Perfluoroalkyl Substances Exposure Research Articles

Gestational perfluoroalkyl substance exposures and early adolescent bone mineral density in the HOME Study

Background/Aim: Perfluoroalkyl substances (PFAS) may impair bone health via endocrine disruption and nuclear hormone receptor activation. Bone mineral accrual during adolescence is important for long-term bone health, but human studies of PFAS and bone mineral density are primarily in adults or use a cross-sectional study design. We estimated associations of gestational PFAS exposures with early adolescent areal bone mineral density (aBMD) in a prospective cohort study. Methods: We examined 225 pregnant mothers enrolled from 2003-2006 in Cincinnati, OH and their children in the HOME Study. We measured concentrations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononaoic acid (PFNA), and perfluorohexanesulfonic acid (PFHxS) in maternal serum collected at 16 weeks gestation. When children were 12 years old, we measured lean body mass and total body, spine, total hip, femoral neck, and distal forearm (1/3 radius) aBMD with dual x-ray absorptiometry and calculated height-, age-, sex-, and race-specific aBMD z-scores. Using linear regression, we estimated covariate-adjusted associations in aBMD z-scores per doubling of gestational PFAS concentrations overall and stratified by sex. We estimated the proportion of total effects that were mediated by lean mass using structural equation modeling. Results: In adjusted models, higher PFOA concentrations were associated with lower aBMD z-scores of the forearm (β: -0.28, 95% CI: -0.49, -0.08), total hip (β: -0.28, 95% CI: -0.54, -0.02), and spine (β: -0.34, 95% CI: -0.61, -0.06) in males but not females. Lean mass mediated 29-50% of these associations. Higher PFHxS and PFNA concentrations were associated with lower aBMD z-scores of the forearm (PFHxS β: -0.11, 95% CI: -0.23, 0.00; PFNA β: -0.14, 95% CI: -0.35, 0.06), with no modification by sex or mediation by lean mass. PFOS was not associated with aBMD measures in either sex. Conclusions: Gestational PFAS exposures may reduce bone accrual in early adolescence, possibly in a sex-dependent manner.

Plasma metabolites associated with exposure to perfluoroalkyl substances and risk of type 2 diabetes – A nested case-control study

Perfluoroalkyl substances (PFAS) are widespread persistent environmental pollutants. There is evidence that PFAS induce metabolic perturbations in humans, but underlying mechanisms are still unknown. In this exploratory study, we investigated PFAS-related plasma metabolites for their associations with type 2 diabetes (T2D) to gain potential mechanistic insight in these perturbations.We used untargeted LC-MS metabolomics to find metabolites related to PFAS exposures in a case-control study on T2D (n = 187 matched pairs) nested within the Västerbotten Intervention Programme cohort. Following principal component analysis (PCA), six PFAS measured in plasma appeared in two groups: 1) perfluorononanoic acid, perfluorodecanoic acid and perfluoroundecanoic acid and 2) perfluorohexane sulfonic acid, perfluorooctane sulfonic acid and perfluorooctanoic acid. Using a random forest algorithm, we discovered metabolite features associated with individual PFAS and PFAS exposure groups which were subsequently investigated for associations with risk of T2D.PFAS levels correlated with 171 metabolite features (0.16 ≤ |r| ≤ 0.37, false discovery rate (FDR) adjusted p < 0.05). Out of these, 35 associated with T2D (p < 0.05), with 7 remaining after multiple testing adjustment (FDR < 0.05). PCA of the 35 PFAS- and T2D-related metabolite features revealed two patterns, dominated by glycerophospholipids and diacylglycerols, with opposite T2D associations. The glycerophospholipids correlated positively with PFAS and associated inversely with risk for T2D (Odds Ratio (OR) per 1 standard deviation (1-SD) increase in metabolite PCA pattern score = 0.2; 95% Confidence Interval (CI) = 0.1–0.4). The diacylglycerols also correlated positively with PFAS, but they associated with increased risk for T2D (OR per 1-SD = 1.9; 95% CI = 1.3–2.7). These results suggest that PFAS associate with two groups of lipid species with opposite relations to T2D risk.

Environmental Exposure to Perfluoroalkyl Substances in Early Pregnancy, Maternal Glucose Homeostasis and the Risk of Gestational Diabetes: A Prospective Cohort Study

Background: Humans are widely exposed to environmental perfluoroalkyl substances ( PFAS ), which may alter glucose homeostasis . However, research linking PFAS exposure to glucose tolerance during pregnancy is limited and the results were inconsistent. We aimed to investigate the association between PFAS exposure and glucose homeostasis in pregnancy in a large prospective cohort. Methods: A total of 2747 pregnant women who participated in the Shanghai Birth Cohort, had blood samples in early pregnancy and completed a 75 g oral glucose tolerance test (OGTT) at 24-28 gestational weeks were included. 10 PFAS were determined by high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS-MS) in the plasma samples in early pregnancy. Logistic regression was used to explore the associations between PFAS concentrations and gestational diabetes mellitus (GDM), while multiple linear regression was used to model the associations between PFAS and OGTT fasting, 1-h and 2-h glucose levels. Potential confounders were adjusted. Bayesian kernel machine regression (BKMR) and a quantile-based g-computation approach were employed to explore the joint and independent effects of PFAS on glucose homeostasis. Findings: The incidence of GDM was 11·8%. One log-unit increment in plasma concentrations in early pregnancy was associated with an increased risk of GDM for perfluorobutane sulfonate (PFBS) [adjusted odd ratio (aOR)=1·23, 95% confidence interval (95% CI): 1·05,1·44] and perfluoroheptanoic acid (PFHpA) (aOR=1·25, 95% CI: 1·07,1·46). Perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorohexanesulfonate (PFHxS) and PFHpA were positively correlated with 1-h and 2-h glucose levels. Results of the mixed exposure model showed that the joint effects of PFAS were significantly associated with abnormal glucose homeostasis; PFOS, PFNA and PFHpA may be the main contributors. The above associations were more prominent among women with a normal prepregnant BMI. Interpretation: Environmental exposure to PFAS may affect glucose homeostasis in pregnancy and increase the risk of GDM, especially in normal weight women. Funding Statement: This study was funded by the National Nature Science Foundation of China (41991314 and 81530086) and the Collaborative Innovation Program of the Shanghai Municipal Health Commission (2020CXJQ01), the Ministry of Science and Technology of China (2019YFA0802501), and supported in part by the National Human Genetic Resources Sharing Service Platform (2005DKA21300). Declaration of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Ethics Approval Statement: This project was approved by the Research Ethics Committees of Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine.

PFAS concentration during pregnancy in relation to cardiometabolic health and birth outcomes

IntroductionPoly- and perfluoroalkyl substances (PFAS) are persistent organic pollutants with pervasive exposure and suspected associations with metabolic abnormalities and adverse pregnancy outcomes. The goal of the present study was to examine the relationship between serum-PFAS concentrations measured in late pregnancy with relevant outcomes. MethodsThe study sample included 433 pregnant women enrolled in the Vanguard Pilot Study of the National Children's Study. Six PFAS were measured in primarily third trimester serum, as well as fasting insulin, total cholesterol, and triglycerides. The PFAS were examined in quartiles in relation to serum biomarkers, gestational age at birth and birth weight standardized for gestational age using multivariable-adjusted regression models. ResultsOver 98% of the study population had detectable concentrations of four of the PFAS, and concentrations varied by race/ethnicity. Total cholesterol was positively associated with PFDA, PFNA, and PFOS, and triglycerides with PFDA, PFNA, PFOS, and PFOA, but PFAS were not associated with fasting insulin in adjusted models. Only PFNA was associated with an increased odds of birth at <37 weeks gestation. PFAS were generally not associated with birth weight, though PFHxS was associated with the first quartile of birth weight among males only. ConclusionsThis study of pregnant U.S. women supports the ubiquitous exposure to PFAS and positive associations between PFAS exposure with serum-lipid concentrations. PFAS were largely unassociated with gestational age at birth and birth weight, though PFNA was associated with preterm birth. The results support the vulnerability to PFAS exposure of pregnancy.

Perfluorooctanesulfonate and perfluorooctanoate exacerbate airway inflammation in asthmatic mice and in vitro

Emerging evidence suggests associations between Perfluoroalkyl substances (PFASs) exposure and asthma, but the findings are inconsistent. The current study sought to investigate whether perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) could contribute to asthma exacerbation and to clarify the underlying biological mechanisms. The objectives are a) to determine whether PFOS or PFOA could aggravate the mouse asthma and pulmonary inflammation b) to investigate whether PFOS and PFOA regulate the balance of Th1/Th2 through the JAK-STAT signaling pathway and aggravated asthma. Ovalbumin (OVA) induced asthmatic mice were exposed to PFOS or PFOA by gavage. PFOS and PFOA serum level and toxicity in organs were assessed; and the impacts on respiratory symptoms, lung tissue pathology, T helper cell (Th2) response, and STAT6 pathway activity were also evaluated. In vitro Jurkat cells were used to study the mechanisms of PFOS and PFOA mediated Th1 and Th2 responses. Both PFOS and PFOA exacerbated lung tissue inflammation (greater number of eosinophils and mucus hyperproduction), upregulated Th2 cytokine production (IL-4 and IL-13), and promoted Th2 cells and STAT6 activation. Furthermore, PFOS and PFOA enhanced the Th2 response in Jurkat cells via STAT6 activation; and the effect of PFOS exposure on GATA-3, IL-4 and IFN-γ was blocked after the expression of STAT6 was suppressed in Jurkat cells, however, the effects of PFOA exposure were only partially blocked. PFOS and PFOA aggravated inflammation among OVA-induced asthmatic mice, by promoting the Th2 response in lymphocytes and disturbing the balance of Th1/Th2 through the JAK-STAT signaling pathway.

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.

Dysregulated lipid and fatty acid metabolism link perfluoroalkyl substances exposure and impaired glucose metabolism in young adults

BackgroundPer- and polyfluoroalkyl substances (PFASs) exposure is ubiquitous among the US population and has been linked to adverse health outcomes including cardiometabolic diseases, immune dysregulation and endocrine disruption. However, the metabolic mechanism underlying the adverse health effect of PFASs exposure is unknown. ObjectiveThe aim of this project is to investigate the association between PFASs exposure and altered metabolic pathways linked to increased cardiometabolic risk in young adults. MethodsA total of 102 young adults with 82% overweight or obese participants were enrolled from Southern California between 2014 and 2017. Cardiometabolic outcomes were assessed including oral glucose tolerance test (OGTT) measures, body fat and lipid profiles. High-resolution metabolomics was used to quantify plasma exposure levels of three PFAS congeners and intensity profiles of the untargeted metabolome. Fasting concentrations of 45 targeted metabolites involved in fatty acid and lipid metabolism were used to verify untargeted metabolomics findings. Bayesian Kernel Machine Regression (BKMR) was used to examine the associations between PFAS exposure mixture and cardiometabolic outcomes adjusting for covariates. Mummichog pathway enrichment analysis was used to explore PFAS-associated metabolic pathways. Moreover, the effect of PFAS exposure on the metabolic network, including metabolomic profiles and cardiometabolic outcomes, was investigated. ResultsHigher exposure to perfluorooctanoic acid (PFOA) was associated with higher 30-minute glucose levels and glucose area under the curve (AUC) during the OGTT (p < 0.001). PFAS exposure was also associated with altered lipid pathways, which contributed to the metabolic network connecting PFOA and higher glucose levels following the OGTT. Targeted metabolomics analysis indicated that higher PFOA exposure was associated with higher levels of glycerol (p = 0.006), which itself was associated with higher 30-minute glucose (p = 0.006). ConclusionsIncreased lipolysis and fatty acid oxidation could contribute to the biological mechanisms linking PFAS exposure and impaired glucose metabolism among young adults. Findings of this study warrants future experimental studies and epidemiological studies with larger sample size to replicate.

Perfluoroalkyl acids and sulfonamides and dietary, biological and ecological associations in peregrine falcons from the Laurentian Great Lakes Basin, Canada

Perfluoroalkyl substances (PFAS) are a large, diverse group of chemicals and several perfluoroalkyl acids (PFAAs) are known environmental contaminants. Wildlife exposure to PFAAs and precursors has been shown, but less is known regarding replacements such as shorter-chain PFAS. In the present study, exposure to a suite of PFAAs and associations with dietary, biological and ecological factors were investigated in populations of a sentinel apex species – the peregrine falcon (Falco peregrinus). Nestling blood (n = 57) and sibling eggs (n = 9) were sampled in 2016 and 2018 from nests in rural and urban regions across the Laurentian Great Lakes Basin, Canada. PFSAs (perfluorinated sulfonic acids) including PFHxS, PFOS, and PFDS were detected in most egg and plasma samples, whereas 11 PFCAs (perfluorinated carboxylic acids; C5–C14, C16) compared to eight PFCAs (C8–C14, C16) were detected in most eggs and plasma, respectively. Shorter-chain C8–C10 PFCAs were more dominant in plasma and longer-chain C12–C14 PFCAs in eggs, but profiles were similar for PFOS, PFDS, PFUdA and PFHxDA. The exposure to PFAAs in peregrine falcons is likely mediated by dietary factors such as foraging location (δ13C and δ34S) and trophic position (δ15N) given the associations observed in eggs and nestling plasma, respectively. Moreover, significant relationships were observed for circulating ΣPFCAs and region (rural/urban), and nestling body condition after adjusting for sampling year and dietary tracers, suggesting that compared to rural nestlings, urban nestlings may be more exposed to ΣPFCAs and prone to their potential physiological impacts. Our findings highlight the importance of integrating dietary, biological and ecological factors when studying PFAS exposure in birds.

Association between prenatal exposure to perfluoroalkyl substances and respiratory tract infections in preschool children

BackgroundPrenatal exposure to perfluoroalkyl substances (PFAS) is considered to affect adversely the immune function. However, the effect of prenatal PFAS exposure on respiratory tract infections (RTIs) in children is unclear. Thus, we evaluated whether cord blood PFAS levels were associated with RTI in the first 5 years of life. MethodsThe Shanghai Prenatal Cohort is an on-going birth cohort, which included all the mothers during pregnancy. Children were followed by paediatricians once a year after birth. The levels of 10 PFAS in cord blood were tested using liquid chromatography-mass spectrometry. RTIs were diagnosed based on face-to-face interviews with the parents and review of medical records. Immunoglobulin G (IgG) and immunoglobulin E (IgE) levels, as biomarkers of humoral immunity, were assessed using enzyme-linked immunosorbent assay at age 5 years. Multivariable logistic and linear regression models were applied to study the association between prenatal PFAS exposure and RTIs. ResultsA total of 743 children completed the follow-up, 344 of them had detail information of cord blood PFAS, IgG, and IgE concentrations. Eight PFAS were detected in more than 90% of the cord blood samples, except for perfluoroheptanoic acid (PFHpA) and perfluorooctane sulfonamide (FOSA). During the 5-year follow-up period, the frequency of RTIs increased with age, reaching a peak at age 4. Moreover, 20.6% of the children were diagnosed with recurrent RTIs. Children with recurrent RTIs had higher prenatal perfluorobutane sulfonic acid (PFBS) concentration. Higher prenatal PFBS concentration was positively associated with total RTI frequency (β = 6.05, 95% CI [0.84, 11.26]) in first 5 years of life and negatively associated with IgG level (β = −0.82, 95% CI [-1.67, −0.01]) at age 5. ConclusionsChildren with higher prenatal PFBS were more vulnerable to RTIs in early life, which may be attributed to immunosuppression of IgG production. These findings need to be further verified in larger prospective studies.

Proteomics and lipidomics analyses reveal modulation of lipid metabolism by perfluoroalkyl substances in liver of Atlantic cod (Gadus morhua)

The aim of the present study was to investigate effects of defined mixtures of polycyclic aromatic hydrocarbons (PAHs) and perfluoroalkyl substances (PFASs), at low, environmentally relevant (1× = L), or high (20× = H) doses, on biological responses in Atlantic cod (Gadus morhua). To this end, farmed juvenile cod were exposed at day 0 and day 7 via intraperitoneal (i.p.) injections, in a two-week in vivo experiment. In total, there were 10 groups of fish (n = 21-22): two control groups, four separate exposure groups of PAH and PFAS mixtures (L, H), and four groups combining PAH and PFAS mixtures (L/L, H/L, L/H, H/H). Body burden analyses confirmed a dose-dependent accumulation of PFASs in cod liver and PAH metabolites in bile. The hepatosomatic index (HSI) was significantly reduced for three of the combined PAH/PFAS exposure groups (L-PAH/H-PFAS, H-PAH/L-PFAS, H-PAH/H-PFAS). Analysis of the hepatic proteome identified that pathways related to lipid degradation were significantly affected by PFAS exposure, including upregulation of enzymes in fatty acid degradation pathways, such as fatty acid β-oxidation. The increased abundances of enzymes in lipid catabolic pathways paralleled with decreasing levels of triacylglycerols (TGs) in the H-PFAS exposure group, suggest that PFAS increase lipid catabolism in Atlantic cod. Markers of oxidative stress, including catalase and glutathione S-transferase activities were also induced by PFAS exposure. Only minor and non-significant differences between exposure groups and control were found for cyp1a and acox1 gene expressions, vitellogenin concentrations in plasma, Cyp1a protein synthesis and DNA fragmentation. In summary, our combined proteomics and lipidomics analyses indicate that PFAS may disrupt lipid homeostasis in Atlantic cod.

Serum Perfluoroalkyl Substances, Vaccine Responses, and Morbidity in a Cohort of Guinea-Bissau Children.

Background:Perfluoroalkyl substances (PFAS) are a group of widely used persistent chemicals with suspected immunotoxic effects.Objectives:The present study aimed to examine the association between infant PFAS exposure and antibody responses to measles vaccination as well as morbidity in a low-income country.Methods:In a randomized controlled trial, children from Guinea-Bissau, West Africa, were followed from inclusion (4–7 months of age) through 2 years of age. Half the children received two measles vaccinations (at inclusion and at 9 months of age), and the other half received only one (at 9 months of age). In a subset of 237 children, six PFAS were quantified in serum at inclusion, and measles antibody concentrations were assessed at inclusion and at approximately 9 months and 2 years of age. At inclusion and at the 9-month visit, mothers were interviewed about infant morbidity.Results:All but one child had detectable serum concentrations of all six PFAS, although levels were lower than seen elsewhere. A doubling in perfluorooctane sulfonic acid (PFOS) and perfluorodecanoic acid (PFDA) were associated with 21% (95% CI: 2, 37%) and 25% (95% CI: 1, 43%), respectively, lower measles antibody concentrations at the 9-month visit among the children who had received a measles vaccine at inclusion. Elevated serum PFAS concentrations were also associated with reduced prevaccination measles antibody concentrations and increased morbidity.Discussion:The present study documents that PFAS exposure has reached West Africa and that infants show PFAS-associated increases in morbidity and decreases in measles-specific antibody concentrations before and after vaccination. These findings support the evidence on PFAS immunotoxicity at comparatively low serum concentrations. https://doi.org/10.1289/EHP6517

Exposure to PFAS is Associated with Telomere Length Dynamics and Demographic Responses of an Arctic Top Predator.

Environmental factors that can influence telomeres are diverse, but the association between telomeres and exposure to environmental contaminants is yet to be elucidated. To date, prior studies have focused on legacy persistent chlorinated pollutants (POPs), while the effects of poly- and perfluoroalkyl substances (PFAS) have been poorly documented. Here, we investigated the associations among PFAS congeners, absolute telomere length (cross-sectional approach), and telomere dynamics (rate of telomere length change over time, longitudinal approach) in one of the most contaminated arctic top predators, the glaucous gull Larus hyperboreus from Svalbard. We further estimated the effect of PFAS on apparent survival rates and re-sighting probabilities using a 10-year capture/recapture dataset (2010-2019). We found that birds exposed to higher concentrations of perfluorononadecanoate (PFNA) (median of 1565 pg/mL of ww in males and 1370 pg/mL of ww in females) and perfluorotetradecanoate (PFTeDA) (median of 370 pg/mL of ww in males and 210 pg/mL of ww in females) showed the slowest rate of telomere shortening. We also found that high blood concentrations of perfluorooctanoate (PFOA) (median of 120 pg/mL of ww in males and 150 pg/mL of ww in females) and perfluorohexanesulfonate (PFHxS) (median of 495 pg/mL of ww in males and 395 pg/mL of ww in females) were positively associated with higher re-sighting probabilities and apparent survival in males but not in females. Our work is the first to report an association between single PFAS compounds and telomeres, and the first to link PFAS exposure with survival probabilities, suggesting that the effect of PFAS exposure might be more tied to the type of compound rather than the total concentration of PFAS.

Prenatal exposure to perfluoroalkyl substances modulates neonatal serum phospholipids, increasing risk of type 1 diabetes

In the last decade, increasing incidence of type 1 diabetes (T1D) stabilized in Finland, a phenomenon that coincides with tighter regulation of perfluoroalkyl substances (PFAS). Here, we quantified PFAS to examine their effects, during pregnancy, on lipid and immune-related markers of T1D risk in children. In a mother-infant cohort (264 dyads), high PFAS exposure during pregnancy associated with decreased cord serum phospholipids and progression to T1D-associated islet autoantibodies in the offspring. This PFAS-lipid association appears exacerbated by increased human leukocyte antigen-conferred risk of T1D in infants. Exposure to a single PFAS compound or a mixture of organic pollutants in non-obese diabetic mice resulted in a lipid profile characterized by a similar decrease in phospholipids, a marked increase of lithocholic acid, and accelerated insulitis. Our findings suggest that PFAS exposure during pregnancy contributes to risk and pathogenesis of T1D in offspring.

Rapid biomonitoring of perfluoroalkyl substance exposures in serum by multisegment injection-nonaqueous capillary electrophoresis-tandem mass spectrometry.

Perfluoroalkyl substances (PFASs) are a major contaminant class due to their ubiquitous prevalence, persistence, and putative endocrine disrupting activity that may contribute to chronic disease risk notably with exposures early in life. Herein, multisegment injection-nonaqueous capillary electrophoresis-tandem mass spectrometry (MSI-NACE-MS/MS) is introduced as a high throughput approach for PFAS screening in serum samples following a simple methyl-tert-butyl ether (MTBE) liquid extraction. Separation and ionization conditions were optimized to quantify low nanomolar concentration levels of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) from serum extracts when using multiple reaction monitoring under negative ion mode conditions. Multiplexed separations of PFOA and PFOS were achieved with excellent throughput(<3min/sample), adequate concentration sensitivity (LOD ∼ 20nM, S/N=3) and good technical precision over three consecutive days of analysis (mean CV=9.1%, n=84). Accurate quantification of PFASs was demonstrated in maternal serum samples (n=16) when using MSI-CE-MS/MS following pre-column sample enrichment with median concentrations of 3.46nM (0.7-9.0nM) and 3.29nM (1.5-6.6nM) for PFOA and PFOS, respectively. This was lower than average PFAS exposures measured in pregnant women who had serum collected prior to 2009 likely due to subsequent phase out of their production. Overall, this method offers a convenient approach for large-scale biomonitoring of environmental exposures to legacy PFASs and their emerging replacements that is relevant to maternal health and chronic disease risk assessment in children.

Perfluoroalkyl substances exposure in early pregnancy and preterm birth in singleton pregnancies: a prospective cohort study

BackgroundPreterm birth (PTB, < 37 completed weeks’ gestation) is one of the global public health concerns. Epidemiologic evidence on the potential impact of perfluoroalkyl substances (PFAS) on PTB is still limited and inconsistent. We aimed to investigate the associations between prenatal PFAS exposure and PTB among singleton live births.MethodsWe studied 2849 mother-infant pairs in the Shanghai Birth Cohort (SBC) from 2013 to 2016. Ten PFAS in maternal plasma in early pregnancy (gestational age, median (interquartile range): 15 (13–16) weeks) were measured. Primary outcomes were duration of gestation, PTB, spontaneous PTB and clinically indicated PTB. A linear regression model was used to assess the associations between ln-transformed PFAS and duration of gestation (in weeks). Logistic regression models were applied to estimate the relative risks of these outcomes.ResultsThe incidence of overall PTB was 4.8% (95% confidence limit: 4.0–5.6%, n = 136) in this study population. In the linear regression analyses, PFAS were not associated with the duration of gestation after controlling for potential confounders. In the multiple logistic models, no significant associations were observed between PFAS and overall PTB, spontaneous or indicated PTB.ConclusionIn this prospective cohort study, we did not observe significant associations between maternal plasma PFAS concentrations in early pregnancy and gestational length, overall PTB, spontaneous or indicated PTB.

Perfluoroctanoic acid (PFOA) enhances NOTCH-signaling in an angiogenesis model of placental trophoblast cells.

Exposure to perfluoroalkyl substances (PFAS) was found to be associated with several pathological endpoints, including high cholesterol levels, specific defective functions of the immune system and reduced birth weight. While environmental PFAS have been recognized as threats for public health, surprisingly little is known about the underlying mechanisms of toxicity. We hypothesized that some of the observed vascular and developmental effects of environmental PFAS may share a common molecular pathway. At elevated levels of exposure to PFAS, a reduction in mean birth weight of newborns has been observed in combination with a high incidence rate of preeclampsia. As both, preeclampsia and reduced birth weight are consequences of an inadequate placental vascularization, we hypothesized that the adaptation of placental vasculature may get compromised by PFAS. We analyzed pseudo-vascular network formation and protein expression in the HTR8/SVneo cell line, an embryonic trophoblast cell type that is able to form vessel-like vascular networks in 3D-matrices, similar to endothelial cells. PFOA (perfluoroctanoic acid), but not PFOS (perfuoroctanesulfonic acid), induced morphological changes in the vascular 3D-network structure, without indications of compromised cellular viability. Incubation with PFOA reduced cellular sprouting and elongated isolated stalks in pseudo-vascular networks, while a γ-secretase inhibitor BMS-906024 induced directional opposite effects. We found a PFOA-induced increase in NOTCH intracellular domain (NICD) abundance in HTR8/SVneo, indicating that PFOA enhances NOTCH-signaling in this cell type. Enhancement of NOTCH-pathway by PFOA may be a key to understand the mode of action of PFAS, as this pathway is critically involved in many confirmed physiological/toxicological symptoms associated with PFAS exposure.

Perfluoroalkyl Substance Exposure Early In Pregnancy Was Negatively Associated With Late Pregnancy Cortisone Levels

During pregnancy, maternal cortisol levels are increased 3-fold by the third trimester. The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD, isoforms 1 and 2) regulates the balance between cortisol and cortisone levels. Perfluoroalkyl substances (PFAS) have been reported to inhibit 11β-HSD1 and more potently 11β-HSD2, which could lead to reduced levels of cortisol and more extensively cortisone. The aim of this work is to investigate a possible effect of early pregnancy PFAS exposure on late pregnancy activity of 11β-HSD1 and 11β-HSD2 assessed by cortisol and cortisone levels in diurnal urine (dU) and blood samples. This study is part of the prospective cohort study, Odense Child Cohort (OCC). A total of 1628 pregnant women had serum (S) concentrations of 5 PFAS (perfluorooctanoic acid [PFOA], perfluorooctane sulfonic acid [PFOS], perfluorohexane sulfonic acid [PFHxS], perfluorononanoic acid [PFNA], and perfluorodecanoic acid (PFDA)) measured in the first trimester (median gestational week, GW 11). dU cortisol and cortisone (n = 344) and S-cortisol (n = 1048) were measured in the third trimester (median GW 27). In multiple regression analyses, a 2-fold increase in S-PFOS was significantly associated with lower dU-cortisone (β = -9.1%, P < .05) and higher dU-cortisol/dU-cortisone (dU-C/C) (β = 9.3%, P < .05). In crude models, a doubling in PFOS, PFOA, PFHxS, and PFNA concentrations were associated with a significant increase in S-cortisol; however, these associations became insignificant after adjustment. Early pregnancy maternal S-PFAS were inversely associated with late pregnancy dU-cortisone, indicating reduced activity of 11β-HSD2.

Perfluoroalkyl substances exposure and hearing impairment in US adults

BackgroundPer- and polyfluoroalkyl substances (PFAS) are widely applied in consumer and industrial products such as nonstick cookware, waterproof clothing, food packaging materials, and fire-fighting foams. These “forever chemicals” are hypothesized to impact neurobehavioral functions. Yet no previous study has explored the role of PFAS on audiometrically determined hearing impairment (HI). ObjectivesTo investigate the associations of serum concentrations of perfluoroalkyl substances with low-frequency HI (LFHI) and high-frequency HI (HFHI) in US adults. MethodsWe evaluated the cross-sectional associations in 2371 adults aged 20–69 years who participated in the National Health and Nutrition Examination Survey (NHANES) 2003–2004, 2011–2012 and 2015–2016; and 449 adults aged ≥70 years from NHANES 2005–2006 and 2009–2010. Serum concentrations of perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA), were measured using solid-phase extraction coupled to High Performance Liquid Chromatography-Turbo Ion Spray ionization-tandem Mass Spectrometry. LFHI was defined as a pure-tone average (PTA) of thresholds across 0.5-1-2 kHz >25 dB; HFHI defined as a PTA across 3-4-6 kHz >25 dB in the worse ear. Survey-weighted logistic regression models were used to compute odds ratios (ORs) and 95% confidence intervals (CIs) with adjustment for age, age-squared, sex, race/ethnicity, education, poverty-to-income ratio, body mass index, smoking status, exposures to occupational, recreational and firearm noises, and NHANES cycles. ResultsThere were no significant associations when perfluoroalkyl variables were fitted as a linear (log-transformed) term. However, statistically significant associations of HFHI with PFNA (OR = 1.70, 95% CI: 1.13–2.56) and PFDA (OR = 1.75, 95% CI: 1.00–3.05) were observed when comparing participants with serum concentrations ≥90th vs. <90th percentiles of PFNA (90th percentile = 1.8 ng/mL) and PFDA (90th percentile = 0.5 ng/mL), respectively, in adults aged 20–69 years. No significant associations were observed for other compounds in adults aged 20–69 years and for all compounds in adults ≥70 years. ConclusionsOur study does not provide strong evidence to support the ototoxicity of PFAS exposure. Non-linear threshold dose-response associations between serum concentrations of PFNA and PFDA and HFHI need further investigation.

MON-LB131 Perfluoroalkyl Substance Exposure Was Negatively Associated With Cortisone Levels in Pregnancy

Introduction: During pregnancy, maternal cortisol levels are increased threefold by third trimester. The enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD, isoforms 1 and 2) regulates cortisol levels by the conversion between cortisol and cortisone. Perfluoroalkyl substances (PFAS) are persistent chemicals with suspected endocrine disrupting abilities applied in consumer products. PFAS have been reported to inhibit 11β-HSD1 and 11β-HSD2, which could lead to reduced levels of cortisol and cortisone. Aim: To investigate a possible effect of early pregnancy PFAS exposure on late pregnancy activity of 11β-HSD1 and 11β-HSD2 assessed by cortisol and cortisone levels in urine and blood samples. Methods: The study is part of the prospective cohort study, Odense Child Cohort (OCC). A total of 1,826 pregnant women had serum (S) concentrations of five PFAS (Perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA)) measured in first trimester (median gestational week (GW) 11). Diurnal urinary (dU) cortisol and cortisone (n=344), and S-cortisol (n=1,048) were measured in third trimester (median GW 27). Results: In multiple regression analyses, a two-fold increase in S-PFOS was significantly associated with lower dU-cortisone (β=-9.1%, p<0.05) and higher dU-cortisol/dU-cortisone (dU-C/C) (β=9.3%, p<0.05). The same trend was demonstrated for PFOA, PFHxS, PFNA, and PFDA. In crude models, a doubling in PFOS, PFOA, PFHxS, and PFNA concentrations were associated with a significant increase in S-cortisol, however, these associations became insignificant after adjustment. Conclusion: Early pregnancy concentrations of maternal S-PFAS were inversely associated with late pregnancy dU-cortisone, indicating reduced activity of 11β-HSD2.

Early Life Exposure to Perfluoroalkyl Substances (PFAS) and ADHD: A Meta-Analysis of Nine European Population-Based Studies.

Introduction:To date, the evidence for an association between perfluoroalkyl substances (PFAS) exposure and attention deficit and hyperactivity disorder (ADHD) is inconclusive.Objective:We investigated the association between early life exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), and ADHD in a collaborative study including nine European population-based studies, encompassing 4,826 mother–child pairs.Methods:Concentrations of PFOS and PFOA were measured in maternal serum/plasma during pregnancy, or in breast milk, with different timing of sample collection in each cohort. We used a validated pharmacokinetic model of pregnancy and lactation to estimate concentrations of PFOS and PFOA in children at birth and at 3, 6, 12, and 24 months of age. We classified ADHD using recommended cutoff points for each instrument used to derive symptoms scores. We used multiple imputation for missing covariates, logistic regression to model the association between PFAS exposure and ADHD in each study, and combined all adjusted study-specific effect estimates using random-effects meta-analysis.Results:A total of 399 children were classified as having ADHD, with a prevalence ranging from 2.3% to 7.3% in the studies. Early life exposure to PFOS or PFOA was not associated with ADHD during childhood [odds ratios (ORs) ranging from 0.96 (95% CI: 0.87, 1.06) to 1.02 (95% CI: 0.93, 1.11)]. Results from stratified models suggest potential differential effects of PFAS related to child sex and maternal education.Conclusion:We did not identify an increased prevalence of ADHD in association with early life exposure to PFOS and PFOA. However, stratified analyses suggest that there may be an increased prevalence of ADHD in association with PFAS exposure in girls, in children from nulliparous women, and in children from low-educated mothers, all of which warrant further exploration. https://doi.org/10.1289/EHP5444