Per- and polyfluoroalkyl substances (PFAS) bioaccumulate in different organ systems, including bone. While existing research highlights the adverse impact of PFAS on bone density, a critical gap remains in understanding the specific effects on the bone marrow microenvironment, especially the bone marrow adipose tissue (BMAT). Changes in BMAT have been linked to various health consequences, such as the development of osteoporosis and the progression of metastatic tumors in bone. Studies presented herein demonstrate that exposure to a mixture of five environmentally relevant PFAS compounds promotes marrow adipogenesis in vitro and in vivo. We show that among the components of the mixture, PFHxS, an alternative to PFOS, has the highest propensity to accumulate in bone and effectively promote marrow adipogenesis. Utilizing RNAseq approaches, we identified the peroxisome proliferator-activated receptor (PPAR) signaling as a top pathway modulated by PFHxS exposure. Furthermore, we provide results suggesting the activation and involvement of PPAR-gamma (PPARγ) in PFHxS-mediated bone marrow adipogenesis, especially in combination with high-fat diet. In conclusion, our findings demonstrate the potential impact of elevated PFHxS levels, particularly in occupational settings, on bone health, and specifically bone marrow adiposity. This study contributes new insights into the health risks of PFHxS exposure, urging further research on the relationship between environmental factors, diet, and adipose tissue dynamics.

Per- and polyfluoroalkyl substances (PFASs), one of the persistent organic pollutants, have immunosuppressive effects. The evaluation of this effect has been the focus of regulatory toxicology. In this investigation, 146 PFASs (immunosuppressive or nonimmunosuppressive) and corresponding concentration gradients were collected from literature, and their structures were characterized by using Dragon descriptors. Feature importance analysis and stepwise feature elimination are used for feature selection. Three machine learning (ML) methods, namely Random Forest (RF), Extreme Gradient Boosting Machine (XGB), and Categorical Boosting Machine (CB), were utilized for model development. The model interpretability was explored by feature importance analysis and correlation analysis. The findings indicated that the three models developed have exhibited excellent performance. Among them, the best-performing RF model has an average AUC score of 0.9720 for the testing set. The results of the feature importance analysis demonstrated that concentration, SpPosA_X, IVDE, R2s, and SIC2 were the crucial molecular features. Applicability domain analysis was also performed to determine reliable prediction boundaries for the model. In conclusion, this study is the first application of ML models to investigate the immunosuppressive activity of PFASs. The variables used in the models can help understand the mechanism of the immunosuppressive activity of PFASs, allow researchers to more effectively assess the immunosuppressive potential of a large number of PFASs, and thus better guide environmental and health risk assessment efforts.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are now considered global contaminants posing health risks. Recent human biomonitoring data in Japan are presented.
METHODS: Human biomonitoring data from Japan, dating back to 2000, were reviewed. In addition, 399 serum samples collected in a primary care clinic in Urayasu City, Okinawa Island-one of the highest PFAS-exposed areas in Japan-between 2021 and 2022 were analyzed. Serum levels of four PFAS were compared with risk levels based on the assessment by Sonne et al. and the European Food Safety Agency.
RESULTS: The PFAS levels in the general population from various areas other than Hokkaido (16.1-43.5 ng/mL) are classified at moderate to severe risk for immunotoxicity based on the assessment.
CONCLUSIONS: A portion of the Japanese population has had high exposure to PFAS and was at high risk of immunotoxicity, and this situation remained in PFAS-contaminated areas in the 2020s.

Per- and polyfluoroalkyl substances (PFAS), particularly the perfluorinated ones, are recalcitrant to biodegradation. By integrating an enrichment culture of reductive defluorination with biocompatible electrodes for the electrochemical process, a deeper defluorination of a C6-perfluorinated unsaturated PFAS was achieved compared to the biological or electrochemical system alone. Two synergies in the bioelectrochemical system were identified: i) The in-series microbial-electrochemical defluorination and ii) the electrochemically enabled microbial defluorination of intermediates. These synergies at the material-microbe interfaces surpassed the limitation of microbial defluorination and further turned the biotransformation end products into less fluorinated products, which could be less toxic and more biodegradable in the environment. This material-microbe hybrid system brings opportunities in the bioremediation of PFAS driven by renewable electricity and warrants future research on mechanistic understanding of defluorinating and electroactive microorganisms at the material-microbe interface for system optimizations.

OBJECTIVE: To explore the effect of mixed exposure to per- and polyfluoroalkyl substances (PFAS) on metabolic syndrome (MetS).
METHODS: This cross-sectional study used data from the Korean National Environmental Health Survey Cycle 4 (2018-2020). The serum concentrations of five PFAS (perfluorooctanoic acid [PFOA], perfluorooctanesulfonic acid [PFOS], perfluorohexanesulfonic acid, perfluorononanoic acid [PFNA], and perfluorodecanoic acid [PFDeA]) were measured, and the relative potency factor approach was employed for the mixture of PFAS (Cmix) assessment. MetS was diagnosed if the patient satisfied three of five criteria: central obesity, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated blood pressure (BP), and elevated glycated hemoglobin (HbA1c). Age, sex, smoking, drinking, and exercise status were considered as covariates. The risk of MetS for single and mixed exposure to PFAS was analyzed using binomial regression and Bayesian kernel machine regression (BKMR).
RESULTS: A total of 2984 (male:female = 1:1.3; age range, 19-80 years) adults were enrolled. The prevalence of MetS was 45.6%. Each PFAS and Cmix levels were higher in participants with MetS than in those without MetS. Cmix increased the risk of elevated BP and HbA1c, and eventually MetS (odds ratio [OR] = 2.00, 95% confidence interval [CI] 1.11-3.60 per log10Cmix; OR = 1.57, 95% CI 1.07-2.31 in the highest quartile of Cmix [Q4] vs. the lowest [Q1]). Sex-specific analyses revealed that the impact of Cmix was valid in females but not in males (Cmix Q4 vs. Q1: OR = 1.01, 95% CI 0.57-1.8 in males; OR = 2.30, 95% CI 1.38-3.84 in females). In the BKMR analysis, mixed exposure to PFAS dose-dependently increased the risk of MetS, particularly in females. Among single exposures, PFNA contributed significantly to the cumulative effect.
CONCLUSIONS: Mixed exposure to PFAS was associated with a higher risk of MetS in females. Further studies on potential health concerns associated with PFAS mixtures are warranted.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are global contaminants. Seafood consumption is a possible PFAS exposure route to humans while the isomer specific analysis has not been conducted.
METHODS: Perfluorooctane sulfonate (PFOS), perfluoroheptane sulfonate (PFHpS) and perfluorohexane sulfonate (PFHxS) were investigated in residents of Kyoto, Japan (n = 51). The relationship between plasma PFAS and seafood consumption biomarker, the ratio of eicosapentaenoic acid to arachidonic acid (EPA/AA) was examined by multiple regression analysis.
RESULTS: Linear PFOS concentrations showed a significant positive correlation with the EPA/AA ratio in plasma samples (β = 6.80, p = 0.0014). Linear PFHpS was marginally associated with EPA/AA ratio (β = 0.178, p = 0.0874). Branched PFOS isomers and PFHxS had no associations with EPA/AA ratios.
CONCLUSIONS: Seafood intake may be a significant exposure pathway for PFAS, such as PFOS but the isomers differ.

Per- and polyfluoroalkyl substances (PFAS) comprise >4000 synthetic substances used in industrial applications and consumer products. PFAS used daily in households and manufacturing plants end up in domestic sewage, and industrial effluents can be discharged to surface water. Urban watersheds located in low and middle-income countries (LMIC), which lack sanitation infrastructure, are potential recipients of waste containing PFAS. Yet, only a few studies report PFAS occurrence in urban reservoirs and lakes, especially those located in the Global South due to resource limitations. This is the first study aimed to assess PFAS occurrence and ecological risks in Pampulha Lake, Brazil, a site which represents the reality of many other urban watersheds in LMIC as it is surrounded by densely populated areas and manufacturing plants. Surface water samples were collected monthly for 1 year from four sampling points at Pampulha Lake. Sample analysis was based on US Environmental Protection Agency Method 1633, which employs solid phase extraction followed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Species sensitivity distribution (SSD) curves were built to identify potentially susceptible species based on detected water concentrations. Bioaccumulation was estimated for fish tissue. Short-chain (perfluorobutanesulfonic acid, PFBS and perfluorohexanoic acid, PFHxA) and long-chain PFAS (perfluorodecanoic acid, PFDA; perfluorooctanoic acid, PFOA; perfluorododecanoic acid, PFDoA; and perfluorooctanesulfonic acid, PFOS) were detected at the μg L-1 range. Total PFAS concentrations in the wet season were generally higher than in the dry season, likely due to limited capacity of the treatment plant processing water from tributaries which receive raw sewage. More than 5 % of aquatic species are potentially susceptible to chronic effects of PFOS at detected concentrations (0.2-2.2 μg L-1). Predicted bioaccumulation of PFOS in fish was above advisory diet intake levels for humans. Results emphasize the need for studies related to PFAS occurrence in watersheds located in LMIC.

The impact of watershed comprehensive management (WCM) on per- and polyfluoroalkyl substances (PFAS) pollution in rapidly urbanizing areas remains unclear. In a typical rapidly urbanizing watershed of Shenzhen, China, we investigated temporal variations in contamination level, primary source and ecological risk of 50 emerging and legacy PFAS, as well as the replacement trends of emerging PFAS before and after WCM during a six-year sampling campaign. We found that large-scale dredging was a non-negligible factor in abnormally increased PFAS concentrations (6.43 %-456.16 %) during WCM through their release from river sediments. To better characterize the diverse and complex PFAS contamination, a novel pollution assessment method, PFAS \"diversity\", was adopted based on a modified Shannon-Weiner diversity index and Pielou evenness index, reflecting numbers of PFAS detected and how evenly each PFAS contributed to the total PFAS concentrations at specific sampling sites. Importantly, we found that the Pielou evenness index can indicate and quantify abnormal pollution sources (especially point sources) along the river. The results revealed that WCM did not effectively reduce total PFAS concentrations and diversity in the rapidly urbanizing watershed but obviously improved point source pollution. Furthermore, 6:2 polyfluorinated phosphate diesters and hexafluoropropylene oxide dimer acid (GenX) that posed high ecological risks emerged and the number of sampling sites with high risk increased from 16 to 20 after WCM. Finally, we summarize several important issues related to PFAS contamination during WCM and propose specific countermeasures, such as adopting environmental dredging and reducing the proportion of ecological water replenished by wastewater treatment plant effluent for better control of PFAS pollution. Our study highlighted the limited effectiveness of WCM in mitigating PFAS pollution and the importance of emerging contaminant regulation in rapidly urbanizing watersheds during WCM.

There has been widespread concern about the health hazards of per- and polyfluoroalkyl substances (PFAS), which may be the risk factor for hyperuricemia with evidence still insufficient in the general population in China. Here, we conducted a nationwide study involving 9,580 adults aged 18 years or older from 2017 to 2018, measured serum concentrations of uric acid and PFAS (PFOA, PFOS, 6:2 Cl-PFESA, PFNA, PFHxS) in participants, to assess the associations of individual PFAS with hyperuricemia, and estimated a joint effect of PFAS mixtures. We found positive associations of higher serum PFAS with elevated odds of hyperuricemia in Chinese adults, with the greatest contribution from PFOA (69.37%). The nonmonotonic dose-response (NMDR) relationships were observed for 6:2 Cl-PFESA and PFHxS with hyperuricemia. Participants with less marine fish consumption, overweight, and obesity may be the sensitive groups to the effects of PFAS on hyperuricemia. We highlight the potential health hazards of legacy long-chain PFAS (PFOA) once again because of the higher weights of joint effects. This study also provides more evidence about the NMDR relationships in PFAS with hyperuricemia and emphasizes a theoretical basis for public health planning to reduce the health hazards of PFAS in sensitive groups.

Hexafluoropropylene oxide dimer acid (HFPO-DA) and perfluoroethylcyclohexane sulfonate (PFECHS) are increasingly used as alternatives for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). However, their immunotoxicity and underlying molecular mechanisms remain poorly understood. Here, to assess immunotoxic effects, zebrafish embryos were exposed to environmentally relevant concentrations of PFOA, PFOS, HFPO-DA, and PFECHS for four days. Results revealed that all four per- and polyfluoroalkyl substances (PFAS) resulted in decreased heart rate and spontaneous movement, and induced oxidative stress in zebrafish larvae. Notably, HFPO-DA exhibited more severe oxidative stress than PFOA. Immune dysfunction was observed, characterized by elevated cytokine, complement factor, nitric oxide, and neutrophil content, along with a significant decrease in lysozyme content. Transcriptomic analysis revealed the activation of Toll-like receptor (TLR)/NOD-like receptor (NLR)/RIG-I-like receptor (RLR) and associated downstream genes, indicating their pivotal role in PFAS-induced immunomodulation. Molecular docking simulations demonstrated stable interactions between PFAS and key receptors (TLR2, NOD2 and RIG-I). Overall, HFPO-DA and PFECHS exhibited immunotoxic effects in zebrafish larvae similar to legacy PFAS, providing important information for understanding the toxic mode of action of these emerging alternatives.