isomers exposure with MetS and its components as well after adjusting for covariates., Results: The MetS prevalence in our study was 43.0%. The serum levels of both PFOS and PFOA isomers were higher in participants with MetS than that with non-MetS (p < 0.05). We found positive associations for per natural log-transformed ng/mL of branched perfluorooctane sulfonate (br-PFOS) (odds ratio (OR) = 1.18, 95% confidence interval (CI): 1.01, 1.38)) linear perfluoronanoic acid (n-PFOA) (OR = 1.35, 95% CI: 1.16, 1.58) and perfluoro-6-methylpheptanoic acid (6 m-PFOA) (OR = 1.32, 95% CI: 1.11, 1.57) with higher odds of MetS after covariates adjustment, while null association was observed for linear isomers of PFOS (OR = 1.09, 95% CI: 0.94, 1.25). We found a nonlinear dose-response relationship with a "threshold" effect in serum br-PFOS isomers with MetS, in which the odds of MetS increased quickly with increasing serum br-PFOS isomers under low exposure (p for nonlinearity = 0.030)., Conclusion: We report new evidence of associations between PFAAs isomers and MetS and the nonlinearity of dose-response relationship with br-PFOS isomers. Our findings indicate that more attention is needed to pay on the nonlinearity of dose-response relationship when investigate the association of PFAAs isomers with human health., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Emerging evidence suggests associations between Perfluoroalkyl substances (PFASs) exposure and asthma, but the findings are inconsistent. The current study sought to investigate whether perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) could contribute to asthma exacerbation and to clarify the underlying biological mechanisms. The objectives are a) to determine whether PFOS or PFOA could aggravate the mouse asthma and pulmonary inflammation b) to investigate whether PFOS and PFOA regulate the balance of Th1/Th2 through the JAK-STAT signaling pathway and aggravated asthma. Ovalbumin (OVA) induced asthmatic mice were exposed to PFOS or PFOA by gavage. PFOS and PFOA serum level and toxicity in organs were assessed; and the impacts on respiratory symptoms, lung tissue pathology, T helper cell (Th2) response, and STAT6 pathway activity were also evaluated. In vitro Jurkat cells were used to study the mechanisms of PFOS and PFOA mediated Th1 and Th2 responses. Both PFOS and PFOA exacerbated lung tissue inflammation (greater number of eosinophils and mucus hyperproduction), upregulated Th2 cytokine production (IL-4 and IL-13), and promoted Th2 cells and STAT6 activation. Furthermore, PFOS and PFOA enhanced the Th2 response in Jurkat cells via STAT6 activation; and the effect of PFOS exposure on GATA-3, IL-4 and IFN-γ was blocked after the expression of STAT6 was suppressed in Jurkat cells, however, the effects of PFOA exposure were only partially blocked. PFOS and PFOA aggravated inflammation among OVA-induced asthmatic mice, by promoting the Th2 response in lymphocytes and disturbing the balance of Th1/Th2 through the JAK-STAT signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

The detrimental effects of perfluoroalkyl substances (PFASs) on several physiological systems have been reported, but the association of PFASs with eye, one of the most sensitive and exposed organ, has never been explored. To investigate the association between eye diseases including visual impairment (VI) and PFASs isomers, a cross-sectional stratified study was conducted in 1202 Chinese population, aged 22-96 years, from Shenyang, China. A standard protocol including Snellen vision chart, slit-lamp microscopy and direct ophthalmoscopy was used to examine eye diseases/conditions relating to anterior and posterior segment of eyes. In addition, we measured the blood concentrations of 19 linear and branched PFASs at one-time point. Results indicated that blood levels of PFASs were significantly higher in eye disease group than normal group. PFASs exposure were positively associated with both combined eye diseases and individual eye diseases. Among other PFASs, linear perfluorooctane sulfonate (n-PFOS; odds ratio [OR] = 3.37, 95% confidence interval [CI]: 2.50, 4.56), branched perfluorooctane sulfonate (Br-PFOS; OR = 2.25, 95% CI: 1.72, 2.93) and linear perfluorooctanoic acid (n-PFOA; OR = 1.79, 95% CI: 1.36, 2.37) significantly increases the odds of VI. Vitreous disorder was adversely associated with long-chain PFASs exposure. For example, perfluorotridecanoic acid (PFTrDA; OR = 1.86, 95% CI: 1.51, 2.29) and perfluorodecanoic acid (PFDA; OR = 1.79, 95% CI: 1.36, 2.36) showed the most significant association. In conclusion, this study suggests higher serum PFASs levels were associated with increase odds of VI and vitreous disorder in Chinese adults., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Previous epidemiological and experimental studies have shown that legacy perfluoroalkyl acids (PFAAs) are immunotoxic. However, whether the immunosuppressive effects in PFAA alternatives which recently have been widely detected in the environment are unknown. To address this knowledge gap, we investigated the relationship of serum legacy PFAAs and PFAA alternatives with the antibody of hepatitis B virus in adults. We recruited 605 participants from a cross-sectional study, the Isomer of C8 Health Project in China. We measured two representative legacy PFAAs (perfluorooctane sulfonate, PFOS and perfluorooctanoic acid, PFOA), and three PFAA alternatives (two chlorinated polyfluorinated ether sulfonic acids, Cl-PFESAs and perfluorobutanoic acid, PFBA) in serum using ultra-performance liquid chromatograph-tandem mass spectrometry (UPLC-MS/MS). We applied linear and logistic regression models to analyze associations between serum PFAAs and hepatitis B surface antibody (HBsAb) with multivariable adjustments. We found negative associations between serum PFAAs concentrations and HBsAb. Lower serum HBsAb levels (log mIU/mL) were observed for each log-unit increase in linear PFOS (β = -0.31, 95% confidential interval: 0.84, -0.18), 6:2 PFESA (β = -0.81, 95% CI: 1.20, -0.42), 8:2 PFESA (β = -0.29, 95% CI: 0.43, -0.14) and PFBA (β = -0.18, 95% CI: 0.28, -0.08). The association between PFAAs and HBsAb seronegative seemed to be higher for 6:2 PFESA (odds ratio = 3.32, 95% CI: 2.16, 5.10) than its predecessors, linear PFOS (OR = 1.96, 95% CI: 1.37, 2.81) and branched PFOS isomers (OR = 1.64, 95% CI: 1.05, 2.56). We report new evidence that exposure to PFAA alternatives are associated with lower HBsAb in adults. This association seems to be stronger in 6:2 PFESA than PFOS. Our results suggest that more studies are needed to clarify the potential toxicity of PFAA alternatives in human which will facilitate better chemical regulations for PFAAs., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Experimental studies show that chlorinated polyfluorinated ether sulfonic acids (Cl-PFESA 6:2 and 8:2), one of perfluoroalkyl substances (PFAS) used as perfluorooctane sulfonate (PFOS) alternatives, are reproductive toxicants in vivo and in vitro. However, the associations between gestational exposure to Cl-PFESAs and birth outcomes are unknown., Objectives: We investigated associations between 6:2 Cl-PFESA and 8:2 Cl-PFESA in maternal serum and birth outcomes., Methods: We measured four PFAS, including 6:2 Cl-PFESA, 8:2 Cl-PFESA, PFOS, and perfluorooctanoic acid (PFOA) in third-trimester maternal serum collected from 372 mother-child dyads participating in the Guangzhou Birth Cohort Study. Characteristics of mothers and infants were gathered from medical records and by interviewer-administered questionnaires., Results: PFOS was the most abundant PFAS in maternal serum (median: 7.15 ng/mL), followed by 6:2 Cl-PFESA (median: 2.41 ng/mL). Greater maternal serum levels of all PFAS alternatives were significantly associated with lower birth weight, adjusted for confounding variables. For example, each ln-ng/mL greater concentration of 6:2 Cl-PFESA and 8:2 Cl-PFESA was associated with a 54.44 g [95% confidence interval (CI): -95.66, -13.22] and 21.15 g (95% CI: -41.44, -0.86) lower birth weight, respectively. Greater continuous maternal serum 6:2 Cl-PFESA (OR: 2.67, 95% CI: 1.73, 4.15) and PFOS (OR: 2.03, 95% CI: 1.24, 3.32) were also associated with higher risks for preterm birth, adjusted for confounders, with a possible threshold effect at the highest quartile of 6:2 Cl-PFESA., Conclusions: For the first time, we report associations between maternal serum 6:2 Cl-PFESA and 8:2 Cl-PFESA concentrations and adverse birth outcomes. Our findings suggest that PFOS alternatives may be reproductive toxicants in human populations and should be considered with caution before widespread use. Given the preliminary nature of our results, additional epidemiological and toxicological investigations are needed to more definitively assess the risks., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Greater levels of serum per- and polyfluoroalkyl substances (PFAS) are known to be associated with higher uric acid which itself leads to a number of chronic diseases. However, whether this association varies across PFAS isomers which recently have been found to be associated with human health remains unknown., Objectives: To address this research gap, we explored isomer-specific associations between serum PFAS and uric acid in Chinese adults., Methods: We conducted a cross-sectional study of associations between serum PFAS isomer and serum uric acid in 1612 participants from the Isomer of C8 Health Project. We used multivariable linear and logistic regression models to analyze serum isomers of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), and other PFASs as continuous and categorical predictors of uric acid, adjusted for confounders. The association was also stratified by kidney function stage based on estimated glomerular filtration rate (GF-1, GF-2, GF-3a, and GF-3b/4)., Results: We found positive associations between serum PFAS isomer concentrations and uric acid. Uric acid levels were greater for each log-unit increase in branched PFOA (β = 0.30, 95% CI: 0.21, 0.40), linear PFOA (β = 0.18, 95% CI: 0.09, 0.26), branched PFOS (β = 0.09, 95% CI: 0.02, 0.17) and linear PFOS (β = 0.06, 95% CI: -0.01, 0.14) concentration. The associations between PFAS and uric acid showed an inverted 'U' shaped pattern across kidney function stages. For example, uric acid level was greater with each log-unit increase in total-PFOA among GF-1 (β = 0.21, 95% CI: 0.06, 0.37), this relationship was greater in GF-3a (β = 0.49, 95% CI: 0.09, 0.89) and decreased in GF-3b/4 (β = -0.22, 95% CI: -0.83, 0.39). We also found the odds of hyperuricemia increased linearly with increasing branched PFOA in quartiles (odds ratio = 2.67, 95% CI: 1.86, 3.85 at the highest quartile)., Conclusion: We report novel results in which PFAS associations with uric acid varied according to isomer and adult kidney function. Besides, our findings are consistent with previous epidemiologic studies in finding a positive association between serum PFAS concentrations and serum uric acid, especially for PFOA. Our results indicate that more research is needed to more clearly assess the impact of PFAS isomers on human health, which will help to refine regulation policies for PFAS., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Exposure to chemicals may affect liver enzyme to increase the risk of liver diseases. Perfluoroalkyl acids (PFAAs) are one kind of persistent organic pollutants with hepatotoxic effect in organism. However, data is scarce to characterize the hepatotoxic effects of specific structural PFAA isomers in general population. To address this data gap, we evaluated the association between serum PFAAs concentration and liver function biomarkers in the Isomers of C8 Health Project in China. High performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to measure 18 serum PFAAs, except for linear and branched isomers of PFOA/PFOS, nine perfluorinated carboxylic acids (PFCAs) and two perfluorinated sulfonic acids (PFSAs) were also included, in 1605 adult residents of Shenyang, China. Values for nine serum liver function biomarkers were determined by full-automatic blood biochemical analyzer. Linear regression was used to evaluate associations between PFAAs and continuous liver function biomarkers and logistic regression to assess markers dichotomized per clinical reference intervals. Results indicated that serum PFAAs concentrations were associated with liver biomarker levels suggestive of hepatotoxicity, especially for liver cell injury. For example, a 1 ln-unit increase in total- perfluorooctanoic acid (PFOA) exposure was associated with a 7.4% [95% confidence interval (CI): 3.9%, 11.0%] higher alanine aminotransferase (ALT) level in serum. Interestingly, we observed association between branched PFAA isomers and liver biomarkers. For example, one ln-unit increase in branched perfluorooctane sulfonate (PFOS) isomers exposure was associated with a 4.3% increase in ALT level (95% CI: 1.2%, 7.4%) and a 33.0% increased odds of having abnormal ALT (95% CI: 5.0%, 67.0%). Also, we found that PFNA had positive association with ALT [(6.2%, 95% CI: 3.1%, 9.4%) and AST levels (2.5%, 95% CI: 0.5%, 4.5%)]. Logistic regression results showed that PFPeA, PFHxA, PFNA, PFDoDA, PFTrDA and PFTeDA had statistically association with abnormal prealbumin. Conclusively, our results support previous studies showing association between PFAAs exposure and liver function biomarkers. We found new evidence that branched PFAAs isomer exposure is associated with the risk of clinically relevant hepatocellular dysfunction., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Perfluoroalkyl substances (PFASs) are synthetic chemicals widely used in industry and for commercial products. Their immunomodulatory effects are a growing health concern in children. Hand, Foot and Mouth Disease (HFMD) is a common childhood viral infection, and increased incidence of which has parallel the rise in PFAS exposure in the Asia-Pacific region., Objective: We conducted the first study to assess whether prenatal exposure to PFAS was associated with a reduction in HFMD virus antibodies in infants., Methods: We enrolled 201 mother-infant pairs from the Guangzhou Birth Cohort Study from July to October 2013. High performance liquid chromatography-mass spectrometry was employed to determine concentrations of specific PFAS isomers in cord blood. Neutralizing antibodies titers were measured against two HFMD viruses, enterovirus 71 (EV71) and coxsackievirus A 16 (CA16), in cord blood serum and blood serum at three months of age., Results: Higher umbilical cord blood PFAS concentrations were associated with lower EV71 and CA16 antibody concentrations. A doubling in the composite sum of cord blood PFASs in three month old infants was associated with significant increase in the risk of HFMD antibody concentration below clinical protection level (≥1:8 titers) for CA16 (odds ratio, OR: 2.74 [95% confidence interval (CI): 1.33, 5.61] and for EV71 (OR = 4.55, 95% CI: 1.45, 4.28). This association was higher in boys at three months of age for CA16., Conclusions: Our findings suggest that cord blood PFAS exposure is associated with lower HFMD antibody in infancy. Given the widespread nature of PFAS exposures and the high global incidence of HFMD globally, these findings have substantial public health implications and therefore, these associations need to be replicated in a larger study to more definitively address the risk., (Copyright © 2019. Published by Elsevier B.V.)

Previous investigations on the associations of polyfluoroalkyl substances (PFASs) with overweight/obesity are mixed. Moreover, little information has been reported about the association between isomers of PFASs with body mass index (BMI), waist circumference (WC) or overweight. To address this shortcoming in the literature, we conducted a study involving 1612 Chinese adults (1204 men and 408 women), ages 22-96 years old, from Shenyang, China, to analyze serum isomers of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and other PFASs. Height, weight and WC were measured by a standardized protocol of WHO. Results indicated that increased serum concentrations of all (both branched and linear) isomers of PFASs were associated with a higher prevalence of overweight, and these associations were more pronounced in women. The adjusted odds ratios (ORs) from logistic regression analyses among women were 1.45 (95% confidence interval [CI]: 1.06, 1.99) for linear PFOS isomers, 1.33 (95% CI: 1.00, 1.77) for branched PFOS isomers, 1.39 (95% CI: 1.06, 1.81) for 3 + 4 + 5m PFOS, 1.54 (95% CI: 1.08, 2.21) for linear PFOA isomers, and 1.62 (95% CI: 1.05, 2.51) for branched PFOA isomers, respectively. Associations with increased WC were yielded a similar pattern. Linear regression models also showed positive associations between PFASs and BMI or WC. In conclusion, this study suggests that PFASs and their isomers are positively associated with overweight or increased WC, and the associations are stronger in women. Furthermore, PFOA and its isomers displayed the most robust obesogenic associations., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Perfluoroalkyl substances (PFASs) are widely-utilized synthetic chemicals commonly found in industrial and consumer products. Previous studies have examined associations between PFASs and renal function, yet the results are mixed. Moreover, evidence on the associations of isomers of PFASs with renal function in population from high polluted areas is scant. To help to address this data gap, we used high performance liquid chromatography-mass spectrometry to measure serum isomers of perfluorooctanoate (PFOA), perfluorooctanesulfonate (PFOS), and other PFASs from 1612 adults residing in Shenyang, China, and characterized their associations with estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). Results showed that after adjusted for multiple confounding factors, most of the higher fluorinated PFASs, except for PFOA and PFDA, were negatively associated with eGFR and positively associated with CKD. Compared with linear PFOS (n-PFOS), branched PFOS isomers (Br-PFOS) were more strongly associated with eGFR (Br-PFOS; β = -1.22, 95%CI: 2.02, -0.42; p = 0.003 vs. n-PFOS; β = -0.16, 95%CI: 0.98, 0.65; p = 0.691) and CKD (Br-PFOS; OR = 1.27; 95% CI: 1.02, 1.58; p = 0.037 vs. n-PFOS; OR = 0.98; 95% CI: 0.80, 1.20; p = 0.834). In conclusion, branched PFOS isomers were negatively associated with renal function whereas their linear counterparts were not. Given widespread exposure to PFASs, potential nephrotoxic effects are of great public health concern, Furthermore, longitudinal research on the potential nephrotoxic effects of PFASs isomers will be necessary to more definitively assess the risk., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Previous studies have demonstrated associations of perfluoroalkyl substances (PFASs), a group of highly persistent chemicals ubiquitous in wildlife and humans, with hypertension, but the relationships are mixed. Furthermore, academic literature on the relationship between isomers of PFASs and blood pressure (BP) and hypertension in populations from a higher pollution area is scant. We studied 1612 Chinese adults, ages 22-96years old, from Shenyang, China, utilizing high performance liquid chromatography-mass spectrometry to analyze isomers of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and other PFASs in blood serum. We used a mercury sphygmomanometer to measure BP. Hypertension was defined as a mean systolic BP (SBP) of at least 140mmHg, and/or diastolic BP (DBP) of at least 90mmHg, and/or use of antihypertensive medications. The results showed that increased serum concentrations of all (both branched and linear) isomers of PFASs were associated with higher prevalence of hypertension. Adjusted odds ratios for hypertension per ln-unit (ng/mL) increase in PFASs ranged from 1.10 (95%CI: 1.04, 1.17) for perfluorobutanoic acid (PFBA) to 1.26 (95%CI: 1.12, 1.42) for 3+4+5m PFOS, and the estimated increases in mean SBP and DBP ranged from 0.80mmHg (95%CI: 0.25, 1.34) for PFBA to 4.51mmHg (95%CI: 3.52, 5.51) for 3+4+5m PFOS, and from 0.51mmHg (95%CI: 0.01, 1.01) for perfluorodecanesulfonate (PFDS) to 2.48 (1.80, 3.16) for perfluorononanoic acid (PFNA), respectively. Compared with linear PFASs isomers, we identified more and stronger associations among branched PFASs isomers and blood pressure. Furthermore, females exhibited consistently stronger effects than males. In conclusion, this study is the first of its kind to show that not only PFASs positively associated with elevated blood pressure, but also that branched PFAS isomers are more frequently associated with blood pressure than linear PFAS isomers., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Previous studies have demonstrated associations between serum levels of perfluoroalkyl substances (PFASs) and asthma or asthma related-biomarkers. However, no studies have reported a possible relationship between PFASs exposure and lung function among children. The objective of the present study is to test the association between PFASs exposure and lung function in children from a high exposure area by using a cross-sectional case-control study, which included 132 asthmatic children and 168 non-asthmatic controls recruited from 2009 to 2010 in the Genetic and Biomarkers study for Childhood Asthma. Structured questionnaires were administered face-to-face. Lung function was measured by spirometry. Linear regression models were used to examine the influence of PFASs on lung function. The results showed that asthmatics in our study had significantly higher serum PFAS concentrations than healthy controls. Logistic regression models showed a positive association between PFASs and asthma, with adjusted odds ratios (ORs) ranging from 0.99 (95% confidence interval [CI]: 0.80-1.21) to 2.76 (95% CI: 1.82-4.17). Linear regression modeling showed serum PFASs levels were significantly negatively associated with three pulmonary function measurements (forced vital capacity: FVC; forced expiratory volume in 1s: FEV 1 ; forced expiratory flow 25-75%: FEF 25-75 ) among children with asthma, the adjusted coefficients between lung function and PFASs exposure ranged from -0.055 (95%CI: -0.100 to -0.010) for FVC and perfluorooctane sulfonate (PFOS) to -0.223 (95%CI: -0.400 to -0.045) for FEF 25-75 and perfluorooctanoic acid (PFOA). PFASs were not, however, significantly associated with pulmonary function among children without asthma. In conclusion, this study suggests that serum PFASs are associated with decreased lung function among children with asthma., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Prior investigations on the associations of polyfluoroalkyl substances (PFASs) with fetal growth are mixed. Moreover, little research has accrued pertaining to the association between isomers of PFASs with gestational age and birth weight. To address this gap and present novel information, we conducted a study including 321 pairs of mothers and their infants recruited from Guangzhou, China. High performance liquid chromatography-mass spectrometry was utilized to analyze isomers of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA) along with other PFAS levels in cord serum samples. Mothers' and infants' characteristics were gathered from medical records. The resulting data revealed that higher PFOS, PFOA and isomers of PFOS were associated with lower birth weight. Per ln-unit (ng/mL) increase in cord serum total branched PFOS isomers was associated with a 126.3g (95% CI: -195.9, -56.8) reduction in the weight of infants at birth, while an ln-unit (ng/mL) increase of serum linear PFOS isomers (n-PFOS) was associated with a 57.2g (95% CI: -103.1, -11.3) reduction in the weight of infants at birth upon the subsequent adjustment for potential confounding variables. Notably, the association between cord PFAS level and birth weight was more pronounced in male infants. Furthermore, a positive association among branched PFOS isomers (1m-PFOS and 3+4+5m-PFOS) and gestational age was found. No associations could be found among other PFASs in conjunction with gestational age or birth weight. In conclusion, this investigation suggests that higher PFAS concentrations are associated with lower birth weight, and branched PFOS isomers show greater impact on infant birth weight than linear PFOS., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Perfluoroalkyl substances (PFASs) are a class of widely used chemicals that have been detected in the environment and general population. However, the isomer patterns in human are poorly characterized. Previous studies observed the isomer-specific maternal-fetal transfer of PFASs in human. In our current study, we first examined the profile of PFASs and isomers, including 17 linear PFASs and 10 branched PFOS/PFOA isomers by using isotopic internal standards in umbilical cord serum samples from Guangzhou, China. We collected a total of 321 of cord blood serum samples from July to October in 2013, and analyzed the PFASs concentration with isomer-specific PFASs analysis method. The results showed that 9 out of 17 PFASs (linear PFASs) were detected (>50% detection rate). Perfluorohexane sulfonate (PFHxS, median 3.87 ng/mL) was the predominant, followed by total PFOS (median 2.99 ng/mL) and total PFOA (median 1.23 ng/mL) in cord serum. In addition, 1m-, iso-, ∑3+4+5m-PFOS and iso-PFOA were the branched PFASs detected in the current study. The proportion of linear PFOS (n-PFOS) was 75.16% of ∑PFOS which was similar to the proportion of electrochemical fluorination that produces ca. 70% linear PFOS and 30% branched. On the contrary, linear PFOA (n-PFOA) accounted for 98.69% ∑PFOA in cord serum samples. Our finding indicates distinct PFASs and PFOS/PFOA isomer profile in cord serum, suggesting there might be a different exposure pathway and metabolism of PFASs.

To evaluate the interactions between polyfluoroalkyl substances (PFASs) and reproductive hormones and associated asthma, a total of 231 asthmatic and 225 non-asthmatic adolescents were selected from northern Taiwan in the Genetic and Biomarkers study for Childhood Asthma from 2009-2010. The interaction between PFASs and reproductive hormones on asthma was analyzed with a two-level binary logistic regression model. The results showed that, among asthmatics, PFASs were positively associated with estradiol levels and negatively associated with testosterone levels. However, only significant association was identified for PFNA and estradiol in control group. After controlling for hormone levels, associations between PFAS exposure and asthma were consistently stronger among children with higher than lower estradiol, with odds ratios (OR) for asthma ranging from 1.25 for PFOS (95% Confidence Interval [CI]: 0.90, 1.72) to 4.01 for PFDA (95% CI: 1.46, 11.06) among boys and 1.25 for PFOS (95% CI: 0.84, 1.86) to 4.16 for PFNA (95% CI: 1.36, 12.73) among girls. Notably, the interactions between estradiol and PFASs were significant for PFOS (p = 0.026) and PFNA (p = 0.043) among girls. However, testosterone significantly attenuated the association between PFOS and asthma across sex. In conclusions, our findings suggested that reproductive hormones amplify the association between PFASs and asthma among adolescents.

Little information exists about the evaluation of potential developmental immunotoxicity induced by perfluorooctane sulfonate (PFOS), a synthetic persistent and increasingly ubiquitous environmental contaminant. To assess potential sex-specific impacts of PFOS on immunological health in the offspring, using male and female C57BL/6 mice, pups were evaluated for developmental immunotoxic effects after maternal oral exposure to PFOS (0.1, 1.0 and 5.0 mg PFOS/kg/day) during Gestational Days 1-17. Spontaneous TH1/TH2-type cytokines, serum levels of testosterone and estradiol were evaluated in F1 pups at four and eight weeks of age. The study showed that male pups were more sensitive to the effects of PFOS than female pups. At eight weeks of age, an imbalance in TH1/TH2-type cytokines with excess TH2 cytokines (IL-4) was found only in male pups. As for hormone levels, PFOS treatment in utero significantly decreased serum testosterone levels and increased estradiol levels only in male pups, and a significant interaction between sex and PFOS was observed for serum testosterone at both four weeks of age (pinteraction = 0.0049) and eight weeks of age (pinteraction = 0.0227) and for estradiol alternation at four weeks of age (pinteraction = 0.0351). In conclusion, testosterone-mediated endocrine function may be partially involved in the TH1/TH2 imbalance induced by PFOS, and these deficits are detectable among both young and adult mice and may affect males more than females., Competing Interests: The authors declare no conflicts of interest.

Perfluoroalkyl acids (PFAAs) are a group of common chemicals that ubiquitously exist in wildlife and humans. Experimental data suggest that they may alter T-lymphocyte functioning in situ by preferentially enhancing the development of T-helper 2 (TH2)- and inhibiting TH1-lymphocyte development and might increase allergic inflammation, but few human studies have been conducted. To evaluate the association between serum PFAAs concentrations and T-lymphocyte-related immunological markers of asthma in children, and further to assess whether gender modified this association, 231 asthmatic children and 225 non-asthmatic control children from Northern Taiwan were recruited into the Genetic and Biomarker study for Childhood Asthma. Serum concentrations of ten PFAAs and levels of TH1 [interferon (IFN)-γ, interleukin (IL)-2] and TH2 (IL-4 and IL-5) cytokines were measured. The results showed that asthmatics had significantly higher serum PFAAs concentrations compared with the healthy controls. When stratified by gender, a greater number of significant associations between PFAAs and asthma outcomes were found in males than in females. Among males, adjusted odds ratios for asthma among those with the highest versus lowest quartile of PFAAs exposure ranged from 2.59 (95% CI: 1.14, 5.87) for the perfluorobutanesulfonate (PFBS) to 4.38 (95% CI: 2.02, 9.50) for perfluorooctanesulfonate (PFOS); and serum PFAAs were associated positively with TH2 cytokines and inversely with TH1 cytokines among male asthmatics. Among females, no significant associations between PFAAs and TH2 cytokines could be detected. In conclusion, increased serum PFAAs levels may promote TH cell dysregulation and alter the availability of key TH1 and TH2 cytokines, ultimately contributing to the development of asthma that may differentially impact males to a greater degree than females. These results have potential relevance in asthma prevention., (Copyright © 2016 Elsevier B.V. All rights reserved.)

To investigate the risk of hyperuricemia in relation to Perfluoroalkyl substances (PFASs) in children from Taiwan, 225 Taiwanese children aged 12-15 years were recruited from 2009 to 2010. Linear and logistic regression models were employed to examine the influence of PFASs on serum uric acid levels. Findings revealed that eight of ten PFASs analyses were detected in >94% of the participants' serum samples. Multivariate linear regression models revealed that perfluorooctanic acid (PFOA) was positively associated with serum uric acid levels (β = 0.1463, p < 0.05). Of all the PFASs analyses, only PFOA showed a significant effect on elevated levels of hyperuricemia (aOR = 2.16, 95%CI: 1.29-3.61). When stratified by gender, the association between serum PFOA and uric acid levels was only evident among boys (aOR = 2.76, 95%CI: 1.37-5.56). In conclusion, PFOA was found to be associated with elevated serum levels of uric acid in Taiwanese children, especially boys. Further research is needed to elucidate these links., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Perfluorinated compounds (PFCs), such as perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), are a family of commonly used industrial chemicals whose persistence and ubiquity in blood samples of humans and wildlife have become a growing concern. Despite PFOS and PFOA having been found in human blood and tissue samples from occupationally exposed workers and the general worldwide population, little systematic knowledge has accrued with respect to exposure levels in Uyghurs in the Sinkiang-Uighur Autonomous Region of China, which is predominantly agricultural and pastoral. Our goal was to provide background data for biological monitoring in the general population of this region. In this study, 110 self-reported healthy human serum samples were collected from nonoccupationally exposed Uyghurs volunteers and analyzed by microbore HPLC-electrospray tandem mass spectrometry. Among the 110 blood specimens, PFOS was detected in 102 samples (93%) and ranged from the lower limit of quantification of 0.01 to 22.63 μg/L with a median of 1.93 μg/L (interquartile range 1.00-3.43 μg/L). The median was higher among males (2.39 μg/L; interquartile range 1.23-4.40 μg/L) than that among females (1.20 μg/L; interquartile range 0.83-2.77 μg/L). No significant difference was observed with respect to age. The concentration of PFOA was lower than that of PFOS and was found only in seven samples (6%) at concentrations above the limit of quantification. This study is the first investigation to reveal serum PFOS and PFOA levels in the general population of Uyghurs. PFOS and PFOA concentrations found in the present investigation were lower than those found in recent studies consisting of subjects from different geographic locations (PFOS 5.0-44.7 μg/L, PFOA 1.5-10 μg/L).