Polyfluoroalkyl Substances Mixtures Research Articles

Mid-Childhood Plasma Concentrations of Per- and Polyfluoroalkyl Substances, Modifiable Lifestyle Factors, and Bone Mineral Density Through Late Adolescence.

There is limited research on associations of per- and polyfluoroalkyl substances (PFAS) with areal bone mineral density (aBMD) through adolescence and whether bone-strengthening factors ameliorate effects. In the Project Viva cohort (N = 484; 50% female), we used sex-stratified linear regression and quantile g-computation mixture models to examine associations of mid-childhood (median: 7.8 years; 2007-2010) plasma PFAS concentrations with a dual-energy X-ray absorptiometry total-body aBMD Z-score in early and late adolescence (median: 12.9 and 17.6 years, respectively). We explored stratum-specific estimates by parent/self-reported physical activity and dairy intake. Using linear mixed models, we evaluated associations with aBMD accrual from mid-childhood through late adolescence. Females with higher perfluorooctanoate (PFOA) and perfluorodecanoate (PFDA) had lower early adolescent aBMD Z-score [e.g., β(95%CI)] per doubling PFOA: -0.19(-0.41, 0.03)]. Youth with higher PFOA and PFDA had lower late adolescent aBMD Z-score, but CIs were wide [e.g., PFOA: females, -0.12(-0.40, 0.16); males, -0.10(-0.42, 0.21)]. Mixture models generally corroborated single PFAS results, and in linear mixed models, females with higher PFAS concentrations, and males with higher PFOA, had slower aBMD accrual. Less active males with higher PFOA, PFDA, and the PFAS mixture had lower late adolescent aBMD Z-score. Some PFAS appeared more negatively associated with the aBMD Z-score among those who consumed less dairy, but there was not consistent evidence of effect modification. Exposure to select PFAS may affect bone accrual through adolescence, with possible resilience conferred by greater physical activity and dairy intake.

Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and their influence on inflammatory biomarkers in pregnancy: Findings from the LIFECODES cohort

BackgroundPer- and polyfluoroalkyl substances (PFAS) are fluorinated chemicals linked to adverse pregnancy and birth outcomes. However, the underlying mechanisms, specifically their effects on maternal inflammatory processes, are not well characterized. ObjectiveWe examined associations between prenatal PFAS exposure and repeated measures of inflammatory biomarkers, including C-reactive protein (CRP) and four cytokines [Interleukin-10 (IL-10), IL-1β, IL-6, and tumor necrosis factor-α (TNF-α)]. MethodsWe analyzed data from 469 pregnant women in a nested case-control study of preterm birth at Brigham and Women’s Hospital in Boston, Massachusetts (2006–2008). We measured nine PFAS in early pregnancy plasma samples (median gestation: 10 weeks), with inflammatory biomarkers measured at median gestations of 10, 18, 26, and 35 weeks. We used linear mixed effects models for repeated measures and multivariable regression for visit-specific analysis to examine associations between each PFAS and inflammation biomarker, adjusting for maternal demographics, pre-pregnancy BMI, and parity. We examined PFAS mixture effects using sum of all PFAS (∑PFAS) and quantile-based g-computation approaches. ResultsWe observed consistent inverse associations between most PFAS and cytokines, specifically IL-10, IL-6, and TNF-α, in both single pollutant and mixture analyses. For example, an interquartile range increase in perfluorooctanesulfonic acid was associated with −10.87 (95% CI: −19.75, −0.99), −13.91 (95% CI: −24.11, −2.34), and −8.63 (95% CI: −14.51, −2.35) percent change in IL-10, IL-6, and TNF-α levels, respectively. Fetal sex, maternal race, and visit-specific analyses showed associations between most PFAS and cytokines were generally stronger in mid-pregnancy and among women who delivered males or identified as African American. ConclusionsThe observed suppression of both regulatory (IL-10) and pro-inflammatory (TNF-α) cytokines suggests that PFAS may alter maternal inflammatory processes or immune functions during pregnancy. Further research is needed to understand the effects of both legacy and newer PFAS on inflammatory pathways and their broader clinical implications.

Transport and competitive interfacial adsorption of PFOA and PFOS in unsaturated porous media: Experiments and modeling

Among emerging contaminants, per- and polyfluoroalkyl substances (PFAS) have captured public attention based upon their environmental ubiquity and potential risks to human health. Due to their typical surface release conditions and amphiphilic properties, PFAS tend to sorb to soil and accumulate at the air-water interface within the vadose zone. These processes can result in substantial plume attenuation. Although there is a growing body of literature on vadose zone transport, few studies have explored PFAS mixture transport, particularly under conditions where nonlinear sorption processes are important. The present study aims to advance our understanding of PFAS transport in variably saturated porous media through integration of experiments and mathematical modeling. Experiments include batch studies to quantify sorption to the solid phase, interfacial tension (IFT) measurements to estimate adsorption at the air-water interface (AWI), and column studies with F-70 Ottawa sand at 100 % and ca. 50 % water saturation to explore transport mechanisms. Employed PFAS solutions encompass individual solutes and binary mixtures of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) at concentration levels spanning four orders of magnitude to assess competitive and nonlinear sorption at the AWI. Observations demonstrate that concentration levels and competitive effects substantially influence PFAS transport in unsaturated systems. In the presence of PFOS, PFOA experienced less retention than would be anticipated based on single-solute behavior, and effluent breakthrough curves exhibited chromatographic peaking. The presented mathematical model for simultaneous flow and transport of PFAS was able to capture experimental observations with a consistent set of parameters and minimal curve fitting. These results demonstrate the robustness of the model formulation that included rate-limited interfacial mass transfer, an extended Langmuir-Szyszkowski model for adsorption at the AWI, and a scaled Leverett thermodynamic model to predict the AWI specific area. Overall, the results of this work underscore the importance of the AWI in PFAS transport and highlight the relevance of competition effects in adsorption formulations.

Per and poly-fluoroalkyl substances and respiratory health in an Inuit community

BackgroundConcentrations of plasma per and poly-fluoroalkyl substances (PFAS) are elevated in the Inuit population of Nunavik and may be causing adverse health effects. Respiratory health outcomes have been associated with PFAS, but have not been explored in Inuit communities. The aim of the study was to examine the association between PFAS and respiratory health outcomes, and the moderating role of nutritional biomarkers.MethodsWe included up to 1298 participants of the Qanuilirpitaa? 2017 survey aged 16–80 years. Generalized regression models were used to estimate the associations between six individual PFAS congeners and four self-reported symptoms, four spirometry measures, and physician-diagnosed asthma. Outcomes associated with PFAS from single chemical models were further explored using Bayesian Kernel Machine Regression (BKMR). The modifying effect of n-3 PUFA in red blood cell quartiles and vitamin D deficiency were examined on the associations between PFAS and respiratory outcomes.ResultsPFNA and PFOS were associated with asthma (odds ratio (OR) 1.61, 95% confidence interval (CI) 1.12, 2.32; OR 1.45 95% CI 1.04, 2.03). PFOA, PFNA, PFDA and PFHxS were associated with a decrease in the ratio between the forced expiratory volume in the first second and forced vital capacity (FEV1/FVC). No associations were observed with self-reported respiratory symptoms. No associations were observed between a PFAS mixture and asthma. Some associations were modified by nutritional factors, namely, stronger associations between PFOA and PFHxS and asthma with lower n-3 PUFA levels and stronger associations between PFDA, PFUnDA and PFOS and FEV1/FVC with vitamin D deficiency.ConclusionThese findings add to the growing literature on the impacts of PFAS on respiratory health, and the importance of their global regulation. Associations were modified by nutritional factors pointing to the nutritional value of traditional Inuit foods.

Exposure to PFOA, PFOS, and PFHxS induces Alzheimer's disease-like neuropathology in cerebral organoids

Per- and polyfluoroalkyl substances (PFASs), a class of ubiquitous synthetic organic chemicals, are widely utilized across various industrial applications. However, the long-term neurological health effects of PFAS mixture exposure in humans remain poorly understood. To address this gap, we have designed a comprehensive study to predict and validate cell-type-specific neurotoxicity of PFASs using single-cell RNA sequencing (scRNA-seq) and cerebral organoids. Cerebral organoids were exposed to a PFAS mixture at concentrations of 1 × (10 ng/ml PFOS and PFOA, and 1 ng/ml PFHxS), 30 × , and 900 × over 35 days, with a follow-up analysis at day 70. Pathological alterations and lipidomic profiles were analyzed to identify disrupted molecular pathways and mechanisms. The scRNA-seq data revealed a significant impact of PFASs on neurons, suggesting a potential role in Alzheimer's Disease (AD) pathology, as well as intellectual and cognitive impairments. PFAS-treated cerebral organoids exhibited Aβ accumulation and tau phosphorylation. Lipidomic analyses further revealed lipid disturbances in response to PFAS mixture exposure, linking PFAS-induced AD-like neuropathology to sphingolipid metabolism disruption. Collectively, our findings provide novel insights into the PFAS-induced neurotoxicity, highlighting the significance of sphingolipid metabolism in the development of AD-like neuropathology. The use of cerebral organoids and scRNA-seq offers a powerful methodology for evaluating the health risks associated with environmental contaminants, particularly those with neurotoxic potential.

Prenatal exposure to per- and polyfluoroalkyl substances, fetoplacental hemodynamics, and fetal growth

IntroductionThe impact of legacy per- and polyfluoroalkyl substances (PFAS) on fetal growth has been well studied, but assessments of next-generation PFAS and PFAS mixtures are sparse and the potential role of fetoplacental hemodynamics has not been studied. We aimed to evaluate associations between prenatal PFAS exposure and fetal growth and fetoplacental hemodynamics. MethodsWe included 747 pregnant women from the BiSC birth cohort (Barcelona, Spain (2018–2021)). Twenty-three PFAS were measured at 32 weeks of pregnancy in maternal plasma, of which 13 were present above detectable levels. Fetal growth was measured by ultrasound, as estimated fetal weight at 32 and 37 weeks of gestation, and weight at birth. Doppler ultrasound measurements for uterine (UtA), umbilical (UmA), and middle cerebral artery (MCA) pulsatility indices (PI), as well as the cerebroplacental ratio (CPR – ratio MCA to UmA), were obtained at 32 weeks to assess fetoplacental hemodynamics. We applied linear mixed effects models to assess the association between singular PFAS and longitudinal fetal growth and PI, and Bayesian Weighted Quantile Sum models to evaluate associations between the PFAS mixture and the aforementioned outcomes, controlled for the relevant covariates. ResultsSingle PFAS and the mixture tended to be associated with reduced fetal growth and CPR PI, but few associations reached statistical significance. Legacy PFAS PFOS, PFHpA, and PFDoDa were associated with statistically significant decreases in fetal weight z-score of 0.13 (95%CI (−0.22, −0.04), 0.06 (−0.10, 0.01), and 0.05 (−0.10, 0.00), respectively, per doubling of concentration. The PFAS mixture was associated with a non-statistically significant 0.09 decrease in birth weight z-score (95%CI −0.22, 0.04) per quartile increase. ConclusionThis study suggests that legacy PFAS may be associated with reduced fetal growth, but associations for next generation PFAS and for the PFAS mixture were less conclusive. Associations between PFAS and fetoplacental hemodynamics warrant further investigation.

Prenatal exposure to per- and polyfluoroalkyl substances and sex-specific associations with offspring adiposity at 10 years of age: Metabolic perturbation plays a role

BackgroundPer- and polyfluoroalkyl substances (PFAS) have been suspected as potential environmental obesogens, with several mechanisms being proposed, including the role of metabolomics. However, current epidemiological studies have yielded inconclusive findings. ObjectivesWe aimed to estimate the associations of prenatal exposure to PFAS with offspring adiposity measures, and to explore the potential metabolic pathways underlying these associations. MethodsA total of 464 mother–child pairs from the Sheyang Mini Birth Cohort Study (SMBCS) were included in this study. Cord serum concentrations of 12 PFAS and urine metabolite profiles at age 10 were obtained from the SMBCS database. Adiposity-related anthropometric measurements and body composition estimates of children aged 10 were used to assess offspring obesity. Multiple linear regression models and quantile g-computation were conducted to estimate the associations of prenatal exposure to individual and multiple PFAS with obesity at 10 years old. Metabolomics analysis was performed to characterize the biological pathways associated with PFAS exposure or obesity, subsequently identifying the overlapping metabolic pathways underlying the PFAS-obesity relationship. ResultsPrenatal exposure to several PFAS was significantly associated with elevated obesity-related markers in 10-year-old children. After stratification by sex, the effects were more pronounced in girls. Quantile g-computation results indicated that exposure to higher levels of PFAS mixtures during pregnancy was associated with increased odds of obesity in girls, with PFNA emerging as the predominant driving compound. Untargeted metabolomics results showed that several amino acid metabolic pathways were characterized as the overlapping pathways underlying the above associations. ConclusionsTaken together, our findings suggested the potential obesogenic effects of prenatal exposure to PFAS and offered insight into the possible metabolic mechanisms underlying PFAS-related offspring obesity.

Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances and childhood bone mineral density: A prospective birth cohort study

Background and aimPerfluoroalkyl and polyfluoroalkyl substances (PFAS) have demonstrated potential toxicity in skeletal development. However, the relationship between prenatal PFAS exposure and offspring bone health remains unclear in epidemiological studies. Therefore, we aim to investigate whether prenatal exposure to PFAS is associated with bone mineral density (BMD) in offspring. MethodThis study population included 182 mother-child pairs in the Shanghai Obesity and Allergy Cohort, enrolled during 2012–2013. 10 PFAS were measured by liquid chromatography-mass spectrometry (LC-MS) in cord plasma. The child's spinal BMD was measured using a dual-energy X-ray absorptiometry (DXA) scanner at the age of 8. Multivariable linear regression models were used to estimate the associations between individual PFAS concentrations (as a continuous variable or categorized into quartiles) and child BMD. Bayesian kernel machine regression (BKMR) was employed to explore the joint effects of PFAS mixtures on BMD. ResultsAmong the 10 PFAS, 8 of them had a detection rate >90% and were included in the subsequent analysis. We observed no significant associations between individual PFAS (as a continuous variable) and spinal BMD in 8-year-old children using the multivariable linear regression model. When treated as quartile categories, the second and fourth quartiles of perfluorobutane sulfonate (PFBS) was associated with higher BMD in the first lumbar vertebra, compared with the lowest quartile. BKMR analysis revealed no association between the PFAS mixture and child BMD. ConclusionWe observed no associations of prenatal PFAS exposure with child BMD at 8 years of age. Given the inconsistent epidemiological evidence, further research is needed to confirm these findings from other studies or elucidate the potentially toxic effects of PFAS on bone.

Applications of mixture methods in epidemiological studies investigating the health impact of persistent organic pollutants exposures: a scoping review.

Persistent organic pollutants (POPs) are environmental chemicals characterized by long half-lives in nature and human bodies, posing significant health risks. The concept of the exposome, encompassing all lifetime environmental exposures, underscores the importance of studying POP as mixtures rather than in isolation. The increasing body of evidence on the health impacts of POP mixtures necessitates the proper application of statisticalmethods. We aimed to summarize studies on the overall effects of POP mixtures, identify patterns in applications of mixture methods-statistical methods for investigating the association of mixtures-and highlight current challenges in synthesizing epidemiologic evidence of POP mixtures on health effects as illustrated through a case study. We conducted a systematic literature search on PubMed and Embase for epidemiological studies published between January 2011 and April 2023. We included 240 studies that met our eligibility criteria. 126 studies focused on per- and polyfluoroalkyl substances (PFAS) mixtures only, while 40 analyzed three or more classes of POPs in mixture analyses. We identified 23 unique mixture methods used to estimate the overall effects of POP mixtures, with Bayesian Kernel Machine Regression (BKMR), a type of response-surface modeling, being the most common. Additionally, 22.9% of studies used a combination of methods, including response-surface modeling, index modeling, dimension reduction, and latent variable models. The most extensively explored health outcome category was body weight and birth sizes (n = 43), and neurological outcomes (n = 41). In the case study of PFAS mixtures and birth weight, 12 studies showed negative associations, while 4 showed null results, and 2 showed positive associations. This scoping review consolidates the existing literature on the overall effects of POP mixtures using statistical methods. By providing a comprehensive overview, our study illuminates the present landscape of knowledge in this field and underscores the methodological hurdles prevalent in epidemiological studies focused on POP mixtures. Through this analysis, we aim to steer future research directions, fostering a more nuanced comprehension of the intricate dynamics involved in assessing the health effects of POP mixtures. Our work stands as a significant contribution to the ongoing exploration of the chemicalexposome.

Prenatal Exposure to Per- and Polyfluoroalkyl Substances and ASD-Related Symptoms in Early Childhood: Mediation Role of Steroids.

Previous studies regarding the associations between perfluoroalkyl and polyfluoroalkyl substances (PFAS) and autism spectrum disorder (ASD) have yielded inconsistent results, with the underlying mechanisms remaining unknown. In this study, we quantified 13 PFAS in cord serum samples from 396 neonates and followed the children at age 4 to assess ASD-related symptoms. Our findings revealed associations between certain PFAS and ASD-related symptoms, with a doubling of perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) concentrations associated with respective increases of 1.79, 1.62, and 1.45 units in language-related symptoms and PFDA exhibiting an association with higher score of sensory stimuli. Nonlinear associations were observed in the associations of 6:2 chlorinated polyfluorinated ether sulfonate (Cl-PFAES) and 8:2 Cl-PFAES with ASD-related symptoms. Employing weighted quantile sum (WQS) regression, we observed significant mixture effects of multiple PFAS on all domains of ASD-related symptoms, with PFNA emerging as the most substantial contributor. Assuming causality, we found that 39-40% of the estimated effect of long-chain PFAS (PFUnDA and PFDoDA) exposure on sensory stimuli was mediated by androstenedione. This study provides novel epidemiological data about prenatal PFAS mixture exposure and ASD-related symptoms.

PFAS Levels, Early Life Factors, and Mammographic Breast Density in Premenopausal Women.

Mammographic breast density (MBD) is a strong risk factor and an intermediate phenotype for breast cancer, yet there are limited studies on how environmental pollutants are associated with MBD. We investigated associations of perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexane sulfonate (PFHxS) levels with measures of MBD and evaluated if early life factors modified any associations. Metabolon performed metabolomics analysis using ultrahigh-performance liquid chromatography/tandem accurate mass spectrometry in fasting blood from 705 premenopausal women completing their annual screening mammogram in St. Louis, Missouri. We calculated least square means (LSM) of mammographic volumetric percent density (VPD), dense volume (DV), and nondense volume (NDV) by quartiles (Q) of PFOS, PFOA, and PFHxS from multivariable linear regression modeling overall and stratified by recruitment period, race, age at menarche, and body shape at age 10. Models were adjusted for age, age at menarche, body fat percentage, race, family history of breast cancer, oral contraceptive use, alcohol consumption, parity/age at first birth, and body shape at age 10. PFOS, PFOA, and PFHxS were not significantly associated with VPD or NDV. PFHxS was significantly positively associated with DV (, , , ; ). PFOS was positively associated with DV (, , , ; ) with DV being 8.1%, 12%, and 12.3% higher in Q2, Q3, and Q4 compared to Q1. Among women who were underweight/normal weight at age 10, PFOS was positively associated with VPD (, , , ; ) while there was an inverse association among women who were overweight/obese at age 10 (, , , ; ) (). We report novel associations of PFHxS and PFOS with DV in premenopausal women. PFOS, PFOA, and PFHxS were not associated with VPD and NDV. In addition, body shape at age 10 may modify the associations of PFOS with MBD. Further studies are needed to validate our findings and to evaluate the associations of other per- and polyfluoroalkyl substances (PFAS), as well as mixtures of PFAS, with MBD. https://doi.org/10.1289/EHP14065.

Maternal Exposure to Per- and Polyfluoroalkyl Substances and Offspring Chromosomal Abnormalities: The Japan Environment and Children's Study.

Although recent in vitro experimental results have raised the question of whether maternal exposure to per- and polyfluoroalkyl substances (PFAS) may be a potential environmental risk factor for chromosomal abnormalities, epidemiological studies investigating these associations are lacking. This study examined whether prenatal PFAS exposure is associated with a higher prevalence of chromosomal abnormalities among offspring. We used data from the Japan Environment and Children's Study, a nationwide birth cohort study, and employed logistic regression models to examine the associations between maternal plasma PFAS concentrations in the first trimester and the diagnosis of chromosomal abnormalities in all births (artificial abortions, miscarriages, stillbirths, and live births) up to 2 years of age. In addition, we examined associations with mixtures of PFAS using multipollutant models. The final sample consisted of 24,724 births with singleton pregnancies, of which 44 confirmed cases of chromosomal abnormalities were identified (prevalence: 17.8/10,000 births). When examined individually, exposure to perfluorononanoic acid (PFNA) and perfluorooctane sulfonic acid (PFOS) showed positive associations with any chromosomal abnormalities with age-adjusted odds ratios of 1.81 (95% CI: 1.26, 2.61) and 2.08 (95% CI: 1.41, 3.07) per doubling in concentration, respectively. These associations remained significant after Bonferroni correction, although they did not reach the adjusted significance threshold in certain sensitivity analyses. Furthermore, the doubling in all PFAS included as a mixture was associated with chromosomal abnormalities, indicating an age-adjusted odds ratio of 2.25 (95% CI: 1.34, 3.80), with PFOS as the predominant contributor, followed by PFNA, perfluoroundecanoic acid (PFUnA), and perfluorooctanoic acid (PFOA). The study findings suggested a potential association between maternal exposure to PFAS, particularly PFOS, and chromosomal abnormalities in offspring. However, the results should be interpreted cautiously, because selection bias arising from the recruitment of women in early pregnancy may explain the associations. https://doi.org/10.1289/EHP13617.

Dissect the association between per- and polyfluoroalkyl substances (PFAS) and kidney function from the perspective of lipid molecules

Per- and polyfluoroalkyl substances (PFAS) have been linked to kidney function. Studies have shown that PFAS can cause changes in lipid metabolism and that lipids play an important role in regulating kidney function. However, few studies have explored the overall impact of PFAS mixture on kidney function. Moreover, the mechanisms by which PFAS influences kidney function remain unclear. This study was performed to investigate the overall impact of PFAS mixture on kidney function indexes, dissect the mechanism by which PFAS affect kidney function by analyzing lipid molecule profiles, and analyze the associations between different subclasses of lipids and kidney function indexes. We measured blood PFAS levels and kidney function indexes in a community population containing 278 males. Metabolomic analysis detected 332 lipid molecules. A quantile-based g-computation model was applied to assess the overall effect of PFAS mixture on kidney function index, and revealed that PFAS mixture were associated with a higher level of uric acid (UA). Linear regression analysis demonstrated a positive association between PFOA and UA, and logistic regression analysis indicated a positive association between PFOA and hyperuricemia odds. Notably, none of the PFAS were associated with the estimated glomerular filtration rate, indicating that PFAS didn't have an obvious effect on glomerular filtration. Further analysis identified 20 lipid molecules associated with both PFOA and UA. High-dimensional mediation effect analysis showed that seven lipid molecules (one glycerophospholipid, three fatty acyls, and three prenol lipids) mediated the association between PFOA and UA. Additionally, quantile-based g-computation analysis revealed positive associations between specific lipid subclasses—mainly fatty acid esters, fatty acids and conjugates, and sesquiterpenoids—and kidney function indexes. Our findings provide insights into the renal toxicity of PFAS and may also lead to more in-depth investigations using animal models and other population studies.

Gestational per- and polyfluoroalkyl substance mixtures in association with birth size and postnatal growth: The New Hampshire Birth Cohort Study

Gestational per- and polyfluoroalkyl substance mixtures in association with birth size and postnatal growth: The New Hampshire Birth Cohort Study

Adolescent exposure to a mixture of per- and polyfluoroalkyl substances (PFAS) depletes the ovarian reserve, increases ovarian fibrosis, and alters the Hippo pathway in adult female mice.

Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals known for their environmental persistence and resistance to biodegradation. This study investigated the impact of adolescent exposure to a PFAS mixture on adult ovarian function. Female CD-1 mice were orally exposed to vehicle control or a PFAS mixture (comprised of perfluorooctanoic acid, perfluorooctanesulfonic acid, undecafluoro-2-methyl-3-oxahexanoic acid, and perfluorobutanesulfonic acid) for 15 d. After a 42-d recovery period, reproductive hormones, ovarian fibrosis, and ovarian gene and protein expression were analyzed using ELISA, Picrosirius red staining, qPCR, and immunoblotting, respectively. Results revealed that PFAS exposure did not affect adult body or organ weight, although ovarian weight slightly decreased. PFAS-exposed mice exhibited a disturbed estrous cycle, with less time spent in proestrus than control mice. Follicle counting indicated a reduction in primordial and primary follicles. Serum analysis revealed no changes in steroid hormones, follicle-stimulating hormone, or anti-Müllerian hormone, but a significant increase in luteinizing hormone was observed in PFAS-treated mice. Ovaries collected from PFAS-treated mice had increased mRNA transcripts for steroidogenic enzymes and fatty acid synthesis-related genes. PFAS exposure also increased collagen content in the ovary. Additionally, serum tumor necrosis factor-α levels were higher in PFAS-treated mice. Finally, transcripts and protein abundance for Hippo pathway components were upregulated in the ovaries of the PFAS-treated mice. Overall, these findings suggest that adolescent exposure to PFAS can disrupt ovarian function in adulthood.

Association of per- and polyfluoroalkyl substances with the antioxidant bilirubin across pregnancy

BackgroundIn mechanistic and preliminary human studies, prenatal exposure to per- and polyfluoroalkyl substances (PFAS) is associated with oxidative stress, a potential contributor to maternal liver disease. Bilirubin is an endogenous antioxidant abundant in the liver that may serve as a physiological modulator of oxidative stress in pregnant people. Hence, our objective was to estimate the association between repeated measures of PFAS and bilirubin during pregnancy. MethodsThe study population included 332 participants in the Atlanta African American Maternal-Child Cohort between 2014 and 2020. Serum samples were collected up to two times (early pregnancy: 6–18 gestational weeks; late pregnancy: 21–36 gestational weeks) for the measurement of perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and total bilirubin. We analyzed single PFAS with linear mixed effect regression and a mixture of the four PFAS with quantile g-computation. Models were repeated with a multiplicative interaction term to explore effect modification by study visit. ResultsOverall, PFHxS was positively associated with bilirubin (β = 0.08, 95 % CI = 0.01, 0.15). We also found during late pregnancy, there was a positive association of PFHxS and the PFAS mixture with bilirubin (β = 0.12, 95 % CI = 0.02, 0.22; ψ = 0.19, 95 % CI = 0.03, 0.34, respectively). Finally, study visit modified the PFOA-bilirubin association (interaction p-value = 0.09), which was greater during early pregnancy (β = 0.08, 95 % CI = 0.01, 0.15). ConclusionIn a prospective cohort of pregnant African Americans, an increase in PFOA, PFHxS, and the PFAS mixture was associated with an increase in bilirubin. Our results suggest that, depending on pregnancy stage, prenatal PFAS exposure disrupts the maternal liver antioxidant capacity.

Exposure of Mice to a PFAS Mixture and Outcomes Related to Circulating Lipids, Bile Acid Excretion, and the Intestinal Transporter ASBT.

Previous epidemiological studies have repeatedly found per- and polyfluoroalkyl substances (PFAS) exposure associated with higher circulating cholesterol, one of the greatest risk factors for development of coronary artery disease. The main route of cholesterol catabolism is through its conversion to bile acids, which circulate between the liver and ileum via enterohepatic circulation. Patients with coronary artery disease have decreased bile acid excretion, indicating that PFAS-induced impacts on enterohepatic circulation may play a critical role in cardiovascular risk. Using a mouse model with high levels of low-density and very low-density lipoprotein (LDL and VLDL, respectively) cholesterol and aortic lesion development similar to humans, the present study investigated mechanisms linking exposure to a PFAS mixture with increased cholesterol. Male and female mice were fed an atherogenic diet (Clinton/Cybulsky low fat, 0.15% cholesterol) and exposed to a mixture of 5 PFAS representing legacy, replacement, and emerging subtypes (i.e., PFOA, PFOS, PFHxS, PFNA, GenX), each at a concentration of , for 7 wk. Blood was collected longitudinally for cholesterol measurements, and mass spectrometry was used to measure circulating and fecal bile acids. Transcriptomic analysis of ileal samples was performed via RNA sequencing. After 7 wk of PFAS exposure, average circulating PFAS levels were measured at 21.6, 20.1, 31.2, 23.5, and in PFAS-exposed females and 12.9, 9.7, 23, 14.3, and in PFAS-exposed males for PFOA, PFOS, PFHxS, PFNA, and GenX, respectively. Total circulating cholesterol levels were higher in PFAS-exposed mice after 7 wk ( vs. in female mice and vs. in male mice exposed to vehicle or PFAS, respectively). Total circulating bile acid levels were higher in PFAS-exposed mice ( vs. in female mice and vs. in male mice exposed to vehicle or PFAS, respectively). In addition, total fecal bile acid levels were lower in PFAS-exposed mice ( vs. in females and vs. in males exposed to vehicle or PFAS, respectively). In the ileum, expression levels of the apical sodium-dependent bile acid transporter (ASBT) were higher in PFAS-exposed mice. Mice exposed to a PFAS mixture displayed higher circulating cholesterol and bile acids perhaps due to impacts on enterohepatic circulation. This study implicates PFAS-mediated effects at the site of the ileum as a possible critical mediator of increased cardiovascular risk following PFAS exposure. https://doi.org/10.1289/EHP14339.

Large-Scale Screening of Per- and Polyfluoroalkyl Substance Binding Interactions and Their Mixtures with Nuclear Receptors.

Despite their significant impact, comprehensive screenings and detailed analyses of per- and polyfluoroalkyl substance (PFAS) binding strengths at the orthosteric and allosteric sites of NRs are currently lacking. This study addresses this gap by focusing on the binding interaction analysis of both common and uncommon PFAS with the nuclear receptors (NRs) vitamin D receptor (VDR), peroxisome proliferator-activated receptor gamma (PPARγ), pregnane X receptor (PXR), and estrogen receptor alpha (ERα). Advanced docking simulations were used to screen 9507 PFAS chemicals at the orthosteric and allosteric sites of PPARγ, PXR, VDR, and ERα. All receptors exhibited strong binding interactions at the orthosteric and allosteric site with a significant number of PFAS. We verified the accuracy of the docking protocol through multiple docking controls and validations. A mixture modeling analysis indicates that PFAS can bind in various combinations with themselves and endogenous ligands simultaneously, to disrupt the endocrine system and cause carcinogenic responses. These findings reveal that PFAS can interfere with nuclear receptor activity by displacing endogenous or native ligands by binding to the orthosteric and allosteric sites. The purpose of this study is to explore the mechanisms through which PFAS exert their endocrine-disrupting effects, potentially leading to more targeted therapeutic strategies. Importantly, this study is the first to explore the binding of PFAS at allosteric sites and to model PFAS mixtures at nuclear receptors. Given the high concentration and persistence of PFAS in humans, this study further emphasizes the urgent need for further research into the carcinogenic mechanisms of PFAS and the development of therapeutic strategies that target nuclear receptors.

Association between mixed exposure to per- and polyfluoroalkyl substances and metabolic syndrome in Korean adults: Data from the Korean National environmental health survey cycle 4

AimTo explore the effect of mixed exposure to per- and polyfluoroalkyl substances (PFAS) on metabolic syndrome (MetS). MethodsThis 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). ResultsA 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. ConclusionMixed 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.

Associations of Serum Per- and Polyfluoroalkyl Substances with Hyperuricemia in Adults: A Nationwide Cross-Sectional Study.

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.