Effects of PFOS on the behavior, growth, emergence, and predation susceptibility of larval mosquitoes (Culex quinquefasciatus)

BackgroundIncreased exposure to perfluoroalkyl substances (PFAS) potentially affects infant and childhood health through immunosuppression. Given rapidly evolving research on PFAS, it is important to comprehensively examine the impact of PFAS exposure among the pediatric population as new research becomes available due to potential fragility of the developing immune system. ObjectivesThis review assessed the effects of PFAS fetal, infant and childhood exposures upon the development of immune function during early life stages. MethodsResearchers completed a literature review, searching PubMed for human studies published since 2010 for PFAS and health outcomes among infants and children. Included articles incorporated key search terms in the title or abstract; non-research reports and non-English papers were excluded. The search identified 518 studies for possible inclusion. Following hands-on review, 34 were determined relevant. Subsequent analyses found 8 additional relevant articles, totaling 42 studies. ResultsMajor immune-related sequelae from PFAS exposures on infant and child health outcomes documented in recent literature include:• Strong indication of immunosuppression, with diminished childhood antibody response to vaccination, particularly with PFOA, PFOS and PFHxS exposures.• Some indication of increased risks of childhood infectious diseases/infections, particularly from PFOS exposures.• Limited indication of an effect of PFAS exposure on allergic reactions/allergen specific IgE antibodies.• Limited indication of an effect of PFAS exposure on atopic dermatitis (AD).• Limited indication of an effect of PFAS exposure on asthma and lung function. ConclusionThis review summarizes recent findings of PFAS effects on infant and childhood immune health. Evidence of immunosuppression, diminished vaccine efficacy, and increased risk of infections, allergies, asthma and AD were described following in utero, infant, and early childhood PFAS exposures. Further investigation is warranted to characterize PFAS exposure pathways and potential modes of action in relation to PFAS effects on the developing immune system. Incontrovertible proof of PFAS immunotoxic effects could optimally be obtained by a large prospective study cohort of mothers and children from infancy through school-age. Regular assessments of circulating antibodies and response to infant and childhood vaccines during growth years could prove invaluable.

BackgroundThere is increasing global concern regarding the health impacts of perfluoroalkyl and polyfluoroalkyl substances (PFAS), which are emerging environmental endocrine disruptors. Results from previous epidemiological studies on the associations between PFAS exposure and sex hormone levels are inconsistent.ObjectiveWe examined the associations between serum PFAS compounds (PFDeA, PFHxS, PFNA, PFOA, PFOS) and sex hormones, including total testosterone (TT), free testosterone (FT), estradiol (E), and serum hormone binding globulin (SHBG).ResultsAfter adjusting for potential confounders, PFDeA, PFOS, and PFHxS exposures were significantly associated with increased serum testosterone concentrations in males. PFDeA, PFOA, and PFOS exposures were positively correlated with FT levels in 20–49-year-old women, while PFOS exposure was negatively associated with TT levels in 12–19-year-old girls. PFAS exposure was negatively associated with estradiol levels including: PFDeA in all females, PFHxS, PFNA, PFOS, and PFOA in 12–19-year-old girls, PFNA in women above 50 years, and PFOA in 12–19-year-old boys, while PFDeA and PFOS exposures were positively associated with estradiol levels in these boys. n-PFOS exposure was positively associated with SHBG levels in men older than 20 and in all females.ConclusionsUsing a large cohort of males and females aged from 12 to 80, we found that PFAS exposure appears to disrupt sex hormones in a sex-, age-, and compound-specific manner. Future work is warranted to clarify the causality and mechanisms involved.

Introduction: Per-and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals that are highly persistent, mobile, and bioaccumulative.Their release into the environment from various sources results in widespread contamination with a high likelihood of causing adverse effects on human health and the environment.Objectives: (1) to assess the non-carcinogenic and carcinogenic risks associated with exposure to PFAS present in water sources used for drinking water production in the state of So Paulo, Brazil, using deterministic and probabilistic approaches.(2) to estimate the cancer burden attributable to PFOS and PFOA.(3) to explore factors associated with the presence of PFAS in groundwater and surface water.(4) to evaluate the non-carcinogenic health risks for populations residing in Latin America and the Caribbean, based on human biomonitoring data obtained through a systematic review.Methods: Ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QToF-MS) was used to determine PFAS concentrations in water.Exposure assessment for populations in Latin America and the Caribbean was based on studies published between 2001 and 2024 in the PubMed, Lilacs, and Web of Science databases.Human health risk was estimated using the Incremental Lifetime Cancer Risk (ILCR) and hazard quotient (HQ) or hazard index (HI) for non-carcinogenic effects.Probabilistic risk analysis was performed using the Monte Carlo method.The cancer burden attributable to PFOS and PFOA exposure was assessed using a two-stage model, expressed as Disability-Adjusted Life Years (DALY).Results: PFAS (n = 17) were detected in nearly all surface water (n = 116) and groundwater samples (n = 42) collected from different areas in So Paulo state.The most abundant PFAS were PFHxS and PFOA.The fluorotelomer sulfonic acid 6:2 FTS showed the highest concentrations.Risk assessment for PFNA, PFDA, and PFHxS exposure indicated risk (HQ > 1) for the population across four age groups (adults, adolescents, children, and infants).For populations in six Latin American and Caribbean countries, the HI indicated that the median serum concentration of PFAS in Colombia represents a risk (HI > 1) for hepatic, immunological, cardiovascular, and developmental effects.The Brazilian population showed risk for immunological and developmental effects.Conversely, no risk was observed for populations in Peru, Chile, Argentina, and Puerto Rico.The ILCR associated with PFOA exposure in surface and groundwater exceeded the negligible risk threshold suggested by the U.S. EPA (1 10).Risk was higher for men and women over 20 years old compared to younger age groups.PFOS, on the other hand, had a lower average ILCR (7.58 10), indicating a relatively smaller lifetime cancer risk compared to PFOA.Overall, the disease burden attributable to PFOA exposure for kidney cancer was higher in women (2,350 personyears) than in men (1,760 person-years).The highest DALY rate for kidney cancer was observed in the 20-29 age group (4.04).For testicular cancer, the 45-69 age group showed the highest burden attributable to PFOA exposure (200 persons per year), followed by the 20-29 and 30-44 age groups, which had similar DALYs (153 persons per year).DALY calculations stratified by sex and age revealed how the evaluated cancer types affect different age groups in the population.The burden attributable to PFOA was 2,365 persons per year for kidney cancer in women and 3.17 persons per year for testicular cancer.The burden attributable to PFOS was estimated at 6.99 persons per year for liver cancer in men.Conclusions: PFAS contamination in surface and groundwater is widespread, although at low levels in most sampled locations.However, the concentrations of certain PFAS found may cause non-carcinogenic and carcinogenic health risks to the population.These findings highlight the urgent need for effective strategies to mitigate and control contamination of water resources.

Perfluoroalkyl substances (PFAS) are chemicals with endocrine disrupting properties. Experimental studies indicate that PFAS have estrogenic effects by inducing aromatase activity. Sex hormone-binding globulin (SHBG) is a marker of the balance between estrogen and testosterone, as estrogen stimulates and testosterone inhibits SHBG production. To investigate associations between maternal PFAS concentrations and levels of SHBG and testosterone in pregnancy. In Odense Child Cohort (OCC), concentrations of PFAS: perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured in 1611 eligible women at median gestational week (GW) 12 (25th, 75th percentile: 10, 15). Among these, levels of sex hormone-binding globulin (SHBG), calculated free testosterone (Free-T), free androgen index (FAI), and total testosterone (TT) were assessed in 1048at median GW 29 (25th, 75th percentile: 28, 30). Associations between PFAS concentrations and levels of SHBG and testosterone were estimated using multiple linear regression models. The effect of combined exposure to PFAS was also assessed via Quantile G-Computation. A doubling in PFOS concentration was associated with an increment in SHBG concentration by 2.29% (95%CI: 0.04%, 4.59%) in adjusted analyses. PFOS exposure in the third tertile, as compared to the first tertile, significantly increased SHBG concentrations by 4.60% (95%CI: 0.82%, 8.53%). No significant association was demonstrated between PFAS and TT, however, a non-significant inverse association was found between PFAS and Free-T and FAI. Combined PFAS exposure was non-significantly associated with an increase in SHBG, and decrease in Free-T, FAI, and TT. PFOS exposure was associated with an increase in the proportion of estrogen effects to androgen effects, assessed by higher SHBG concentrations, in pregnant women. Estrogenic effects during pregnancy may have implications on offspring neural, metabolic, and endocrine development, hence supporting the necessity of a follow-up of offspring.

Objectives: PFASs are synthetic chemicals that humans may be exposed to through workplace or the environment. Previous studies have suggested a carcinogenic effect. In our review, we investigated the association between PFAS exposure and risk of bladder and prostate cancer. Methods: We searched through IARC Monographs, ATSDR documents, and PubMed (up to January 2024) to find studies that examined the relationship between PFAS exposure and bladder and prostate cancer. Four reviewers independently screened studies, extracted data, and evaluated quality using a modified version of the Newcastle-Ottawa Scale (NOS). We conducted meta-analyses using random-effects models, stratified analyses, dose-response assessments, and evaluated publication bias. Results: We included 21 independent studies in our meta-analysis. The findings didn’t reveal an association between PFOA, PFOS, and PFAS exposure and bladder cancer, as well PFOA, PFNA and prostate cancer. However, we found an association between prostate cancer and total PFAS (RR = 1.12, 95% CI =1.06-1.18), based on two studies, and an association of borderline statistical significance with PFOS (RR = 1.04, 95% CI =0.98-1.11). There was no difference between outcome, region, year of publication, study design, quality score, and gender, exposure source and different levels of PFASs for both cancer types. Publication bias was excluded for prostate cancer studies (P = 0.71) and bladder cancer (P = 0.79). Conclusion: Our research did not find a link between different types of PFAS exposure and bladder cancer. However, it supports a potential association between PFOS exposure and prostate cancer. Bias and confounding cannot be excluded.

Gestation is a vulnerable window when exposure to per- and polyfluoroalkyl substances (PFAS) may impact child development and health. Epigenetic modification, including DNA methylation (DNAm), may be one mechanism linking prenatal PFAS exposure to offspring outcomes. We tested associations between prenatal PFAS and newborn DNAm in 1017 participants from 6 cohorts in the US Environmental influences on Child Health Outcomes consortium. Concentrations of PFAS [perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid] were measured in maternal serum or plasma. DNAm was quantified in newborn dried blood spot or umbilical cord blood leukocytes using the Infinium HumanMethylation450 (450K) or MethylationEPIC (EPIC) arrays. We tested associations between prenatal PFAS and neonatal blood DNAm on the 450K (n = 772) and EPIC (n = 245) arrays; results were meta-analysed across the platforms. Regional changes in DNAm were investigated, and findings were checked for replication in the Michigan Mother–Infant Pairs (MMIP) cohort (n = 140). Following correction for false discovery rate (q = 0.1 for meta-analyses), we identified an association between PFHxS and one cytosine–guanine (CpG) mapped to CASC3 (q = 0.065) that replicated in MMIP (P = .006). PFOS was associated with six CpG sites, of which five were mapped to the genes KIAA1841, ABR, LEP, SERPINA1, and LOXL1. One differentially methylated region (DMR) was associated with prenatal PFOA exposure, and one DMR was associated with PFOS exposure. In this multicohort analysis including a diverse group from the USA, PFOA, PFOS, PFHxS, and PFNA exposures in pregnancy were associated with offspring DNAm, and the implications for children’s health merit further exploration.

Exposure to perfluoroalkyl substances and risk of hepatocellular carcinoma in a multiethnic cohort

Per- and polyfluoroalkyl substances (PFAS) have carcinogenic potential but are understudied in relation to childhood cancers. We examined associations between targeted and non-targeted PFAS measured in newborn dried blood spots (DBS) and the risk of childhood acute lymphoblastic leukemia (ALL) in Los Angeles County, California, accounting for maternal and child characteristics. ALL cases (n = 125) diagnosed before age 18 years during 2000-2015 and controls (n = 219) were selected from a registry-based study using stratified sampling based on birth year and birth address within a PFAS-contaminated water district according to the USEPA Third Unregulated Contaminant Monitoring Rule. We calculated design-based odds ratios (OR) and 95% confidence intervals (CI) for the effect of PFAS exposures, independently and adjusting for other PFAS. We also conducted non-linear and stratified analyses. Of the 17 PFAS quantified using targeted analysis, perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) had the highest mean concentrations in DBS, with 4690 and 10,307 pg/g dried blood among cases compared to 4245 and 8142 pg/g dried blood among controls, respectively. The highest risks were observed for the 4th exposure quartile compared with the 1st quartile (PFOA OR = 1.56, CI: 0.42, 5.73; PFOS OR = 1.64, CI: 0.44, 6.14). In non-linear statistical analyses of joint PFOA and PFOS exposures adjusted for other detected PFAS, we also found that ALL risk increased with increasing levels of log2-PFOA and log2-PFOS. Non-targeted analysis identified 26 additional PFAS, for which elevated risk of childhood ALL was associated with a doubling of C4HF7O3 exposure (OR = 5.04, CI: 1.08, 23.63) and the highest quartile of C10HF19O5 exposure (OR = 5.20, CI: 1.15, 23.56). Associations were generally stronger among non-Hispanic participants compared to Hispanic participants, but these analyses were limited by small sample sizes and should be considered exploratory. There was some suggestion that high PFOA and PFOS exposures measured at birth, as well as certain PFAS detected by non-targeted approaches, were related to childhood ALL risk. This study of childhood ALL in Los Angeles County, California found increased risk among children with the highest PFOA and PFOS levels measured in neonatal dried blood spots. These risks were stronger among non-Hispanic children, and the greatest risk was observed for joint PFOA and PFOS exposure adjusting for other detected PFAS and maternal/child characteristics. We also observed possible associations with PFAS discovered by non-targeted analysis. Our results highlight the utility of dried blood spots as a matrix for assessing early life exposures as well as the value of hybrid targeted and non-targeted approaches to measure PFAS in health studies.

Background: Chronic exposure to long-term exposures to per- and polyfluoroalkyl substances (PFAS), widely known as “forever chemicals”, has been associated with multiple negative health outcomes including increased risk of cancer. Perfluorooctanesulfonic acid (PFOS), a “long-chain” subtype of PFAS, has high bioaccumulation potential with a long elimination half-life. PFOS is frequently detected in drinking water leading to its high absorption through the gastrointestinal tract. Recent studies demonstrate that PFAS exposures promote intestinal inflammation and gut barrier dysfunction. However, how a long-term PFOS exposure affects colorectal cancer (CRC) progression is not known. Therefore, the purpose of this study is to delineate the effect of PFOS exposure on CRC cell proliferation and test the potential mitigation strategy for the harmful effects of PFOS. Methods: SW480 and HCT116 cells have been treated with 1 ug/mL PFOS and proliferation was measured at 1, 2, and 3 months using the Presto Blue Cell Viability Reagent fluorescence assay. Proliferation markers were assessed by qPCR and Western blot. Control and PFOS exposed cells were treated with sulforaphane, a nuclear factor erythroid 2-related factor 2 (Nrf-2) inducer, at concentration 5, 10 and 20 uM for 72 hours. Results: We show that chronic, low-dose PFOS exposure promotes proliferation of SW480 and HCT116 cell lines starting at 3 months since the first exposure. The increase in proliferation is associated with upregulation of Cyclin D, pAkt and FASN. We also show that sulforaphane significantly decreases proliferation of HCT116 and SW480 cells, and its efficacy is significantly higher in PFOS exposed CRC cells. The current studies show no effect on sulforaphane on normal colon epithelium cells. Conclusion: Our studies suggest that chronic PFOS exposure promotes proliferation of CRC cells by increasing pro-carcinogenic gene expression and signaling. Furthermore, our findings suggest that supplementation of diet sulforaphane can potentially mitigate the harmful effects from PFOS exposure. Our studies warrant further investigation of the mechanisms behind the effect of PFOS exposure on cancer progression that would guide development of effective intervention strategies to mitigate the harmful effects of the exposure to “forever chemicals”. Citation Format: Jerika Durham, Josiane Weber Tessmann, Bernhard Hennig, Yekaterina Zaytseva. Chronic perfluorooctanesulfonic acid exposure promotes proliferation of colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1478.

Background:Per- and polyfluoroalkyl substances (PFAS) are a diverse class of industrial chemicals with widespread environmental occurrence. Exposure to long-chain PFAS is associated with developmental toxicity, prompting their replacement with short-chain and fluoroether compounds. There is growing public concern over the safety of replacement PFAS.Objective:We aimed to group PFAS based on shared toxicity phenotypes.Methods:Zebrafish were developmentally exposed to 4,8-dioxa-3H-perfluorononanoate (ADONA), perfluoro-2-propoxypropanoic acid (GenX Free Acid), perfluoro-3,6-dioxa-4-methyl-7-octene-1-sulfonic acid (PFESA1), perfluorohexanesulfonic acid (PFHxS), perfluorohexanoic acid (PFHxA), perfluoro-n-octanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), or 0.4% dimethyl sulfoxide (DMSO) daily from 0–5 d post fertilization (dpf). At 6 dpf, developmental toxicity and developmental neurotoxicity assays were performed, and targeted analytical chemistry was used to measure media and tissue doses. To test whether aliphatic sulfonic acid PFAS cause the same toxicity phenotypes, perfluorobutanesulfonic acid (PFBS; 4-carbon), perfluoropentanesulfonic acid (PFPeS; 5-carbon), PFHxS (6-carbon), perfluoroheptanesulfonic acid (PFHpS; 7-carbon), and PFOS (8-carbon) were evaluated.Results:PFHxS or PFOS exposure caused failed swim bladder inflation, abnormal ventroflexion of the tail, and hyperactivity at nonteratogenic concentrations. Exposure to PFHxA resulted in a unique hyperactivity signature. ADONA, PFESA1, or PFOA exposure resulted in detectable levels of parent compound in larval tissue but yielded negative toxicity results. GenX was unstable in DMSO, but stable and negative for toxicity when diluted in deionized water. Exposure to PFPeS, PFHxS, PFHpS, or PFOS resulted in a shared toxicity phenotype characterized by body axis and swim bladder defects and hyperactivity.Conclusions:All emerging fluoroether PFAS tested were negative for evaluated outcomes. Two unique toxicity signatures were identified arising from structurally dissimilar PFAS. Among sulfonic acid aliphatic PFAS, chemical potencies were correlated with increasing carbon chain length for developmental neurotoxicity, but not developmental toxicity. This study identified relationships between chemical structures and in vivo phenotypes that may arise from shared mechanisms of PFAS toxicity. These data suggest that developmental neurotoxicity is an important end point to consider for this class of widely occurring environmental chemicals. https://doi.org/10.1289/EHP5843

BACKGROUND AND AIM: Exposure to per- and polyfluoroalkyl substances (PFAS), a class of persistent organic pollutants, is ubiquitous. Animal studies suggest that PFAS may increase risk of fatty liver and hepatocellular carcinoma (HCC) via impacts on hepatic lipid, amino acid, and glucose metabolism, but human data are lacking. We examined associations of PFAS exposure, altered metabolic pathways, and risk of non-viral HCC. METHODS: In this nested case-control study, prediagnostic plasma PFAS and metabolomics were measured in 50 incident HCC cases and 50 individually matched controls from the Multiethnic Cohort Study (MEC). Cases and controls were matched by age, sex, race, and study area. PFAS exposure and risk of HCC were examined using conditional logistic regression. A metabolome wide association study and pathway enrichment analysis was performed for PFAS exposure and HCC risk, and key metabolites/metabolic pathways were identified using a meet in the middle approach. RESULTS: High perfluorooctane sulfonic acid (PFOS) levels (90th percentile from NHANES>55 μg/L) were associated with more than 4 fold increased risk of HCC (OR=4.5; 95% CI: 1.2-16.0). The pathway enrichment analysis showed that PFOS exposure was associated with alterations in amino acid and glycan biosynthesis pathways, which were in turn associated with HCC risk. We identified four metabolites linking PFOS exposure with HCC, including glucose, butyric acid (a short chain fatty acid), α-Ketoisovaleric acid (a branched-chain α-keto acid), and 7alpha-Hydroxy-3-oxo-4-cholestenoate (a bile acid), each of which was positively associated with PFOS exposure and risk of HCC. CONCLUSTIONS: Exposure to high levels of PFOS was associated with increased risk of HCC, and the likely mechanisms were via alterations in glucose, amino acid, and bile acid metabolism. Larger studies are warranted to confirm these findings. Key Words: Chemical exposure, exposome, perfluorinated alkyl substance, hepatocellular carcinoma, metabolome, bile acid, metabolic pathway

Per- and polyfluoroalkyl substances (PFAS) are a unique class of over 15,000 manmade chemicals that are still widely used in manufacturing and are resistant to degradation. Accumulation in the environment and general population has been associated with an array of adverse health outcomes. Perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) specifically have been associated with markers of liver injury, high serum cholesterol, thyroid disease, low fetal birth weight, suppressed vaccine response, and cancer. Exposure to PFAS is commonly investigated individually, however, humans are exposed to a multitude of PFAS daily. Additionally, with the pervasive nature of these chemical, people of all ages are affected by their toxic effects. This dissertation focuses on both a global and targeted approach to elucidating mechanisms of PFAS liver toxicity, both individually and as a mixture, in young and adult mice. The studies herein introduce novel approaches, including offspring liver omics’ analyses of perinatal PFAS mixture exposures and PFOS exposures in targeted protein murine knockout mouse models, to understand and evaluate the underlying mechanisms of PFAS liver toxicity in both neonatal and adult mice. In manuscript 1, livers from pups gestationally and lactationally exposed to individual PFOA, PFOS, PFHxS, or a PFAS mixture were investigated for proteomic alterations at postnatal day (PND) 21. Herein, sequential window acquisition of all theoretical mass spectra - liquid chromatography-mass spectrometry (SWATH-LC/MS) and Ingenuity Pathway Analysis (IPA) software were utilized to investigate global proteomic changes in the exposed offsprings’ liver. Individual and commonly observed proteins between treatments and diets were explored to tease out the differing proteomic signatures. Specific proteins involved in pathways concerning lipid transport, storage, synthesis, and catabolism, xenobiotic metabolism, and inflammation were investigated. In manuscript 2, neonatal livers indirectly exposed to PFOA, PFOS, PFHxS, or a PFAS mixture through gestation and lactation were investigated for transcriptomic alterations at postnatal day (PND) 21. Herein, the QuantSeq 3' mRNA-Seq Library Prep Kit, BlueBee genomics platform, and IPA software were utilized to investigate global transcriptomic changes in the exposed pup livers. Treatment and diet-specific genes that were individually or commonly observed were investigated to tease out the unique transcriptomic signatures. Selected genes involved in pathways regarding xenobiotic metabolism, inflammation, and lipid transport, storage, synthesis, and catabolism were further investigated. In manuscript 3, a knockout (KO) mouse model with a specific targeted deletion of organic anion transporting polypeptide 2b1 (Oatp2b1) was utilized to investigate the contribution of this

BackgroundExisting evidence for associations of per- and polyfluoroalkyl substances (PFASs) with blood lipids, lipoproteins and apolipoproteins (apo), and coronary heart disease (CHD) risk is limited and inconsistent. This study aims to explore associations between plasma PFASs, blood lipoprotein subspecies defined by apolipoproteins, and CHD risk.MethodsA case–control study of CHD was conducted in the Health Professionals Follow-Up Study (HPFS) and Nurses' Health Study (NHS). Among participants initially free of cardiovascular disease at blood collection in 1994 (HPFS) or 1990 (NHS), 101 participants who developed non-fatal myocardial infarction or fatal CHD were identified and confirmed. A healthy control was matched to each case for age, smoking status, and date of blood draw. Plasma levels of perfluorohexane sulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), total perfluorooctane sulfonic acid (PFOS), branched PFOS (brPFOS), linear PFOS (nPFOS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured. Conditional logistic regression and cubic spline regression models were used to examine associations between baseline PFASs and CHD risk. Linear regression models were applied to study PFAS associations with lipids and their subfractions.ResultsAfter multivariate adjustments, total PFOS, brPFOS and nPFOS were significantly associated with increased risk of developing CHD, and HRs (95% CIs) per log(ng/mL) increment of PFASs were 3.66 (1.36–9.89), 3.68 (1.55–8.76), and 3.01 (1.16–7.86), respectively. Significant positive dose–response relationships were identified for these PFASs (Plinearity = 0.01, 0.002, 0.02, respectively). Other PFASs were not associated with CHD risk. PFNA and PFDA were positively associated with total apoE levels among HDL particles with or without apoC-III. No associations were observed for other PFASs with blood lipid subspecies. Blood lipid subfractions did not explain the association between PFOS and CHD risk.ConclusionsPlasma PFOS and its isomers were positively associated with CHD risk. These findings suggest that PFOS exposure causes public health risks that are greater than hitherto believed.

BackgroundEpidemiologic evidence regarding the association between per‐ and polyfluoroalkyl substances (PFAS) exposure and stroke risk remains limited and inconclusive. Consequently, the current study sought to further examine this association and clarify the underlying molecular mechanisms.Materials and MethodsThis cohort study analyzed data from 8081 participants of the 2003–2012 National Health and Nutrition Examination Survey (NHANES), employing multistage weighted logistic regression, weighted quantile sum (WQS) modeling, and partial least squares discriminant analysis (PLS‐DA) to systematically evaluate the association between per‐ and polyfluoroalkyl substances (PFAS) exposure and stroke. Restricted cubic spline analysis was subsequently used to examine the nonlinear dose‐response relationships. To investigate the underlying mechanisms, we integrated data from six databases (e.g., ChEMBL and GeneCards) to identify common molecular targets of PFAS and stroke. A protein‐protein interaction (PPI) network was then constructed to identify core genes, while the binding interactions between PFAS and key targets were evaluated through molecular docking and dynamics simulations. Finally, functional enrichment analysis was performed on these core genes using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases.ResultsAfter adjusting for potential confounders, six individual PFAS compounds, including perfluorooctane sulfonic acid (PFOS) (Odds Ratio [OR] = 1.59, 95% CI: 1.09–2.31), exhibited a significant positive association with the risk of stroke. The WQS model revealed a significant positive association for the PFAS mixture (OR = 1.027, 95% CI: 1.017–1.036), with PFOS contributing the highest weight (0.379). These findings were corroborated by the PLS‐DA model, and the association remained significant in all subgroup analyses. The network toxicology analysis identified 183 common targets between PFOS and stroke, while the subsequent PPI network analysis identified six core genes, including AKT1 and HSP90AA1. GO and KEGG enrichment analyses demonstrated that these targets were markedly enriched in pathways associated with lipid and atherosclerosis metabolism, in addition to the PI3K‐Akt and MAPK signaling pathways. Furthermore, molecular docking and molecular dynamics simulations supported potential interactions between PFOS and core targets such as AKT1. This suggests that PFOS may contribute to stroke pathogenesis by disrupting pathways involved in inflammatory regulation and apoptosis.ConclusionsThis study identified a positive association between PFOS exposure and stroke risk, suggesting that the PI3K/AKT signaling pathway, along with its key effector molecule AKT1, may play a crucial role in mediating PFOS‐induced stroke, thereby offering a theoretical foundation for the prevention and management of PFOS‐associated stroke.

BackgroundPrevious research indicates that per- and polyfluoroalkyl substances (PFAS) can disrupt metabolism and neurological function via endocrine pathway interference and neuroinflammation. These effects may impair melatonin secretion and disrupt circadian rhythm regulation, suggesting potential links to sleep health. However, the impact of PFAS exposure on adolescent sleep remains unclear. This study examines the associations between PFAS exposure and sleep health indicators in U.S. adolescents.MethodsData from 838 adolescents who participated in the 2005–2018 National Health and Nutrition Examination Survey (NHANES) were analyzed to investigate the association between PFAS exposure and physician-diagnosed sleep disorders. Eight PFAS compounds were identified. Multivariate logistic regression models, restricted cubic spline (RCS) curves, Bayesian kernel machine regression (BKMR), and weighted quantile sum (WQS) regression were used to assess single, linear, and combined effects on adolescent sleep disorders.ResultsNegative associations were observed between adolescent sleep disorders and three PFAS compounds, specifically perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorononanoic acid (PFNA). RCS analysis revealed a significant linear relationship (P for non-linear > 0.05). The BKMR and WQS models demonstrated a combined effect of PFAS exposure on sleep disorders, with PFOS demonstrating the most substantial contribution (effect size: 0.91). The stratified analysis revealed that PFOS exposure had a greater impact on females [odds ratio (OR): 0.54, 95% confidence interval (CI): 0.33–0.87] than males (OR: 0.50, 95% CI: 0.24–1.01), suggesting sex-specific differences in vulnerability.ConclusionsOur findings indicate a negative correlation between specific PFAS and specific sleep disorders in adolescents, with PFOS being the dominant effect component in the PFAS mixture and stronger effects observed in females. However, due to the cross-sectional nature of the study, a causal relationship cannot be established. These results highlight the potential public health impact of PFAS exposure and the need to further investigate the underlying mechanisms and causal pathways in future longitudinal or experimental studies.