Association Of Perfluoroalkyl Substances Research Articles

Association of perfluoroalkyl substances (PFAS) with liver function biomarkers in the highly exposed population of the veneto region

IntroductionEpidemiological studies highlight the presence of associations between per- and polyfluoroalkyl substances (PFAS) exposure with liver damage. In 2013, PFAS contamination was discovered in Veneto (Italy), leading to the implementation of a Surveillance Program (SP). Our objective is to investigate the association between PFAS exposure and biomarkers of liver function using single-pollutant and mixture approaches, while exploring the sex-specific differences and the mediating role of obesity in the association. MethodsThe study included 42,094 subjects aged ≥20 years participating in the SP. We used generalized additive models to investigate the association between several PFAS and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, adjusting for possible confounders and stratifying by sex. Results were back-transformed to show predicted percentage changes in outcomes per ln-unit increase in PFAS levels; furthermore, we explored the role of BMI in the abovementioned causal pathway, considering it as a potential confounder or mediator PFAS joint effect was investigated using Quantile G-computation. ResultsOne ln-unit increase in PFHxS concentrations was associated with a 1.49% (95%CI: 0.87, 2.12) and a 0.84% (95% CI: 0.27, 1.40) increase in ALT levels, in males and females respectively; one ln-unit increase in PFOA concentrations was associated with a 1.03% (95%CI: 0.50, 1.55) increase in ALT levels in males, and a 0.52% (95% CI: 0.22, 0.82) and a 0.60% (95% CI: 0.25, 0.96) increase in AST levels in females and males. PFOS showed no association with ALT and AST levels. Quantile G-computation revealed that an interquartile increase in the PFAS mixture was associated with a 3.02% increase (95% CI: 1.65, 4.43) and a 1.65% (95% CI: 0.77, 2.5) increase in ALT levels, in females and males. Mediation analysis suggested that BMI suppressed the association between PFAS and ALT levels, with positive direct effects higher than the total effects. ConclusionOur findings suggest sex-specific associations between PFAS exposure and liver function biomarkers and underscore the need for additional studies on potential mediators.

Associations of perfluoroalkyl substances with metabolic-associated fatty liver disease and non-alcoholic fatty liver disease: NHANES 2017-2018.

This study investigated the potential effects of perfluoroalkyl substance (PFAS) in serum on MAFLD, NAFLD, and liver fibrosis. Our sample included 696 participants (≥ 18years) from the 2017-2018 NHANES study with available serum PFASs, covariates, and outcomes. Using the first quartile of PFAS as the reference group, we used weighted binary logistic regression and multiple ordered logistic regression used to analyze the relationship between PFAS and MAFLD, NAFLD, and liver fibrosis and multiple ordinal logistic regression to investigate the relationship between PFAS and MAFLD, NAFLD, and liver fibrosis and calculated the odds ratio (OR) and 95% confidence interval for each chemical. Finally, stratified analysis and sensitivity analysis were performed according to gender, age, BMI, and serum cotinine concentration. A total of 696 study subjects were included, including 212 NAFLD patients (weighted 27.03%) and 253 MAFLD patients (weighted 32.65%). The quartile 2 of serum PFOA was positively correlated with MAFLD and NAFLD (MAFLD, OR 2.29, 95% CI 1.05-4.98; NAFLD, OR 2.37, 95% CI 1.03-5.47). PFAS were not significantly associated with liver fibrosis after adjusting for potential confounders in MAFLD and NAFLD. Stratified analysis showed that PFOA was strongly associated with MAFLD, NAFLD, and liver fibrosis in males and obese subjects. In women over 60years old, PFHxS was also correlated with MAFLD, NAFLD, and liver fibrosis. The serum PFOA was positively associated with MAFLD and NAFLD in US adults. After stratified analysis, the serum PFHxS was correlated with MFALD, NAFLD, and liver fibrosis.

Abstract 828: Associations of perfluoroalkyl substances with breast cancer incidence risk and mediation role of mitochondrial DNA copy number: A prospective case-cohort study

Abstract Background: Perfluorinated carboxylic acids (PFCAs) and perfluorinated sulfonic acids (PFSAs), notable representatives of perfluoroalkyl substances (PFASs), are synthetic persistent chemicals widely accumulated and detected in humans. Short-chain PFASs [PFCAs with carbon number <8 and PFSAs <6, e.g. perfluoroheptanoic acid (PFHpA)] are considered less bioaccumulative and increasingly used in commercial products, yet their health impacts are rarely investigated. Perfluorooctanoic acid (PFOA) has been categorized as a possible human carcinogen (group 2B) and a potential mammary toxicant. However, few population studies explored the prospective associations of PFOA and other common PFASs with breast cancer risk nor the underlying mechanisms. Methods: Hence, we conducted a case-cohort study within the DongFeng-Tongji Cohort, compromising 226 incident breast cancer cases and a random sub-cohort of 990 individuals. Plasma concentrations of four PFCAs [PFOA, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and PFHpA] and two PFSAs [perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS)], as well as peripheral blood mitochondrial DNA copy number (mtDNAcn) levels, were measured at baseline. Results: Using Barlow-weighted Cox regression, we found 35% and 20% increased incident risk of breast cancer for each 1-unit ln-transformed increase in PFOA and PFHpA, respectively [HR (95% CI) = 1.35 (1.03, 1.78) and 1.20 (1.02, 1.40)]. Quantile g-computation analysis revealed a 19% increased incident risk of breast cancer along with each simultaneous quartile increase in all ln-transformed PFCA concentrations [HR (95% CI) = 1.19 (1.01, 1.41)], driven mainly by contributions from PFOA (56%), PFNA (24%), and PFHpA (20%). Besides, mtDNAcn was positively associated with PFHpA levels [β (95% CI) =0.027 (0.005, 0.048)], but not with PFOA or PFNA (P>0.05). We also found significantly higher breast cancer risk in participants with the highest mtDNAcn (Q4, ≥1.52) than those with the lowest (Q1, <0.87) [HR (95% CI) =2.92 (1.69, 5.04)], and that mtDNAcn mediated 12.77% of PFHpA-breast cancer association [Indirect effect, HR (95% CI) =1.02 (1.00, 1.04)]. No significant mediation effect of mtDNAcn was observed in associations of PFOA and PFNA with breast cancer (P>0.05). Conclusions: Our work unveiled the relationship of short-chain PFHpA with increased incident risk of breast cancer for the first time and highlighted the intermediate role of mtDNAcn in this association, providing a research clue for exploring the potential mechanisms of PFAS-induced breast cancer. Moreover, co-exposure to PFASs was observed as a risk factor for breast cancer, shedding light on breast cancer prevention by regulating PFASs as a chemical class. Citation Format: Yue Feng, Huan Guo. Associations of perfluoroalkyl substances with breast cancer incidence risk and mediation role of mitochondrial DNA copy number: A prospective case-cohort study [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 828.

Sex-specific effect of perfluoroalkyl substances exposure on liver and thyroid function biomarkers: A mixture approach.

Although studies have investigated the effects of perfluoroalkyl substances (PFASs) on liver and thyroid function, little is known about its combined and sex-specific effect. A total of 688 participants were interviewed and serum PFASs concentration was measured using liquid chromatography/mass spectrometry. Five biomarkers of liver and thyroid function (ALT, GGT, TSH, FT3 and FT4) were chosen as outcomes. A restriction cubic spline function was applied to capture the dose-response relationship between PFASs and liver enzymes and thyroid hormones. Multivariable regression and Bayesian kernel machine regression (BKMR) models were performed to assess the single and overall associations of PFASs with targeted biomarkers. Single-pollutant analyses indicated that increased PFASs concentrations were associated with elevated ALT and GGT levels. BKMR models suggested positive dose-response relationships between PFASs mixtures and ALT and GGT levels. Significant associations were only detected between several PFASs and thyroid hormones, and joint effect of PFASs mixtures on FT3 levels was found at higher concentrations. Meanwhile, sex differences were found in the associations of PFASs with ALT and GGT levels, with significant results only in males. Our findings provide epidemiological evidence for combined and sex-specific effects of PFASs on ALT and GGT levels.

Associations of perfluoroalkyl substances (PFAS) with lipid and lipoprotein profiles

BackgroundPerfluoroalkyl substances (PFAS) are man-made chemicals with unique properties that are widely distributed in humans and the environment. Recent studies suggest that PFAS are involved in cholesterol metabolism, however, the mechanisms underlying the associations are poorly understood.ObjectiveWe aimed to evaluate associations of plasma PFAS with detailed lipid and lipoprotein subfractions in an adult population of men and women.MethodsWe measured concentrations of cholesterol and triglycerides in lipoprotein subfractions, apolipoprotein subclasses, as well as fatty acid and different phospholipid measures, using serum proton nuclear magnetic resonance (1H-NMR), and four plasma PFAS using liquid chromatography-mass spectrometry (UHPLC-MS/MS). Measurements were available for 493 participants (all aged 50 years, 50% female). Multivariable linear regression was used to estimate the association of four PFAS with 43 different 1H-NMR measures, with adjustment for body mass index (BMI), smoking, education, and physical activity.ResultsWe found that perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), but not perfluorohexanesulfonate (PFHxS), concentrations were consistently positively associated with concentrations of cholesterol in lipoprotein subfractions, apolipoproteins, as well as composite fatty acid- and phospholipid profiles. The most consistent associations were found for the relationship of PFAS with total cholesterol in intermediate-density lipoprotein (IDL), across all low-density lipoprotein (LDL) subfractions and small high-density lipoprotein (HDL). Moreover, we found weak to null evidence for an association of any of the measured 13 triglyceride lipoprotein subfractions with PFAS.ConclusionsOur results suggest that plasma PFAS concentrations are associated with cholesterol in small HDL, IDL and all LDL subfractions, as well as apolipoproteins and composite fatty acid and phospholipid profiles but to a lesser extent with triglycerides in lipoproteins. Our findings draw attention to the need for more detailed measurements of lipids across various lipoprotein subfractions and subclasses in assessing the role of PFAS in lipid metabolism.ImpactBy performing an in-depth characterization of circulating cholesterol and triglycerides in lipoprotein subfractions, apolipoprotein, fatty acid, and phospholipid concentrations, this study has expanded upon the limited literature available on the associations of plasma PFAS concentrations beyond clinical routine laboratory testing for lipids.

Association of perfluoroalkyl substances with pulmonary function in adolescents (NHANES 2007-2012).

Perfluoroalkyl substances (PFASs) constitute an environmentally persistent and widespread class of anthropogenic chemicals that have been used in industrial and commercial applications in the USA and around the world. Animal studies suggested its toxic impact on lung development, but the adverse effect of PFAS exposure on childhood pulmonary function has not been clearly determined. We investigated the potential cross-sectional association of environmental PFAS exposures with pulmonary function in 765 adolescents aged 12-19years from the US National Health and Nutrition Examination Survey (NHANES) 2007-2012. Exposure to PFASs was estimated by measuring serum concentrations, and pulmonary function was assessed by spirometry. Linear regression and weighted quantile sum (WQS) regression were performed to estimate the associations of individual chemicals and chemical mixtures with pulmonary function. Median concentrations of PFOA, PFOS, PFNA, and PFHxS (detection frequencies > 90%) were 2.70, 6.40, 0.98, and 1.51ng/mL, respectively. No associations were found between the four individual congeners and Σ4PFASs and the pulmonary function measures in total adolescents. Sensitive analyses were further conducted stratified by age (12-15 and 16-19years) and sex (boys and girls). In adolescents aged 12-15years, PFNA was negatively associated with FEV1:FVC (p-trend = 0.007) and FEF25-75% (p-trend = 0.03) among girls, while PFNA was positively associated with FEV1: FVC (p-trend = 0.018) among boys. No associations were found among adolescents aged 16-19years, either boys or girls. The aforementioned associations were confirmed when further applying WQS models, and PFNA was identified to be the most heavily weighing chemical. Our results suggested that environmental exposure to PFNA may affect pulmonary function among adolescents aged 12-15years. Given the cross-sectional analysis and less consistent results, further replications of the association in large prospectivecohort studies are warranted.

The association of perfluoroalkyl substances (PFAS) exposure and kidney function in Korean adolescents using data from Korean National Environmental Health Survey (KoNEHS) cycle 4 (2018-2020): a cross-sectional study.

Perfluoroalkyl substances (PFAS) are chemicals widely used in various products in everyday life. Due to its unique strong binding force, the half-life of PFAS is very long, so bioaccumulation and toxicity to the human body are long-standing concerns. In particular, effects on kidney function have recently emerged and there are no studies on the effect of PFAS on kidney function through epidemiological investigations in Korea. From 2018 to 2020, the Korean National Environmental Health Survey (KoNEHS) cycle 4, conducted an epidemiological investigation on the blood concentration of PFAS for the first time in Korea. Based on this data, the relationship between PFAS blood concentration and kidney function was analyzed for adolescents. We investigated 5 types of PFAS and their total blood concentration in 811 middle and high school students, living in Korea and included in KoNEHS cycle 4, and tried to find changes in kidney function in relation to PFAS concentration. After dividing the concentration of each of the 5 PFAS and the total concentration into quartiles, multivariable linear regression was performed to assess the correlation with kidney function. The bedside Schwartz equation was used as an indicator of kidney function. As a result of multivariable linear regression, when observing a change in kidney function according to the increase in the concentration of each of the 5 PFAS and their total, a significant decrease in kidney function was confirmed in some or all quartiles. In this cross-sectional study of Korean adolescents based on KoNEHS data, a negative correlation between serum PFAS concentration and kidney function was found. A well-designed longitudinal study and continuous follow-up are necessary.

Associations of perfluoroalkyl substances with adipocytokines in umbilical cord serum: A mixtures approach

BackgroundPer- and polyfluoroalkyl substances (PFAS), a kind of emerging environmental endocrine disruptors, may interfere with the secretion of adipokines and affect fetal metabolic function and intrauterine development. However, the epidemiological evidence is limited and inconsistent. We examined the associations of single and multiple PFAS exposures in utero with adipocytokine concentrations in umbilical cord serum. MethodsThis study included 1111 mother-infant pairs from Sheyang Mini Birth Cohort Study (SMBCS), and quantified 12 PFAS and two adipokine in umbilical cord serum. Generalized linear models (GLMs) and Bayesian Kernel Machine Regression (BKMR) models were applied to estimate the associations of single- and mixed- PFAS exposure with adipokines, respectively. Furthermore, sex-stratification was done in each model to assess the sexually dimorphic effects of PFAS. Results10 PFAS were detected with median concentrations (μg/L) ranging from 0.04 to 3.97, (except 2.7% for PFOSA and 1.7% for PFDS, which were excluded). In GLMs, for each doubling increase in PFBS, PFHpA, PFHxS, PFHpS, PFUnDA and PFDoDA, leptin decreased between 14.04% for PFBS and 22.69% for PFHpS (P < 0.05). PFAS, except for PFNA, were positively associated with adiponectin, and for each doubling of PFAS, adiponectin increased between 3.27% for PFBS and 12.28% for PFHxS (P < 0.05). In addition, infant gender modified the associations of PFAS with adipokines, especially the associations of PFBS, PFOA and PFHxS with adiponectin. Similarly, significant associations of PFAS mixtures with leptin and adiponectin were observed in the BKMR models. PFDA, PFOS, PFNA and PFHpS were identified as important contributors. In the sex-stratified analysis of BKMR models, the associations between PFAS mixtures and adipokines were more pronounced in males. ConclusionsPFAS levels were significantly associated with adipokines in cord serum, suggesting that intrauterine mixture of PFAS exposure may be related to decreased fetal leptin level but increased fetal adiponectin level and the associations may be sex-specific.

Associations of perfluoroalkyl substances (PFAS) with non-targeted metabolomics across two independent cohorts of elderly individuals

BACKGROUND AND AIM: Perfluoroalkyl substances (PFAS) have been linked to adverse health effects including increased blood cholesterol levels and hepatic toxicity. Alterations in metabolism and oxidative stress are among the hypothesized mechanisms by which PFAS exposure may exert effects; however, studies of associations between PFAS and metabolome are scarce. The main aim of this study was to assess associations of PFAS exposure and metabolome by using non-targeted metabolomics in two independent cohorts of elderly individuals. METHODS: In two population-based cohorts of elderly individuals from Sweden and California (the Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS, n = 901, median age 70 years]; and the California Teacher Study [CTS, n = 325, median age 69 years]), plasma/serum PFAS concentrations were determined using isotope-dilution ultra-pressure liquid chromatography (UHPLC) coupled to tandem mass spectrometry. Non-targeted metabolomics was performed using UHPLC high-resolution mass spectrometry (QTOFMS). Associations of PFAS and metabolomics signatures was assessed using a discovery-validation approach with multivariable linear regression. RESULTS: In the discovery cohort 89 annotated metabolites out of 204 could be associated with levels of five PFAS following adjustment for age, sex, and correction for multiple testing. Eleven associations could then be replicated in the CTS. The metabolites being replicated in the CTS were primarily lipid related metabolites such as lysophosphatidylcholine, phosphatidylcholine, sphingomyelin as well as amino acids such as betaine. CONCLUSIONS: Using a non-targeted metabolomics discovery-validation approach, we the previously reported associations between PFAS and lipid related metabolites and identified and replicated novel associations. Our results encourage additional studies investigating the underlying mechanisms of our findings. KEYWORDS: PFAS, PFOS, PFOA, Metabolomics, Lipid metabolism

Association of perfluoroalkyl substances (PFAS) with lipid trajectories in midlife women: the Study of Women&amp;#x27;s Health Across the Nation

BACKGROUND AND AIM: Despite lipid-lowering effects of perfluoroalkyl substances (PFAS) observed in rodent models, PFAS have been associated with unfavorable blood lipid profiles in human populations. However, evidence from longitudinal studies in the general population is limited. We examined the association of serum concentrations of PFAS with longitudinal trajectories of blood lipids in the Study of Women&amp;#x27;s Health Across the Nation. METHODS: We included 1143 women aged 45-56 years in 1999-2000. Concentrations of PFAS including linear and branched perfluorooctane sulfonic acid (n-PFOS and Sm-PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS) were measured in serum collected at baseline. Total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol, and triglycerides were measured in blood annually or biannually during follow-up through 2016. Using latent class growth models (LCGMs), trajectories of each lipid were estimated based on the population data. The associations between PFAS and lipid trajectory classes were evaluated by multinomial log-linear models with latent class membership as outcomes and log-transformed PFAS as exposure. RESULTS: Three distinct lipid trajectories (low, medium, and high trajectories) were identified. After adjustment for covariates, n-PFOS and Sm-PFOS were positively associated with higher LDL cholesterol [ORs (95% CI) for high vs. low trajectory per doubling of each PFAS: 1.28 (1.04, 1.56) and 1.24 (1.04, 1.48), respectively]. N-PFOS, n-PFOA, PFNA, and PFHxS were inversely associated with higher triglycerides [ORs (95% CIs) for high vs. low trajectory per doubling of each PFAS: 0.72 (0.55, 0.94), 0.65 (0.50, 0.84), 0.78 (0.62, 1.00), and 0.76 (0.62, 0.93), respectively]. The associations of PFAS with total or HDL cholesterol were insignificant. CONCLUSIONS: Higher serum concentrations of selected PFAS were associated with a higher trajectory of LDL cholesterol and a lower trajectory of triglycerides. Further studies on the underlying mechanisms of the findings are warranted. KEYWORDS: PFAS, dyslipidemia, midlife women

Associations of Perfluoroalkyl Substances with Adipocytokines in Umbilical Cord Serum: A Mixtures Approach

Associations of Perfluoroalkyl Substances with Adipocytokines in Umbilical Cord Serum: A Mixtures Approach

Association between gestational PFAS exposure and Children's adiposity in a diverse population

Perfluoroalkyl substances (PFAS) are widely distributed suspected obesogens that cross the placenta. However, few data are available to assess potential fetal effects of PFAS exposure on children's adiposity in diverse populations. To address the data gap, we estimated associations between gestational PFAS concentrations and childhood adiposity in a diverse mother-child cohort. We considered 6 PFAS in first trimester blood plasma, measured using ultra-high-performance liquid chromatography with tandem mass spectrometry, collected from non-smoking women with low-risk singleton pregnancies (n = 803). Body mass index (BMI), waist circumference (WC), fat mass, fat-free mass, and % body fat were ascertained in 4–8 year old children as measures of adiposity. We estimated associations of individual gestational PFAS with children's adiposity and overweight/obesity, adjusted for confounders. There were more non-Hispanic Black (31.7 %) and Hispanic (42.6 %) children with overweight/obesity, than non-Hispanic white (18.2 %) and Asian/Pacific Islander (16.4 %) children (p < 0.0001). Perfluorooctane sulfonate (PFOS; 5.3 ng/mL) and perfluorooctanoic acid (2.0 ng/mL) had the highest median concentrations in maternal blood. Among women without obesity (n = 667), greater perfluoroundecanoic acid (PFUnDA) was associated with their children having higher WC z-score (β = 0.08, 95%CI: 0.01, 0.14; p = 0.02), fat mass (β = 0.55 kg, 95%CI: 0.21, 0.90; p = 0.002), and % body fat (β = 0.01 %; 95%CI: 0.003, 0.01; p = 0.004), although the association of PFUnDA with fat mass attenuated at the highest concentrations. Among women without obesity, the associations of PFAS and their children's adiposity varied significantly by self-reported race-ethnicity, although the direction of the associations was inconsistent. In contrast, among the children of women with obesity, greater, PFOS, perfluorononanoic acid, and perfluorodecanoic acid concentrations were associated with less adiposity (n = 136). Our results suggest that specific PFAS may be developmental obesogens, and that maternal race-ethnicity may be an important modifier of the associations among women without obesity.

Associations of Perfluoroalkyl Substances with Prevalence of Metabolic Syndrome in Highly Exposed Young Adult Community Residents-A Cross-Sectional Study in Veneto Region, Italy.

Background: Studies on the association between perfluoroalkyl substances (PFAS) and metabolic syndrome (MetS) are limited, and results are inconsistent. We aimed to examine the associations between PFAS serum levels and the prevalence of MetS among highly exposed young adults (ages 20–39) residents of a large area of the Veneto Region (North-Eastern Italy) primarily stemming from PFAS water contamination before September 2013. A total of 15,876 eligible young adult residents living in the investigated municipalities were enrolled in the study from January 2017 to July 2019. Methods: MetS was defined by using a modified harmonized definition requiring the presence of 3 of the following: obesity (body mass index ≥30), elevated triglyceride (TG), reduced high-density lipoprotein cholesterol, elevated blood pressure, and hemoglobin A1c ≥ 6.1% or self-reported diabetes mellitus or drug treatment for hyperglycemia. Multivariable generalized additive models were performed to identify the associations between four serum PFAS, including perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA), and risk of MetS controlling for potential confounders. Results: A total of 1282 participants (8.1%) met the criteria of MetS with a higher prevalence among men. PFOA, PFHxS, and PFNA were not associated with the risk of MetS, whereas PFOS showed a consistent protective effect against the risk of MetS (OR 0.76, (95% CI: 0.69, 0.85) per ln-PFOS). However, we found statistically significant positive associations between PFAS serum levels and individual components of MetS, mainly elevated blood pressure and elevated TG. Conclusion: Our results did not support a consistent association between PFAS and MetS and conflicting findings were observed for individual components of MetS.

Association of perfluoroalkyl substances with gestational hypertension and preeclampsia in the MIREC study

Background: We examined relationships between perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexane sulfonate (PFHxS) and the development of gestational hypertension or preeclampsia in the MIREC Canadian pregnancy cohort. We also explored the potential for fetal sex-stratified effects.Methods: PFOA, PFOS, and PFHxS were analyzed in first trimester maternal plasma samples. Blood pressure and diagnostic information for gestational hypertension and preeclampsia were assessed during each trimester. Logistic regression was used to derive adjusted odds ratios (OR) for associations between PFAS concentrations (per doubling of concentration and by tertile) and gestational hypertension or preeclampsia. Linear mixed models were used to examine associations with changes in blood pressure throughout pregnancy.Results: Of 1739 participants, 90% were normotensive throughout pregnancy, 7% developed gestational hypertension, and 3% developed preeclampsia. In the full sample, neither PFOA nor PFOS were associated with gestational hypertension or preeclampsia. However, each doubling of PFHxS plasma concentration was associated with developing preeclampsia (OR = 1.32; 95%CI: 1.03, 1.70). In addition, participants in the highest PFHxS tertile (1.4 - 40.0 μg/L) had higher odds of developing preeclampsia relative to those in the lowest tertile (OR = 3.06; 95%CI: 1.27, 7.39). In stratified analyses, this effect was only apparent among women carrying a female fetus (OR = 4.90; 95%CI: 1.02, 22.3). However, among women carrying a male fetus, both PFOS and PFHxS were associated with gestational hypertension, but not preeclampsia. Higher concentrations of all three PFAS were associated with increases in diastolic blood pressure, while PFOA and PFHxS were associated with increases in systolic blood pressure.Conclusions: Higher levels of PFHxS were associated with the development of preeclampsia, but not gestational hypertension. Neither PFOA nor PFOS were associated with either outcome. However, we show, for the first time, that fetal sex may modify these associations, a finding which warrants replication and further study.

Associations ofPerfluoroalkyl Substances withIncident Natural Menopause: the Study of Women’s Health Across the Nation

Context: Previous epidemiologic studies of per- and polyfluoroalkyl substances (PFAS) and menopausal timing conducted in cross-sectional settings were limited by reverse causation because PFAS serum concentrations increase after menopause.Objectives: To investigate associations between PFAS serum concentrations and incident natural menopause.Design and Setting: A prospective cohort of midlife women, the Study of Women’s Health Across the Nation, from 1999 to 2017.Participants: 1120 multi-racial/ethnic premenopausal women (White, Black, Chinese and Japanese) aged 45-56 years in 1999-2000.Methods: Serum PFAS concentrations were measured using an online solid phase extraction-high performance liquid chromatography-isotope dilution-tandem mass spectrometry. The final menstrual period was determined during the annual follow-up visits. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs).Results: Participants contributed 5466 person-years of follow-up, and 578 had incident natural menopause. Compared to the lowest tertile, women at the highest tertile of baseline serum concentrations had adjusted HR for natural menopause of 1.26 (95%CI: 1.02-1.57) for n-perfluorooctane sulfonic acid (n-PFOS) (Ptrend=0.03), 1.27 (95%CI: 1.01-1.59) for branched-PFOS (Ptrend=0.03), and 1.31 (95%CI: 1.04-1.65) for n-perfluorooctanoic acid (Ptrend=0.01). Women were classified into four clusters based on their overall PFAS concentrations as mixtures: low, low-medium, medium-high, and high. Compared to the low cluster, the high cluster had a HR of 1.63 (95% CI: 1.44-1.84), which is interpreted as 2.0 years earlier experience of natural menopause.Conclusion: This study suggests that select PFAS serum concentrations are associated with earlier natural menopause, a risk factor for adverse health outcomes in later life.

Plasma perfluoroalkyls are associated with decreased levels of proteomic inflammatory markers in a cross-sectional study of an elderly population

Perfluoroalkyl substances (PFAS) have been linked to immunotoxicity in experimental studies. Although PFAS exposure is associated with altered immune response in epidemiological studies of children, it is less known whether this is observed also in elderly adults. Eight PFAS and 86 proteins were measured in plasma from 965 elderly individuals from Sweden (all aged 70, 50% women). PFAS were measured using isotope-dilution ultra-pressure liquid chromatography coupled to tandem mass spectrometry. Proteins were measured using a multiplex proximity extension assay (PEA) and covered among others inflammatory marker proteins such as monocyte chemoattractant proteins, tumor necrosis factors, and interleukins. We examined cross-sectional associations using multivariable linear regression at two levels of adjustment. We observed significant decreases in levels of 24 proteins in relation to a ln-unit increase in PFAS concentrations following adjustment for sex, sample storage time in freezer, and correction for multiple testing. Associations of PFAS and hepatocyte growth factor (HGF) and macrophage colony-stimulating factor 1 (CSF-1) remained significant (p-value <0.05) following full covariate adjustment for smoking, exercise habits, education, energy, and alcohol intake, body mass index (BMI), glomular filtration rate (GFR) as well as corticoid- and COX-inhibitor treatment. CSF-1 was inversely associated with perfluorohexane sulfonic acid (PFHxS) β: −0.08: 95% confidence interval (CI); −0.13, −0.02), perfluorooctanoic acid (PFOA) β: −0.04: 95% CI; −0.07, −0.006, perfluorononanoic acid (PFNA) β: −0.04: 95% CI; −0.08, −0.003, perfluorodecanoic acid (PFDA) β: −0.03: 95% CI; −0.06, −0.003, and perfluoroundecanoic acid (PFUnDA) β: −0.05: 95% CI; −0.08, −0.02. The magnitude and direction of PFAS vs protein relationships were similar also for HGF. Our findings implicate PFAS exposure with decreased levels of proteomic markers of inflammation in elderly humans.

Associations of Perfluoroalkyl Substances with Incident Natural Menopause: The Study of Women's Health Across the Nation.

Previous epidemiologic studies of per- and polyfluoroalkyl substances (PFASs) and menopausal timing conducted in cross-sectional settings were limited by reverse causation because PFAS serum concentrations increase after menopause. To investigate associations between perfluoroalkyl substances and incident natural menopause. A prospective cohort of midlife women, the Study of Women's Health Across the Nation, 1999-2017. 1120 multiracial/ethnic premenopausal women aged 45-56 years. Serum concentrations of perfluoroalkyls were quantified by high-performance liquid chromatography isotope dilution tandem mass spectrometry. Natural menopause was defined as the bleeding episode prior to at least 12 months of amenorrhea not due to surgery or hormone use. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Participants contributed 5466 person-years of follow-up, and 578 had incident natural menopause. Compared with the lowest tertile, women at the highest tertile of baseline serum concentrations had adjusted HR for natural menopause of 1.26 (95% CI: 1.02-1.57) for n-perfluorooctane sulfonic acid (n-PFOS) (Ptrend = .03), 1.27 (95% CI: 1.01-1.59) for branched-PFOS (Ptrend = .03), and 1.31 (95% CI: 1.04-1.65) for n-perfluorooctanoic acid (Ptrend = .01). Women were classified into four clusters based on their overall PFAS concentrations as mixtures: low, low-medium, medium-high, and high. Compared with the low cluster, the high cluster had a HR of 1.63 (95% CI: 1.08-2.45), which is equivalent to 2.0 years earlier median time to natural menopause. This study suggests that select PFAS serum concentrations are associated with earlier natural menopause, a risk factor for adverse health outcomes in later life.

Association of perfluoroalkyl substances with gestational hypertension and preeclampsia in the MIREC study

BackgroundPerfluoroalkyl substances (PFAS) have been linked with a number of developmental, reproductive, hepatic, and cardiovascular health outcomes. However, the evidence for an association between PFAS and hypertensive disorders of pregnancy (including gestational hypertension and preeclampsia) is equivocal and warrants further investigation. ObjectivesTo examine the relationship between background levels of perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorohexane sulfonate (PFHxS) and the development of gestational hypertension or preeclampsia in a Canadian pregnancy cohort. We also explored the potential for effect modification according to fetal sex. MethodsMaternal plasma samples were collected in the first trimester from participants in the MIREC study and were analyzed for PFOA, PFOS, and PFHxS. Blood pressure was measured during each trimester. Gestational hypertension and preeclampsia were defined using the Society of Obstetricians and Gynaecologists of Canada guidelines. Logistic regression models were used to derive adjusted odds ratios (OR) and 95% confidence intervals (CI) for associations between PFAS concentrations (per doubling of concentration as well as according to tertiles) and gestational hypertension or preeclampsia. Linear mixed models were used to examine the association between PFAS concentrations and changes in blood pressure throughout pregnancy. ResultsData from 1739 participants were analyzed. 90% of women were normotensive throughout pregnancy, 7% developed gestational hypertension without preeclampsia, and 3% developed preeclampsia. In the full analyses, neither PFOA nor PFOS were associated with gestational hypertension or preeclampsia. However, each doubling of PFHxS plasma concentration was associated with higher odds of developing preeclampsia (OR = 1.32; 95% CI: 1.03, 1.70). In addition, participants in the highest PFHxS tertile (1.4–40.0 μg/L) had higher odds of developing preeclampsia relative to those in the lowest tertile (OR = 3.06; 95% CI: 1.27, 7.39). In stratified analyses, this effect was only apparent among women carrying a female fetus (OR = 4.90; 95% CI: 1.02, 22.3). However, among women carrying a male fetus, both PFOS and PFHxS were associated with gestational hypertension, but not preeclampsia. Higher plasma concentrations of all three PFAS were associated with increases in diastolic blood pressure throughout pregnancy, and PFOA and PFHxS were also associated with systolic blood pressure. Discrepant findings were similarly revealed in analyses stratified by fetal sex. ConclusionsHigher levels of PFHxS were associated with the development of preeclampsia, but not gestational hypertension. Neither PFOA nor PFOS were associated with either outcome. However, we show, for the first time, that fetal sex may modify these associations, a finding which warrants replication and further study.

Incidence of ocular conditions associated with perfluoroalkyl substances exposure: Isomers of C8 Health Project in China

The detrimental effects of perfluoroalkyl substances (PFASs) on several physiological systems have been reported, but the association of PFASs with eye, one of the most sensitive and exposed organ, has never been explored. To investigate the association between eye diseases including visual impairment (VI) and PFASs isomers, a cross-sectional stratified study was conducted in 1202 Chinese population, aged 22–96 years, from Shenyang, China. A standard protocol including Snellen vision chart, slit-lamp microscopy and direct ophthalmoscopy was used to examine eye diseases/conditions relating to anterior and posterior segment of eyes. In addition, we measured the blood concentrations of 19 linear and branched PFASs at one-time point. Results indicated that blood levels of PFASs were significantly higher in eye disease group than normal group. PFASs exposure were positively associated with both combined eye diseases and individual eye diseases. Among other PFASs, linear perfluorooctane sulfonate (n-PFOS; odds ratio [OR] = 3.37, 95% confidence interval [CI]: 2.50, 4.56), branched perfluorooctane sulfonate (Br-PFOS; OR = 2.25, 95% CI: 1.72, 2.93) and linear perfluorooctanoic acid (n-PFOA; OR = 1.79, 95% CI: 1.36, 2.37) significantly increases the odds of VI. Vitreous disorder was adversely associated with long-chain PFASs exposure. For example, perfluorotridecanoic acid (PFTrDA; OR = 1.86, 95% CI: 1.51, 2.29) and perfluorodecanoic acid (PFDA; OR = 1.79, 95% CI: 1.36, 2.36) showed the most significant association. In conclusion, this study suggests higher serum PFASs levels were associated with increase odds of VI and vitreous disorder in Chinese adults.

Associations of perfluoroalkyl substances with proteomic biomarkers of inflammation

PDS 62: Chemicals and metals: exposure and biomarkers, Johan Friso Foyer, Floor 1, August 28, 2019, 10:30 AM - 12:00 PM Background: Perfluoroalkyl substances (PFAS) have been linked to immunotoxicity in experimental studies. Although PFAS exposure is associated with altered immune function in epidemiological studies of children, it is less known whether these findings also hold for adults or elderly individuals. Methods: We measured a panel of 92 proteins in plasma from 965 elderly individuals from Sweden (all aged 70, 50% women) using a multiplex proximity extension assay including, among others, immune-related markers such as tumor necrosis factors, interleukins as well as cardiometabolic markers such as monocyte chemoattractant proteins. Plasma PFAS concentrations were determined using isotope-dilution ultra-pressure liquid chromatography coupled to tandem mass spectrometry. We examined associations using adjusted multivariable linear regression. Results: Of the 86 protein markers passing quality control and detection frequency >75%, 20 were negatively associated with levels of five PFAS following adjustment for sex, sample storage time in freezer, and correction for multiple testing. Associations of some PFAS and hepatocyte growth factor (HGF), macrophage colony-stimulating factor 1 (CSF-1), and tumor necrosis factor receptor 1 (TNF-R1) remained significant following further adjustment for smoking, exercise habits, education, energy, and alcohol intake. In this case, plasma concentrations of perfluorohexane sulfonic acid (PFHxS), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) were inversely associated with HGF (βPFHxS: -0.11: 95% confidence interval (CI); -0.17, -0.06; βPFDA: -0.07: 95% CI; -0.10, -0.04, and βPFUnDA: -0.07: 95% CI; -0.11, -0.04). PFUnDA was further inversely associated with CSF-1 (β: -0.09: 95% CI; -0.12, -0.06) and TNF-R1 (β: -0.07: 95% CI; -0.10, -0.04). Conclusions: Our findings implicate PFAS exposure with decreased plasma inflammatory markers and require replication in larger studies.