Estrogenic Activity of Structurally Distinct PFASs Through Estrogen Receptor Pathway.

Invited Perspective: Challenges in Evaluating the Effect of Per- and Polyfluoroalkyl Substance Mixtures on Polycystic Ovarian Syndrome

BackgroundLong-chained poly- and perfluoroalkyl substances (PFAS) have been used in pesticide formulations but their potential impact on human PFAS exposure has not been addressed. ObjectivesTo investigate if occupationally pesticide exposed female greenhouse workers in Denmark had higher serum concentrations of PFAS than a comparable background population. MethodsSerum samples collected between 1996 and 2001 from 181 pregnant greenhouse workers and a contemporary urban population of 48 pregnant women were analyzed for eight PFAS: perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorooctane sulfonamide (FOSA), N-methyl perfluorooctane sulfonamido acetic acid (N-MeFOSAA), and N-ethyl perfluorooctane sulfonamido acetic acid (N-EtFOSAA). ResultsThe concentrations of PFOA, PFOS, and the PFOS precursors N-MeFOSAA, N-EtFOSAA, and FOSA were higher, and PFHxS was lower, among greenhouse workers than the comparison population. After adjusting for age and parity, serum concentrations of N-MeFOSAA, N-EtFOSAA, and FOSA were 2-to-3-fold higher, and the major PFAS in serum, PFOS and PFOA, were 30–50 % higher among the greenhouse workers. ConclusionHigher serum concentrations of some legacy PFAS among female greenhouse workers indicate that exposure to pesticides is a potential pathway of exposure. Although PFAS use in pesticide applications may appear to be a minor source of exposure for the general population, this pathway deserves attention in risk assessment.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) have been extensively used as synthetic fluorine-containing compounds in various consumer products, including surfactants, cookware, lubricants, clothing, and food packaging, since the 1950s. Evidence has shown that PFASs cross the placental barrier and interfere with fetal thyroid hormone homeostasis, which is crucial for fetal growth and neurobehavioral development in children aged 2-9 years. However, no epidemiological data on the association between prenatal PFAS exposure and neonatal neurobehavioral development are available. In this study, we explored the association between prenatal PFAS exposure and neonatal neurobehavioral development based on the Ezhou cohort study. Blood samples (10 mL) were collected during the third trimester of pregnancy (28-36 weeks) at the Ezhou maternal and child health hospital. The blood specimens were centrifuged at 4000 r/min for 15 min immediately after collection, separated, stored at -80 ℃. The samples were analyzed for seven PFASs, namely, perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroheptanesulfonic acid (PFHpS), and perfluorooctane sulfonamide (PFOSA). The PFASs were separated using a C18 column (100 mm×2.1 mm, 1.7 μm) at an oven temperature of 40 ℃, injection volume of 10 μL, and flow rate of 0.4 mL/min via gradient elution with methanol and ammonium acetate aqueous solution. The instrument was operated in negative electrospray ionization mode with multiple reaction monitoring. The correlation coefficients (r2), limits of detection (LODs) and quantification (LOQs), and spiked recoveries of the seven PFASs were 0.993-0.999, 0.006-0.020 ng/mL, 0.020-0.066 ng/mL, and 84.6%-116.8%, respectively. Neonatal behavioral neurological assessment (NBNA) was used to evaluate newborn cognitive development 72 h after birth; this tool consisted of five clusters, including behavior (six items), passive muscle tone (four items), active muscle tone (four items), primitive reflexes (three items), and general assessment (three items). Each item was rated on a three-point scale (0, 1, or 2), with the 20 items having a maximum score of 40. A total of 379 mother-newborn pairs were included in the analysis. The PFASs with the highest exposure levels was PFOA, with median levels of 19.4 ng/mL. Linear regression models were used to test the effects of ln-converted PFAS levels in newborns. After adjusting for confounding factors, the linear regression model showed that PFOS exposure during pregnancy was associated with decreased active muscle tone(β(95% CI): 0.36(-0.64, 0.08)) and general assessment(β(95% CI): 0.34(-0.61, 0.07)) in all newborns. Furthermore, PFNA exposure was associated with decreased passive muscle tone(β(95% CI): 0.38(-0.74, 0.01)) and total NBNA(β(95% CI): 0.37(-0.68, 0.06)). PFDA exposure was associated with decreased behavior(β(95% CI): 0.28(-0.54, 0.01)), while PFHxS exposure was associated with elevated total NBNA(β(95% CI): 0.27(0.05-0.48)). Gender stratification analysis showed that PFOS exposure during pregnancy was associated with decreased active muscle tone(β(95% CI): 0.54(-0.73, 0.35)) and general assessment(β(95% CI): 0.50(-0.88, 0.13)), PFNA exposure during pregnancy was associated with decreased passive muscle tone(β(95% CI): 0.67(-1.2, 0.14)) and total NBNA(β(95% CI): 0.45(-0.91, 0.01)), PFDA exposure during pregnancy was associated with decreased behavior(β(95% CI): 0.44(-0.71, 0.17)), PFHxS exposure was associated with elevated total NBNA(β(95% CI): 0.41(0.02-0.80)) in male newborns, and PFOA exposure was associated with decreased general assessment(β(95% CI): -0.27(-0.51, 0.02)), and PFDA exposure was associated with elevated behavior(β(95% CI): 0.46(0.40-0.52)) in female newborns. The proposed method separates and detects various PFASs without the need for cumbersome pretreatment processes, and has the advantages of low LODs, satisfactory recoveries, and accurate precision. Thus, it allows for the simultaneous analysis of trace PFASs in microserum samples from pregnant women. Our results also showed that prenatal PFAS exposure can lead to neurobehavioral disorders in offspring, with male newborns showing greater sensitivity than female newborns.

BackgroundExposures to perfluoroalkyl substances (PFAS) have shown positive associations with serum lipids in previous studies. While many studies on lipids investigated associations with perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), there are only a few studies regarding other PFAS, such as perfluorohexane sulfonic acid (PFHxS). The purpose of the current study is to investigate if associations with serum lipids were present, not only for serum PFOS and PFOA, but also for PFHxS, and if the associations with PFAS remained also in a comparison based only on residency in areas with contrasting exposure to PFAS.Methods1945 adults aged 20–60 were included from Ronneby, Sweden, a municipality where one out of two waterworks had been heavily contaminated from aqueous fire-fighting foams, and from a nearby control area. The exposure was categorized based on either been living in areas with contrasting PFAS exposure or based on the actual serum PFAS measurements. Regression analyses of serum lipids were fitted against serum PFAS levels, percentile groups, smooth splines and between exposed and reference areas, adjusting for age, sex and BMI.ResultsDrinking water contamination caused high serum levels of PFOS (median 157 ng/ml) and PFHxS (median 136 ng/ml) and PFOA (median 8.6 ng/ml). These serum PFAS levels in the exposed groups were 5 to 100-fold higher than in the controls. In this population with mixed PFAS exposure, predominantly PFOS and PFHxS, PFAS exposure were positively associated with serum lipids. This was observed both when quantifying exposure as contrast between exposed and controls, and in terms of serum PFAS. Due to high correlations between each PFAS, we cannot separate them.ConclusionsIn conclusion, the present study provides further evidence of a causal association between PFAS and serum lipids, especially for PFHxS.

Per- and polyfluoroalkyl substances (PFAS) are thousands of toxic synthetic chemicals that bioaccumulate and persist in the environment. They are known to cause immunotoxicity, organ damage, endocrine disruption, and reproductive impairments in wildlife such as sea otters (Enhydra lutris). However, there is limited information on the distribution of these chemicals across the northeastern Pacific, and baseline data are missing to assess their potential impacts on sea otters in regions such as British Columbia (BC), Canada. We analyzed liver (n = 11) and skeletal muscle samples (n = 5) from 11 deceased sea otters from coastal BC using the U.S. Environmental Protection Agencymethod 1633 with ultrahigh performance liquid chromatography coupled to a triple quadrupole mass spectrometer. We found 8 of the 40 tested PFAS were present in all sampled sea otters, although concentrations of each PFAS varied between individuals. Sea otter livers contained more PFAS compounds at higher total average concentrations than skeletal muscle (i.e., 8 PFAS totaling 10.38 ng/g wet wt vs. 1 PFAS totaling 0.38 ng/g wet wt). Only perfluorooctanesulfonamide (PFOSA) was identified in both liver and muscle tissues, whereas the remaining 7 PFAS were unique to the liver. The three PFAS that dominated the liver PFAS composition (perfluorononanoic acid, PFOSA, and perfluorooctanesulfonic acid) accounted for 84% of the contaminant load in the livers. Geographically, PFAS concentrations were more thanthree times higher on average in sea otters recovered near major cities and shipping routes. Identifying the contaminants accumulating in sea otters provides insights into the health threats confronted by recovering sea otter populations. Our study also establishes baseline PFAS contamination levels in BC sea otters, which can be used to monitor and regulate the presence of PFAS on marine environments in western Canada.

Per- and polyfluoroalkyl substances (PFAS) are persistent chemicals used in many industries, known for their resilience and resistance to degradation. The extended half-lives of PFAS in the human body result in bioaccumulation, with serum half-lives for perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorohexane sulfonic acid (PFHxS) estimated at 3.4, 4.6, and 7.1 years, respectively. PFAS primarily accumulate in the liver, hypothesized due to their resemblance to fatty acids and their binding with liver fatty acid-binding proteins (LFABP), affecting lipid metabolism and leading to liver toxicity. Although extensive research has been performed on long-chain PFAS over the past decade, and despite the increasing industrial production and use of short-chain PFAS, there has been a significant lack of studies addressing their health effects upon exposure, and alteration of short-chain PFAS in the environment. Given the extensive spectrum of toxic effects exerted by PFAS, proteomics emerges as a valuable approach for investigating the underlying mechanisms and pathways involved in PFAS-induced toxicity. This thesis uses animal models to explore the role of FABPs on distribution and hepatotoxicity of the PFOS. Moreover, using proteomics technique, HFD and PFAS adverse effects on pups’ lung development in vivo and the adipogenicity potential of PFAS in vitro were studied. In manuscript 1, we investigated PFOS distribution and retention in wild-type, LFABP-deficient, and IFABP-deficient mice. The study showed that LFABP doesn’t plays a significant role in PFOS preferential distribution to the liver. In manuscript 2 we studied the impact of LFABP deficiency on lipid profiles and liver toxicity in mice exposed to PFOS. LFABP-deficient mice displayed altered lipid profiles and activated lipid metabolism regulators, and a possible protective effect against PFOS-induced liver toxicity. In manuscript 3 we explored the adipogenic potential of ten different PFAS compounds in vitro. 3T3-L1 cells were used to assess changes in protein expression, identifying pathways related to adipogenesis and associated health risks. Manuscript 4 focused on the effects of maternal PFAS exposure on neonatal lung development in mice. Pregnant mice received PFAS compounds with varying diets, showing that maternal exposure to PFAS could impact lung proteomics in offspring, potentially exacerbated by high-fat diets. Overall, these studies highlight the adverse health effects of PFAS emphasizing the urgent need for regulation and ultimately ban these chemicals from being used in consumer goods and industrial settings.

Per-and Polyfluoroalkyl Substances (PFAS), which includes PFOS and PFOA, are recognized as the most important class of emerging contaminants due to their widespread presence in wildlife and humans, their environmental persistence, bioaccumulative potential, and toxicity. Low environmental pH conditions affect the state and physicochemical properties of PFAS, which in turn impacts on their toxicity. Sparse information is available regarding the effect of these compounds on microorganisms, and the possible associated knock-on effect on ecosystem services. The purpose of this study is to investigate the ability of E. coli to tolerate stress in the presence of PFAS compounds. To this end, we carried out phenotypic comparisons of E. coli exposed to a series of environmental conditions in the presence and absence of PFOA and PFOS. Quite remarkably, E. coli growth was not affected by the presence of PFOA and PFOS up to 500 mg/L. The survival of E. coli at pH3, however, decreased by more than three-fold when the medium was supplemented with PFOA. PFOA and PFOS were also found to decrease the growth rates of E. coli in minimal media in the presence of 0.75 and 1M NaCl. We are currently screening further stresses of environmental relevance with the aim to conduct molecular investigations to examine the mechanisms underpinning the effect of PFAS exposure on bacterial stress tolerance. This work will provide some insights into the impact of PFAS on microorganisms, which should shed new light on the assessment of the ecological effects of PFAS.

Distribution, partitioning behavior and potential source of legacy and alternative per- and polyfluoroalkyl substances (PFASs) in water and sediments from a subtropical Gulf, South China Sea

Background/Aim: Animal studies indicate that perfluoroalkyl substances (PFAS), including perfluorohexanesulfonic acid (PFHxS), perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorononanoic acid (PFNA), may be neurotoxicants. Few birth cohorts have studied possible PFAS effects in child brain development longitudinally. We investigated the association between plasma PFAS concentrations at gestational week 12 and neuropsychological development throughout the first 6 years of life. Methods: The study population was 1,239 mother-child pairs from the Gipuzkoa, Sabadell, and Valencia INMA-cohorts, Spain (recruitment period: 2003-2008). Brain development was assessed using two Bayley scales at age 11-18 months (Cognitive and Motor Scales) and three McCarthy scales at age 4-6.5 years (General Cognitive Index, which is a combination of verbal, perceptual-performance, and quantitative domains, and Gross and Fine Motor Scales). Raw scores were standardized to a mean (SD) of 100(15) for child's age in days at evaluation and the psychologist who administered the test. Multivariate regression analyses between log2-transformed (PFAS) and neuropsychological scores were conducted in each sub-cohort and estimates were then pooled by meta-analysis to account for possible heterogeneity. Linearity was accepted after using generalized additive models. Results: Median concentrations of PFHxS, PFOA, PFOS, and PFNA were: 0.58, 2.36, 6.06, and 0.66 ng/mL, respectively. Inverse significant associations (p≤0.05) were found between PFAS and the Bayley Motor Scale with betas ranging between -1.45 (PFNA) and -1.87 (PFOS) per doubling of PFAS concentrations. Negative associations were also found with the Gross Motor McCarthy Scale, but statistical significance was only reached for PFOA (Beta [95%CI]: -1.22[-2.43, 0.00]). No association was found between PFAS and the Bayley or the McCarthy Cognitive scales. Conclusions: Results suggest a possible effect of prenatal PFAS exposure on psychomotor but not cognitive development during childhood, this being clearer during the 1st-2nd years of life. Funding: ISCIII (FIS-FEDER: PI12/01890, PI13/1944, PI14/00891; PFIS-FI14/00099; Miguel Servet-FEDER: CP11/0178, CPII16/00051); FISABIO (UGP-15-230, UGP-15-249, and UGP-15-244).

Background and Aim: Polyfluoroalkyl substances and perfluoroalkyl substances (PFAS) include numerous anthropogenic chemicals used in firefighting foams, non-stick cookware, food packaging, and waterproof clothing. Research has shown some PFAS exposures appear to be decreasing in the general population of Canada. In contrast, prior to a human biomonitoring research completed in Old Crow, Yukon and the Mackenzie Valley, Northwest Territories, much less was known on exposure patterns for Dene and Gwich’in populations. This research aims to describe exposure patterns among these populations by identifying determinants and potential sources of PFAS exposure for participants. Method: Nine PFAS (including: perfluorooctanoic acid (PFOA), perfluorooctane sulphonic acid (PFOS), perfluorohexane sulphonic acid (PFHxS), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUdA), perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), and perfluorobutane sulphonic acid (PFBS)) were quantified using liquid chromatography mass spectrometry in blood samples collected in Old Crow (n=54) and the Dehcho Region, Northwest Territories (n=125). Results: This research showed that, for most PFAS, levels in Old Crow and the Dehcho Region, Northwest Territories were similar or lower to those observed in the Canadian Health Measures Survey. The key exception to this was perfluorononanoic acid (PFNA) which, relative to the CHMS (0.51 μg/L), was approximately 1.8 times higher in Old Crow (0.94 μg/L) and 2.8 times higher in Dehcho (1.42 μg/L) than observed in the general Canadian population. This presentation will report results describing the associations, using multivariable logistic regression, between PFAS levels and consumption of traditional food, lifestyle factors, and demographics. Conclusions: The results highlight the importance of expanding PFAS analytical suites beyond PFOS and PFOA for both human biomonitoring as well as environmental sampling in northern environments. Keywords: Biomonitoring; Contaminants; Indigenous; Traditional Foods; PFAS; PFNA

Perfluoroalkyl substances, airways infections, allergy and asthma related health outcomes – implications of gender, exposure period and study design

A critical assessment of passive air samplers for per- and polyfluoroalkyl substances

BackgroundPerfluoroalkyl substances (PFASs) are a large family of synthetic chemicals, some of which are mammary toxicants and endocrine disruptors. Recent studies have implicated exposure to PFASs as a risk factor for breast cancer in Europe and America. Little is known about the role of PFASs with respect to breast cancer in the Chinese population.MethodsParticipants who were initially diagnosed with breast cancer at Tianjin Medical University Cancer Institute and Hospital between 2012 and 2016 were recruited as cases. The controls were randomly selected from the participants with available blood samples in the Chinese National Breast Cancer Screening Program (CNBCSP) cohort. Ultimately, we enrolled 373 breast cancer patients and 657 controls. Plasma PFASs were measured by an ultra-performance liquid chromatography (UPLC) system coupled to a 5500 Q-Trap triple quadrupole mass spectrometer. A logistic regression model with least absolute shrinkage and selection operator (LASSO) regularization was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationships between PFASs and breast cancer. The three most predictive variables in the LASSO model were selected from 17 PFASs, which was based on the optimal penalty coefficient (λ = 0.0218) identified with the minimum criterion. Additionally, Bayesian kernel machine regression (BKMR) and quantile g-computation models were applied to evaluate the associations between separate and mixed exposure to PFASs and breast cancer.ResultsPerfluorooctanesulfonic acid (PFOS) exhibited the highest concentration in both the cases and controls. Perfluorooctanoic acid (PFOA) and perfluoro-n-decanoic acid (PFDA) were positively associated with breast cancer, and perfluoro-n-tridecanoic acid (PFTrDA) was negatively associated with breast cancer according to both the continuous-PFASs and the quartile-PFASs logistic regression models. Of note, PFOA was associated with the occurrence of estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-positive breast cancer (ORER+ = 1.47, 95% CI: 1.19, 1.80; ORPR+ = 1.36, 95% CI: 1.09, 1.69; ORHER2 = 1.62, 95% CI: 1.19, 2.21).ConclusionsOverall, we observed that PFASs were associated with breast cancer in Chinese women. Prospective cohort studies and mechanistic experiments are warranted to elucidate whether these associations are causal.

New insight into PFOS transformation pathways and the associated competitive inhibition with other perfluoroalkyl acids via photoelectrochemical processes using GOTiO2 film photoelectrodes

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous contaminants which are also found in drinking water. Concentration levels in drinking water vary widely and range from a very low contribution to total daily exposure for humans to being the major source of uptake of PFAS. PFAS concentrations in Norwegian drinking water has been rarely reported. We investigated concentrations of 31 PFAS in 164 water samples, representing both source water (i.e., before drinking water treatment) and finished drinking water. Samples were taken from 18 different water bodies across Norway. The 17 waterworks involved supply drinking water to 41 % of the Norwegian population. Only four of the waterworks utilised treatment involving activated carbon which was able to significantly reduce PFAS from the source water. Samples of source water from waterworks not employing activated carbon in treatment were therefore considered to represent drinking water with regards to PFAS (142 samples). All samples from one of the water bodies exceeded the environmental quality standard (EQS) for perfluorooctane sulfonic acid (PFOS) according to the water framework directive (0.65 ng/L). No concentrations exceeded the sum of (20) PFAS (100 ng/L) specified in the EU directive 2020/2184 for drinking water. Several EU countries have issued lower guidelines for the sum of the four PFAS that the European Food Safety Authority (EFSA) has established as the tolerable weekly intake (TWI) for PFOS, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS). Denmark and Sweden have guidelines specifying 2 and 4 ng/L for the sum of these PFAS. Only one of the 142 drinking water samples exceeded the Danish TWI and contained a sum of 6.6 ng/L PFAS. A population exposure model, for individuals drinking water from the investigated sources, showed that only 0.5 % of the population was receiving PFAS concentrations above the Danish limit of 2 ng/L.