Polyfluoroalkyl Substances Mixtures Research Articles

Prenatal and postnatal exposure to PFAS and cardiometabolic factors and inflammation status in children from six European cohorts.

Developing children are particularly vulnerable to the effects of exposure to per- and polyfluoroalkyl substances (PFAS), a group of endocrine disrupting chemicals. We hypothesized that early life exposure to PFASs is associated with poor metabolic health in children. We studied the association between prenatal and postnatal PFASs mixture exposure and cardiometabolic health in children, and the role of inflammatory proteins. In 1,101 mothers-child pairs from the Human Early Life Exposome project, we measured the concentrations of PFAS in blood collected in pregnancy and at 8years (range=6-12years). We applied Bayesian Kernel Machine regression (BKMR) to estimate the associations between exposure to PFAS mixture and the cardiometabolic factors as age and sex- specific z-scores of waist circumference (WC), systolic and diastolic blood pressures (BP), and concentrations of triglycerides (TG), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) cholesterol. We measured thirty six inflammatory biomarkers in child plasma and examined the underlying role of inflammatory status for the exposure-outcome association by integrating the three panels into a network. Exposure to the PFAS mixture was positively associated with HDL-C and systolic BP, and negatively associated with WC, LDL-C and TG. When we examined the independent effects of the individual chemicals in the mixture, prenatal PFHxS was negatively associated with HDL-C and prenatal PFNA was positively associated with WC and these were opposing directions from the overall mixture. Further, the network consisted of five distinct communities connected with positive and negative correlations. The selected inflammatory biomarkers were positively, while the postnatal PFAS were negatively related with the included cardiometabolic factors, and only prenatal PFOA was positively related with the pro-inflammatory cytokine IL-1beta and WC. Our study supports that prenatal, rather than postnatal, PFAS exposure might contribute to an unfavorable lipidemic profile and adiposity in childhood.

Per- and poly-fluoroalkyl substances (PFAS) and female reproductive outcomes: PFAS elimination, endocrine-mediated effects, and disease

Per- and poly-fluoroalkyl substances (PFAS) are widespread environmental contaminants frequently detected in drinking water supplies worldwide that have been linked to a variety of adverse reproductive health outcomes in women. Compared to men, reproductive health effects in women are generally understudied while global trends in female reproduction rates are declining. Many factors may contribute to the observed decline in female reproduction, one of which is environmental contaminant exposure. PFAS have been used in home, food storage, personal care and industrial products for decades. Despite the phase-out of some legacy PFAS due to their environmental persistence and adverse health effects, alternative, short-chain and legacy PFAS mixtures will continue to pollute water and air and adversely influence women’s health. Studies have shown that both long- and short-chain PFAS disrupt normal reproductive function in women through altering hormone secretion, menstrual cyclicity, and fertility. Here, we summarize the role of a variety of PFAS and PFAS mixtures in female reproductive tract dysfunction and disease. Since these chemicals may affect reproductive tissues directly or indirectly through endocrine disruption, the role of PFAS in breast, thyroid, and hypothalamic-pituitary-gonadal axis function are also discussed as the interplay between these tissues may be critical in understanding the long-term reproductive health effects of PFAS in women. A major research gap is the need for mechanism of action data – the targets for PFAS in the female reproductive and endocrine systems are not evident, but the effects are many. Given the global decline in female fecundity and the ability of PFAS to negatively impact female reproductive health, further studies are needed to examine effects on endocrine target tissues involved in the onset of reproductive disorders of women.

Predicting the effects of per- and polyfluoroalkyl substance mixtures on peroxisome proliferator-activated receptor alpha activity in vitro

Human exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous, with mixtures of PFAS detected in drinking water, food, household dust, and other exposure sources. Animal toxicity studies and human epidemiology indicate that PFAS may act through shared mechanisms including activation of peroxisome proliferator activated receptor α (PPARα). However, the effect of PFAS mixtures on human relevant molecular initiating events remains an important data gap in the PFAS literature. Here, we tested the ability of modeling approaches to predict the effect of diverse PPARα ligands on receptor activity using Cos7 cells transiently transfected with a full length human PPARα (hPPARα) expression construct and a peroxisome proliferator response element-driven luciferase reporter. Cells were treated for 24 h with two full hPPARα agonists (pemafibrate and GW7647), a full and a partial hPPARα agonist (pemafibrate and mono(2-ethylhexyl) phthalate), or a full hPPARα agonist and a competitive antagonist (pemafibrate and GW6471). Receptor activity was modeled with three additive approaches: effect summation, relative potency factors (RPF), and generalized concentration addition (GCA). While RPF and GCA accurately predicted activity for mixtures of full hPPARα agonists, only GCA predicted activity for full and partial hPPARα agonists and a full agonist and antagonist. We then generated concentration response curves for seven PFAS, which were well-fit with three-parameter Hill functions. The four perfluorinated carboxylic acids (PFCA) tended to act as full hPPARα agonists while the three perfluorinated sulfonic acids (PFSA) tended to act as partial agonists that varied in efficacy between 28–67 % of the full agonist, positive control level. GCA and RPF performed equally well at predicting the effects of mixtures with three PFCAs, but only GCA predicted experimental activity with mixtures of PFSAs and a mixture of PFCAs and PFSAs at ratios found in the general population. We conclude that of the three approaches, GCA most accurately models the effect of PFAS mixtures on hPPARα activity in vitro. Understanding the differences in efficacy with which PFAS activate hPPARα is essential for accurately predicting the effects of PFAS mixtures. As PFAS can activate multiple nuclear receptors, future analyses should examine mixtures effects in intact cells where multiple molecular initiating events contribute to proximate effects and functional changes.

Prospective associations of mid-childhood plasma per- and polyfluoroalkyl substances and pubertal timing.

Exposure to per- and polyfluoroalkyl substances (PFAS) may disrupt pubertal timing. Higher PFAS plasma concentrations have been associated with later pubertal timing in girls, but cross-sectional findings may be explained by reverse causation. To assess prospective associations between PFAS plasma concentrations in mid-childhood and markers of pubertal timing in male and female adolescents. We studied 640 children in Project Viva, a Boston-area prospective cohort. We examined associations of plasma concentrations of 6 PFAS measured at mean 7.9 (SD 0.8) years (2007-2010) with markers of pubertal timing. Parents reported a 5-item pubertal development score at early adolescence (mean 13.1 (SD 0.8) years) and reported age at menarche annually. We calculated age at peak height velocity using research and clinical measures of height. We used sex-specific linear and Cox proportional hazards regression to estimate associations of single PFAS with outcomes, and we used Bayesian Kernel Machine Regression (BKMR) to estimate associations of the PFAS mixture with outcomes. Plasma concentrations were highest for perfluorooctane sulfonate (PFOS) [median (IQR) 6.4(5.6) ng/mL], followed by perfluorooctanoate (PFOA) [4.4(3.0) ng/mL]. In early adolescence, girls were further along in puberty than boys [pubertal development score mean (SD) 2.9 (0.7) for girls and 2.2(0.7) for boys; age at peak height velocity mean (SD) 11.2y (1.0) for girls and 13.1y (1.0) for boys]. PFAS was associated with later markers of pubertal timing in girls only. For example, each doubling of PFOA was associated with lower pubertal development score (-0.18 units; 95% CI: -0.30, -0.06) and older age at peak height velocity (0.23years; 95% CI: 0.06, 0.40)]. We observed similar associations for PFOS, perfluorodecanoate (PFDA), and the PFAS mixture. PFAS plasma concentrations were not associated with age at menarche or markers of pubertal timing in boys. Higher PFAS plasma concentrations in mid-childhood were associated with later onset of puberty in girls.

Associations of Maternal Serum Perfluoroalkyl Substances Concentrations with Early Adolescent Bone Mineral Content and Density: The Health Outcomes and Measures of the Environment (HOME) Study.

Background:Per- and polyfluoroalkyl substances (PFAS) may impair bone accrual and strength via endocrine disruption and nuclear receptor agonism, but human studies are primarily of adults or cross-sectional.Objectives:We assessed associations of individual PFAS and their mixture during pregnancy with child bone mineral content (BMC) and areal bone mineral density (aBMD) at age 12 y.Methods:Among 206 mother–child pairs enrolled in a prospective cohort (2003–2006), we quantified perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), and perfluorooctane sulfonic acid (PFOS) in maternal serum collected during gestation or delivery. When children were age 12 y, we performed dual energy X-ray absorptiometry and calculated BMC, aBMD, and bone mineral apparent density (BMAD) -scores for six skeletal sites. We estimated covariate-adjusted -score differences per doubling of individual PFAS using linear regression and assessed the PFAS mixture using quantile g-computation and Bayesian kernel machine regression. We explored whether associations were modified by child’s sex or mediated by whole-body lean mass.Results:In covariate-adjusted models, we found that higher maternal serum concentrations of PFOA, PFNA, and the PFAS mixture were associated with lower total hip and forearm (one-third distal radius) BMC -scores in children. Differences in forearm BMC -scores were [95% confidence interval (CI): , 0.01] and (95% CI: , ) per doubling of PFOA and PFNA, respectively, and (95% CI: , ) per quartile increase in the PFAS mixture. Child’s sex modified PFOA associations for some skeletal sites; for example, differences in spine BMAD -score per doubling were (95% CI: , ) among males and 0.07 (95% CI: , 0.30) among females (modification ). Except for PFNA among females, these associations were not mediated by whole-body lean mass.Discussion:Maternal PFAS concentrations during pregnancy may be associated with lower bone mineral accrual and strength in early adolescence. https://doi.org/10.1289/EHP9424

The role of maternal high fat diet on mouse pup metabolic endpoints following perinatal PFAS and PFAS mixture exposure

Per- and polyfluoroalkyl substances (PFAS) are a family of chemicals that are ubiquitous in the environment. Some of these chemicals, such as perfluorooctanesulfonic acid (PFOS), perfluorohexanesulfonate (PFHxS) and perfluorooctanoic acid (PFOA), are found in human sera and have been shown to cause liver steatosis and reduce postnatal survival and growth in rodents. The purpose of this work is to evaluate the impact of diet and PFAS exposure to mouse dam (mus musculus) on the risk to pup liver and metabolism endpoints later in life, as well as evaluate PFAS partitioning to pups. Timed-pregnant dams were fed a standard chow diet or 60 % kcal high fat diet (HFD). Dams were administered either vehicle, 1 mg/kg PFOA, 1 mg/kg PFOS, 1 mg/kg PFHxS, or a PFAS mixture (1 mg/kg of each PFOA, PFOS, and PFHxS) daily via oral gavage from gestation day 1 until postnatal day (PND) 20. At PND 21, livers of dams and 2 pups of each sex were evaluated for lipid changes while remaining pups were weaned to the same diet as the dam for an additional 10 weeks. Dam and pup serum at PND 21 and PND 90 were also evaluated for PFAS concentration, alanine aminotransferase (ALT), leptin and adiponectin, and glycosylated hemoglobin A1c. Perinatal exposure to a HFD, as expected, increased pup body weight, maternal liver weight, pup liver triglycerides, pup serum ALT, and pup serum leptin. PFOA and the PFAS mixture increased liver weights, and. treatment with all three compounds increased liver triglycerides. The maternal HFD increased dam and pup serum PFAS levels, however, was protective against PFOA-induced increase in serum ALT and observed increases in liver triglycerides. The PFAS mixture had very distinct effects when compared to single compound treatment, suggesting some cumulative effects, particularly when evaluating PFAS transfer from dam to pup. This data highlights the importance of diet and mixtures when evaluating liver effect of PFAS and PFAS partitioning.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) and PFAS Mixtures with Incident Hypertension: the Study of Women’s Health Across the Nation 1999-2017

BACKGROUND AND AIM: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure may cause a variety of hypertension-inducing pathophysiological responses. However, the one epidemiologic study that has examined PFAS and hypertension incidence in adults reported no significant associations. This study aimed to examine the associations between PFAS and incident hypertension. METHODS: This study included 1,058 midlife women free of hypertension from the multi-racial/ethnic Study of Women’s Health Across the Nation (SWAN) Multi-Pollutant Study with approximately annual follow-up visits between 1999 and 2017. Baseline serum PFAS concentrations were quantified by high-performance liquid chromatography-isotope dilution-tandem mass spectrometry. Hypertension was defined as blood pressure ≥140 mmHg systolic or ≥90 mmHg diastolic or receiving anti-hypertensive treatment. Cox proportional hazards (PH) model were utilized to calculate hazards ratios (HR) and 95% confidence intervals (CI) with adjustment for race/ethnicity, study site, educational attainment, financial strain, smoking status, passive smoking, alcohol consumption, total calorie intake, menopausal status, and body mass index. Elastic net-penalized Cox PH regression was implemented to model PFAS mixtures and construct an integrative index, environmental risk score (ERS), to evaluate the joint effect of PFAS mixtures. RESULTS:During 11,843 person-years of follow-up, 470 participants developed incident hypertension. Compared with the lowest tertile, women in the highest tertile of baseline serum concentrations had adjusted HRs of 1.36 (95% CI: 1.08-1.73) for total perfluorooctane sulfonate (PFOS) (P-trend=0.01), 1.31 (95% CI: 1.03-1.67) for linear perfluorooctanoate (n-PFOA) (P-trend=0.01), and 1.37 (95% CI: 1.07-1.75) for 2-(N-ethyl-perfluorooctane sulfonamido) acetate (EtFOSAA) (P-trend=0.01). No significant associations were observed for perfluorononanoate (PFNA) and perfluorohexane sulfonate (PFHxS). In the mixture analysis, women in the highest tertile of ERS had an HR of 1.53 (95% CI: 1.20-1.96) (P-trend=0.0008), compared with those in the lowest tertile. CONCLUSIONS:Our findings suggest an association between PFAS and incident hypertension. PFAS may be an underappreciated contributing factor to women’s cardiovascular disease risk. KEYWORDS: PFAS, Mixtures, Mixture analysis, Cardiovascular diseases

Non-targeted metabolomics in evaluating alterations associated with per-fluoroalkyl and polyfluoroalkyl substances (PFAS) exposure in human studies: a scoping review

BACKGROUND AND AIM: Non-targeted metabolomics has been incorporated into recent epidemiological studies to investigate metabolic mechanisms underlying adverse health effects of per-fluoroalkyl and polyfluoroalkyl substances (PFAS) exposure. The purpose of this review is to summarize the application of non-targeted metabolomics in epidemiological studies that assessed metabolite and metabolic pathway alterations associated with PFAS exposure. METHODS: We performed a scoping review of human studies that conducted non-targeted metabolomics and PFAS analyses including original articles published in PubMed before March 1, 2021. We summarized the study characteristics and the metabolites and metabolic pathways reported to be associated with PFAS exposure. RESULTS:Nine human studies published between 2018 to 2021 were identified. The study sample ranged from 40 to 965 participants, including children and adolescents (n=3), adults (n=3), or pregnant women (n=3). Health outcomes involved included non-alcoholic liver, type 2 diabetes and other cardiometabolic outcomes. Liquid chromatography–mass spectrometry was the primary analytical platform for PFAS measurement and non-targeted metabolomics. PFAS levels were measured in plasma (n=5) or serum (n=4), while the metabolomic profiles were generated in plasma (n=5), serum (n=3), or urine (n=1). The most studied PFAS compounds were PFOS (n=9), PFOA (n=8), PFHxS (n=8), PFNA (n=5), and PFAS mixtures (n=4). Among seven studies that conducted pathway enrichment analysis, the most commonly reported metabolic pathways affected by multiple PFAS compounds were lipid metabolism, including glycerophospholipid, glycosphingolipid, and linoleate metabolism, followed by amino acid-related pathways, such as urea cycle/amino group metabolism, alanine and aspartate metabolism, and beta-alanine metabolism. Other reported metabolomics alterations possibly associated with PFAS include carbohydrate-related metabolism, xenobiotic (drug) related metabolism, and vitamin metabolism. CONCLUSIONS:Multiple PFAS exposures were associated with alterations to lipid- or amino acid-related metabolism in human studies that used non-targeted metabolomics. Whether these PFAS-associated biological changes lead to adverse health risks requires further research. KEYWORDS: PFAS, Metabolomics, Chemical exposures, Obesity and metabolic disorders

Associations of Perfluoroalkyl and Polyfluoroalkyl Substances (PFAS) and PFAS Mixtures with Adipokines in Midlife Women

BACKGROUND AND AIM: Perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure have been associated with obesity and related comorbidities. However, underlying mechanisms are not well understood. We determined if serum PFAS concentrations were associated with adipokine profiles in midlife women. METHODS: We examined 1,245 women aged 45-56 years from the Study of Women’s Health Across the Nation. Concentrations of 11 PFAS were quantified in baseline serum samples collected in 1999-2000. Linear and branched perfluorooctane sulfonic acid isomers (n-PFOS and Sm-PFOS) and their sum (PFOS), linear perfluorooctanoic acid (n-PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (MeFOSAA), and 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid (EtFOSAA) with detection frequencies 60% were included in the analysis. Adipokines including leptin, soluble leptin receptor (sOB-R), free leptin index (FLI, the ratio of leptin to sOB-R), total and high molecular weight (HMW) adiponectin were assessed in 2002-2003. We utilized multivariable linear regressions and Bayesian kernel machine regression (BKMR) to assess individual and overall joint effects of PFAS on adipokines with adjustment for age, race/ethnicity, study site, education, smoking status, physical activity, menopausal status, and waist circumference. RESULTS:A doubling of PFAS concentrations was associated with 7.8% (95% CI: 2.5%, 13.4%) higher FLI for PFOS, 9.4% (95% CI: 3.7%, 15.3%) for n-PFOA, 5.5% (95% CI: 2.2%, 9.0%) for EtFOSAA and 7.4% (95% CI: 2.8%, 12.2%) for MeFOSAA. Similar associations were found for leptin. Only EtFOSAA was associated with lower sOB-R concentrations (1.4% lower, 95% CI: -2.7%, -0.1%). In BKMR analysis, women with PFAS concentrations at the median and the 90th percentile had 30.9% (95% CI: 15.6%, 48.3%) and 52.1% (95% CI: 27.9%, 81.0%) higher FLI, respectively, compared with those with concentrations fixed at the 10th percentile. CONCLUSIONS:Some PFAS may alter circulating levels of leptin. Understanding associations between PFAS and adipokines may help elucidate whether PFAS can influence obesity and metabolic disease. KEYWORDS: PFAS, Mixtures, Mixture analysis, Obesity and metabolic disorders

Prenatal exposure to mixtures of endocrine-disrupting chemicals and autism spectrum disorder

BACKGROUND AND AIM: Mixtures methods have the potential to address the unclear relationship between prenatal exposure to endocrine-disrupting chemicals (EDCs) and risk of autism spectrum disorder (ASD). However, mixtures studies in this area are currently sparse. This study examines the relationship of prenatal exposure to a mixture of 25 EDCs, representing 4 classes of persistent pollutants, and ASD. METHODS: We analyzed data from the Early Markers for Autism (EMA) Study, a population-based, case-control study of children born during 2000-2003 in Southern California. Children diagnosed with ASD (n=491) were identified from clinical records of the Department of Developmental Services and were confirmed by expert review. General population (GP) controls (n=373) were randomly sampled from birth certificate files and frequency matched to children with ASD by sex, birth month, and birth year. Eleven polychlorinated biphenyls (PCBs), 6 brominated flame retardants (BFRs), 2 organochlorine pesticides (OCPs), and 6 polyfluoroalkyl substances (PFAS) were detectable in maternal serum samples collected during the second trimester. To examine the relationship between ASD and EDC mixtures, both within each chemical subclass and across all EDCs, we applied two METHODS: weighted quantile sums regression (WQSR) with repeated-holdout validation and Bayesian kernel machine regression (BKMR). RESULTS:In WQSR adjusted for covariates, PCB, PFAS, and BFR mixtures were not associated with ASD when constrained to the positive direction, but BFRs were associated with ASD in the negative direction (aOR: 0.82; 95%CI: 0.71, 0.95 per quartile increase). Results from BKMR were generally consistent with WQSR, with PBDE 153 contributing the most to both BFR mixture models. WQSR and BKMR analyses showed null associations between the aggregate EDC mixture and ASD. BKMR analyses did not indicate interaction between any of the EDC biomarkers. CONCLUSIONS:Results suggest that prenatal exposure to the mixture of these EDCs is not adversely associated with overall ASD risk. KEYWORDS: autism, mixtures, endocrine-disrupting compounds, prenatal

Exposure to Multiple Per- and Polyfluoroalkyl Substances In Relation To Thyroid Function Among Adolescents and Young Adults from NHANES 2011-2012

BACKGROUND AND AIM: Per- and polyfluoroalkyl substances (PFASs) are persistent chemicals with a wide range of industrial applications, measured in human serum samples. Experimental studies have identified PFASs as endocrine disrupting chemicals and epidemiological studies suggest that PFASs can affect normal thyroid function in humans. We investigated the association between exposure to mixtures of serum PFASs and changes in serum thyroid hormone levels among 12 to 20 year olds. METHODS: Using data from the NHANES 2011-2012 cycle, we employed principal component analysis (PCA) and identified three factors, describing mixtures of PFASs. Using multivariable linear regression models, we estimated associations between exposure to PFAS mixtures and changes in serum thyroid hormone concentrations. RESULTS:Factor 1 was characterized by carboxylates, comprising of PFUnA, PFDA, and PFNA, Factor 2 was described by sulfonates which included PFHxS, PFOS, PFA, and MeFOSAA and Factor 3 was described PFHpA alone. Greater exposure to Factor 1 PFASs was associated with an overall increase in free T4, TSH, and thyroid peroxidase antibodies levels, without any statistical significance. Exposure to Factor 2 PFASs was associated with an overall decrease in free T3, total T3, free T4, and total T4 levels. Factor 3 resulted in an increase in most of the serum thyroid hormone levels with the exception of thyroglobulin and thyroglobulin antibodies levels. CONCLUSIONS:Our results suggest the importance of modeling the effects of exposure to a mixture of PFASs simultaneously. The findings of this analysis can better inform researchers and policy makes on which PFASs behave analogously or inversely in an effort to better assess the effect PFASs may have on health effects. KEYWORDS: biomarkers, chemical mixtures, endocrine disruptors, polyfluoroalkyl substances, thyroid function

Early-life exposure to perfluoroalkyl substances in relation to serum adipokines in a longitudinal birth cohort

BackgroundPer- and polyfluoroalkyl substances (PFAS) exposure has been linked to metabolic health outcomes such as obesity, and changes in adipokine hormones may be one of the underlying biological mechanisms. We prospectively evaluated the associations between prenatal and early childhood exposures to PFASs and adipokines in children. Material and methodsPFAS concentrations were measured in serum samples collected at birth, 18 months, and 5 and 9 years, and adiponectin, leptin, leptin receptor, and resistin were measured in serum samples collected at birth and 9 years. We used multivariable linear regression models to estimate the percent change in serum-adipokine concentrations for a doubling in serum-PFAS concentrations. The potential sex-specific effect of PFAS was assessed by including an interaction term between PFAS and sex in each model. Bayesian kernel machine regression (BKMR) was implemented to evaluate the overall effect of PFAS mixtures. ResultsSignificant associations with leptin, leptin receptor, and resistin at age 9 years were observed for serum-PFAS concentrations at 18 months and 5 and 9 years, whereas associations for PFAS concentrations at birth were mostly null. However, we observed a positive association between serum-PFHxS at birth and leptin receptor at birth. We found limited evidence regarding modification effect of sex on serum-PFAS concentrations. BKMR findings were consistent and suggested some significant effects of the overall PFAS mixtures at 18 months and 5 and 9 years on adipokine concentrations at 9 years. ConclusionsGiven the associations of PFAS exposure with both adipokine hormones and metabolic functions, future studies should include assessment of adipokine hormones when examining PFAS-associated metabolic alterations.

Sonolytic destruction of Per- and polyfluoroalkyl substances in groundwater, aqueous Film-Forming Foams, and investigation derived waste

Per- and polyfluoroalkyl substances (PFASs) are anthropogenic amphipathic heat-resistant materials found in some household products and Aqueous Film-Forming Foams (AFFFs) used to extinguish hydrocarbon fires. There is a critical need for developing destructive technologies for the treatment of PFAS-impacted waters because several PFASs are classified as probable carcinogens and endocrine disruptors. We tested the destruction of 7 individual PFASs, a mix of 24 native PFASs (24Mix), and samples of AFFF and concentrated Investigation Derived Waste (IDW) by high-frequency ultrasound (700 kHz – 1040 W) in deionized water, groundwater containing low total dissolved solids (TDS) (388 mg L−1), and high-TDS groundwater (10.2 g L−1). This study demonstrated the degradation of novel PFASs, hexafluoropropylene oxide dimer acid (HFPO-DA) and 6:2 fluorotelomer sulfonamidoalkyl betaine (6:2 FTAB), with near-stoichiometric fluoride release. The salts and surfactants affect the air-water partitioning coefficients of PFASs and their availability at the ultrasonic cavity, thereby affecting the degradation rates. The degradation rates of sulfonates and short-chain PFASs were 30% to 60% higher in low TDS groundwater than those in deionized water, while the rates were lower in high TDS groundwater. The degradation rates of sulfonates in AFFF were 40% to 60% higher as compared to the 24Mix. The treatment of concentrated, high-TDS IDW resulted in significant defluorination of 41 PFASs, consuming 3 kWh g−1 – 76 kWh g−1 whereas dilute AFFF degradation utilized 5900 kWh g−1. The results inform important parameters for designing and operating ultrasonic reactors for the degradation of PFASs and verify that sonolytic treatment of concentrated PFAS mixtures and AFFF IDWs can effectively degrade and defluorinate PFASs without the formation of disinfection by-products.

Combined effects of mixed per- and polyfluoroalkyl substances on the Nrf2-ARE pathway in ARE reporter-HepG2 cells

Although the Nrf2-ARE pathway plays a critical role in cellular protection against toxicity and oxidative stress from environmental chemical stressors, the association between exposure to per- and polyfluoroalkyl substances (PFAS) mixtures and the changes of Nrf2-ARE pathway remains largely unexplored. This study evaluated the potential of PFAS to induce the Nrf2-ARE pathway as individual compounds and as binary, ternary, and multicomponent mixtures in the ARE reporter-HepG2 cells and compared the mixture toxicity data to the predictions by concentration addition (CA) model. The toxicological interactions between PFAS mixture components were also determined by the model deviation ratio (MDR) between the CA predicted and mixture toxicity values. The induction of the Nrf2-ARE pathway was quantified using the luciferase system, and the endpoint assessed was the concentration that induced an induction ratio (IR) of 1.5 (ECIR1.5). The results showed that exposures to both individual and mixed PFAS induced the Nrf2-ARE pathway in ARE reporter-HepG2 cells. Based on the MDRs, the combinations with PFOS showed synergistic interactive effects, while the combinations with PFOA showed additive effects. These results indicate that the CA model underestimated the mixture toxicity of PFAS with PFOS co-exposures and may have health risk assessment implications.

Perfluoroalkyl Substance Exposure and the BDNF Pathway in the Placental Trophoblast.

BackgroundPer- and polyfluoroalkyl substances (PFAS) are persistent organic pollutants that have become globally ubiquitous in humans and the environment. In utero PFAS exposure is associated with neurodevelopmental effects; however, the mechanism is poorly understood. Brain-derived neurotrophic factor (BDNF) signaling is critical to fetal neurodevelopment during pregnancy and maintains important regulatory roles later in life. This study aims to characterize placental BDNF signaling and investigate whether PFAS exposure disrupts the signaling pathway in placental trophoblast cells.MethodsThe expression and localization of BDNF receptors–p75NTR and TrkB–in first trimester and term human placentas and trophoblast cells were investigated by immunofluorescence staining. To assess the effects of PFAS exposure on the BDNF pathway, BeWo cells were treated with PFAS mixtures that mimicked blood levels in a highly exposed population and major PFAS compounds in the mixture at 0.01, 0.1, 1, and 10 µM concentrations. Changes in pro-BDNF levels and phosphorylation of TrkB receptors were examined by Western blot.ResultsIn first trimester human placentas, TrkB and p75NTR receptors were primarily localized to syncytiotrophoblast and cytotrophoblast cells. At term, TrkB and p75NTR receptors were primarily observed in the placental villous stroma. TrkB receptor staining in trophoblasts was reduced at term, while p75NTR receptor staining was negative. TrkB receptors were confined to the nuclear and perinuclear spaces, and phosphorylation occurred at the Tyr816 residue in BeWo cells. Exposure to PFOS, PFOA, PFBS, and the six-PFAS mixture did not significantly affect BDNF levels or activation (phosphorylation) of TrkB. Treating cells with 1 μM and 10 μM of PFNA resulted in increased TrkB phosphorylation compared to unexposed controls, but BDNF levels were unchanged.ConclusionsBDNF receptors are present in different regions of human placental villi, indicating diverse functions of BDNF signaling in placental development. Our findings suggest that the BDNF pathway in placental trophoblast cells is not disrupted by exposures to PFOS, PFOA, PFBS, and a PFAS mixture, but may be affected by PFNA exposures. Further investigation is needed on how PFAS affects other critical signaling pathways during fetal neurodevelopment.

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and associations with attention-deficit/hyperactivity disorder and autism spectrum disorder in children

BackgroundPrenatal exposure to per- and polyfluoroalkyl substances (PFAS) may be a risk factor for neurodevelopmental deficits and disorders, but evidence is inconsistent. ObjectivesWe investigated whether prenatal exposure to PFAS were associated with childhood diagnosis of attention-deficit/hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). MethodsThis study was based on the Norwegian Mother, Father and Child Cohort Study and included n = 821 ADHD cases, n = 400 ASD cases and n = 980 controls. Diagnostic cases were identified by linkage with the Norwegian Patient Registry. In addition, we used data from the Medical Birth Registry of Norway. The study included the following PFAS measured in maternal plasma sampled mid-pregnancy: Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroundecanoic acid (PFUnDA), perfluorohexane sulfonate (PFHxS), perfluoroheptanesulfonic acid (PFHpS), and perfluorooctane sulfonate (PFOS). Relationships between individual PFAS and ADHD or ASD diagnoses were examined using multivariable adjusted logistic regression models. We also tested for possible non-linear exposure-outcome associations. Further, we investigated the PFAS mixture associations with ASD and ADHD diagnoses using a quantile-based g-computation approach. ResultsOdds of ASD was significantly elevated in PFOA quartile 2 [OR = 1.71 (95% CI: 1.20, 2.45)] compared to quartile 1, and PFOA appeared to have a non-linear, inverted U-shaped dose-response relationship with ASD. PFOA was also associated with increased odds of ADHD, mainly in quartile 2 [OR = 1.54 (95% CI: 1.16, 2.04)] compared to quartile 1, and displayed a non-linear relationship in the restricted cubic spline model. Several PFAS (PFUnDA, PFDA, and PFOS) were inversely associated with odds of ADHD and/or ASD. Some of the associations were modified by child sex and maternal education. The overall PFAS mixture was inversely associated with ASD [OR = 0.76 (95% CI: 0.64, 0.90)] as well as the carboxylate mixture [OR = 0.79 (95% CI: 0.68, 0.93)] and the sulfonate mixture [OR = 0.84 (95% CI: 0.73, 0.96)]. ConclusionPrenatal exposure to PFOA was associated with increased risk of ASD and ADHD in children. For some PFAS, as well as their mixtures, there were inverse associations with ASD and/or ADHD. However, the inverse associations reported herein should not be interpreted as protective effects, but rather that there could be some unresolved confounding for these relationships. The epidemiologic literature linking PFAS exposures with neurodevelopmental outcomes is still inconclusive, suggesting the need for more research to elucidate the neurotoxicological potential of PFAS during early development.

Invited Perspective: PFAS Bioconcentration and Biotransformation in Early Life Stage Zebrafish and Its Implications for Human Health Protection.

Invited Perspective: PFAS Bioconcentration and Biotransformation in Early Life Stage Zebrafish and Its Implications for Human Health Protection.

Associations of perfluoroalkyl and polyfluoroalkyl substances (PFAS) and PFAS mixtures with adipokines in midlife women.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure have been associated with obesity and related comorbidities, possibly through disrupting signaling pathways of adipokines. Both leptin and adiponectin can modulate metabolic processes. However, the effects of PFAS on adipokines are not well understood. We determined if serum PFAS concentrations were associated with adipokine profiles in midlife women. We examined 1245 women aged 45-56 years from the Study of Women's Health Across the Nation. Concentrations of 11 PFAS were quantified in baseline serum samples collected in 1999-2000. Linear and branched perfluorooctane sulfonic acid isomers (n-PFOS and Sm-PFOS) and their sum (PFOS), linear perfluorooctanoic acid (n-PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (MeFOSAA), and 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid (EtFOSAA) with detection frequencies >60% were included in the analysis. Adipokines including leptin, soluble leptin receptor (sOB-R), free leptin index (FLI, the ratio of leptin to sOB-R), total and high molecular weight (HMW) adiponectin were assessed in 2002-2003. We utilized multivariable linear regressions and Bayesian kernel machine regression (BKMR) to assess individual and overall joint effects of PFAS on adipokines with adjustment for age, race/ethnicity, study site, education, smoking status, physical activity, menopausal status, and waist circumference. A doubling of PFAS concentrations was associated with 7.8% (95% CI: 2.5%, 13.4%) higher FLI for PFOS, 9.4% (95% CI: 3.7%, 15.3%) for n-PFOA, 5.5% (95% CI: 2.2%, 9.0%) for EtFOSAA and 7.4% (95% CI: 2.8%, 12.2%) for MeFOSAA. Similar associations were found for leptin. Only EtFOSAA was associated with lower sOB-R concentrations (-1.4%, 95% CI: -2.7%, -0.1%). Results remained in women with overweight or obesity but not those with normal weight or underweight. No statistically significant associations were observed with total or HMW adiponectin, except for PFNA with total and HMW adiponectin observed in women with normal weight or underweight. In BKMR analysis, women with PFAS concentrations at the median and the 90th percentile had 30.9% (95% CI: 15.6%, 48.3%) and 52.1% (95% CI: 27.9%, 81.0%) higher FLI, respectively, compared with those with concentrations fixed at the 10th percentile. Some PFAS may alter circulating levels of leptin. Understanding associations between PFAS and adipokines may help elucidate whether PFAS can influence obesity and metabolic disease.

Considerations for toxicity experiments and risk assessments with PFAS mixtures.

Per- and polyfluoroalkyl substances (PFAS) have been around for decades and have been the subject of laboratory and field research studies for nearly as long. Although attention to PFAS has grown in recent years, many unanswered questions remain. Accordingly, the number of research projects designed to improve our understanding of PFAS toxicity, bioaccumulation, and biomagnification, and to improve our ability to predict the interactions of PFAS mixtures, is also increasing. The growing number of ongoing and future research projects focusing on these chemicals will benefit from lessons learned in previous studies. This perspectives article discusses available approaches to mixture risk assessment with specific focus on application to PFAS mixtures. We discuss ongoing research as well as lessons learned from approaches to handling mixtures of other groups of chemicals. Many of these approaches require some detailed understanding of a manageable number of representative chemicals, yet only limited toxicological data are available for most PFAS. With the limited amount of published data currently available, the need for single-chemical and binary-mixture studies persists. Based on our previous work with single-chemical exposures for understudied PFAS, we explored some of the challenges of trying to design and interpret an aquatic concentration-response experiment for a binary mixture of two commonly detected PFAS: perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonic acid (PFHxS). Based on our findings, we propose that addressing risk from PFAS mixtures will likely require combinations of approaches incorporating findings from traditional whole-organism toxicity studies and novel methods relying on in vitro assays, read-across, or quantitative structure activity relationships. Complicating a limited understanding of PFAS mixture toxicity is that relative concentrations of PFAS mixtures vary across sites and time, even at one site. Thus, reliance on empirical data, such as site-specific toxicity sampling or community structure studies, may be needed to fully understand potential impacts of mixtures. Integr Environ Assess Manag 2021;17:697-704. © 2021 SETAC.

Exposure to novel and legacy per- and polyfluoroalkyl substances (PFASs) and associations with type 2 diabetes: A case-control study in East China.

Associations between per- and polyfluoroalkyl substances (PFASs) and the incidence of type 2 diabetes are controversial in epidemiological studies. In addition, limited data are available for assessing the health effects of novel PFAS alternatives. Our study evaluated the effects of PFAS exposure on type 2 diabetes by estimating the associations of PFASs in human serum with the risk of type 2 diabetes and levels of glycemic biomarkers and lipid fractions. The case-control study consisted of 304 participants from Shandong Province, East China, half of which were diagnosed with type 2 diabetes. Logistic regression showed that most PFASs were inversely associated with the risk of type 2 diabetes after adjusting for age, sex, and body mass index. However, concentrations of perfluorooctanoic acid (PFOA) in the control group were positively associated with fasting plasma glucose levels (β=0.04, 95% confidence interval (CI): 0.0003, 0.08), which may promote the development of type 2 diabetes. Furthermore, each log-unit increase in the concentrations of perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUnDA), and 6:2 chlorinated polyfluoroalkyl ether sulfonic acid (Cl-PFESA) were associated with a total cholesterol increase (i.e., 17.49% (95% CI: 0.93%, 34.90%), 17.49% (95% CI: 4.71%, 31.83%), and 17.49% (95% CI: 4.71%, 31.83%), respectively). Positive associations were also observed between PFNA, PFUnDA, perfluorooctane sulfonate (PFOS), and 6:2 Cl-PFESA and low-density lipoprotein cholesterol. However, no associations between PFASs and hemoglobin A1c, triglycerides, or high-density lipoprotein cholesterol reached statistical significance, nor associations between PFAS mixtures and outcomes of interest. In conclusion, the significant correlations between serum PFASs and glycemic biomarkers and lipid fractions indicated that PFAS exposure may be a potential diabetogenic factor. To the best of our knowledge, this is the first study to assess the associations between novel Cl-PFESAs and type 2 diabetes, although the inverse associations observed require clarification in future studies.