Perfluorooctanoic Acid Exposure Research Articles

Identifying novel mechanisms of per- and polyfluoroalkyl substance-induced hepatotoxicity using FRG humanized mice.

Per- and polyfluoroalkyl substances (PFAS) such as perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) and perfluoro-2-methyl-3-oxahexanoic acid (GenX), the new replacement PFAS, are major environmental contaminants. In rodents, these PFAS induce several adverse effects on the liver, including increased proliferation, hepatomegaly, steatosis, hypercholesterolemia, nonalcoholic fatty liver disease and liver cancers. Activation of peroxisome proliferator receptor alpha by PFAS is considered the primary mechanism of action in rodent hepatocyte-induced proliferation. However, the human relevance of this mechanism is uncertain. We investigated human-relevant mechanisms of PFAS-induced adverse hepatic effects using FRG liver-chimeric humanized mice with livers repopulated with functional human hepatocytes. Male FRG humanized mice were treated with 0.067mg/L of PFOA, 0.145mg/L of PFOS, or 1mg/L of GenX in drinking water for 28days. PFOS caused a significant decrease in total serum cholesterol and LDL/VLDL, whereas GenX caused a significant elevation in LDL/VLDL with no change in total cholesterol and HDL. All three PFAS induced significant hepatocyte proliferation. RNA-sequencing with alignment to the human genome showed a total of 240, 162, and 619 differentially expressed genes after PFOA, PFOS, and GenX exposure, respectively. Upstream regulator analysis revealed that all three PFAS induced activation of p53 and inhibition of androgen receptor and NR1D1, a transcriptional repressor important in circadian rhythm. Further biochemical studies confirmed NR1D1 inhibition and in silico modeling indicated potential interaction of all three PFAS with the DNA-binding domain of NR1D1. In conclusion, our studies using FRG humanized mice have revealed new human-relevant molecular mechanisms of PFAS including their previously unknown effect on circadian rhythm.

Human biomonitoring follow-up study on PFOA contamination and investigation of possible influencing factors on PFOA exposure in a German population originally exposed to emissions from a fluoropolymer production plant

BackgroundIn the past, perfluorooctanoic acid (PFOA) was produced and applied as an emulsifier in a fluoropolymer production plant in the Altötting district, southern Bavaria (Germany). This chemical was released directly into the environment, resulting in the contamination of the local drinking water. During a human biomonitoring (HBM) survey in 2018, increased median PFOA blood serum levels, compared to a normally exposed control group with no known source of PFOA exposure from Munich, Germany, were detected in the resident population (23.18 μg/l in the general population, 20.71 μg/l in the children's group). The follow-up study aimed to investigate whether purification of the drinking water as the main PFOA exposure source has been successful in reducing internal PFOA exposure and to estimate the association of internal PFOA exposure with possible influencing factors. MethodsOnly individuals who had already participated in the HBM study in 2018 were included. For the determination of the PFOA serum concentration, 5 ml of blood was drawn from each participating person. Blood samples were collected in the period from June to August 2022. Furthermore, information on sociodemographic characteristics, health status, dietary behaviour and other lifestyle factors were collected by means of a self-administered questionnaire. To examine the association of PFOA blood serum levels with possible influencing factors, such as age, gender and consumption of fish and game meat, a logistic regression model with a PFOA value > 10 μg/l as outcome was used. ResultsA total of 764 individuals participated in the follow-up study in 2022. Analyses were performed separately for the general population (n = 559), women of reproductive age (15–49 years old) (n = 120), and children under 12 years old (n = 30). Median PFOA blood levels have decreased by 56.9% in the general population, by 59.8% in the group of women of reproductive age and by 73.4% in the group of children under 12 years old. In the general population, a higher probability of a PFOA value > 10 μg/l was found for those aged 40–59 years (Odds ratio (OR) = 2.33 (95%CI: 1.23 to 4.43, p = 0.01) and those aged 60 years and older (OR = 5.32, 95%CI: 2.78 to 10.19, p < 0.001). ConclusionsIn all study groups, the median PFOA serum levels decreased as expected after a half-life of four years, which confirms that contamination via drinking water has ceased. Furthermore, our study identified age as a significant predictor of internal PFOA exposure, while no influence was found for the consumption of fish and game meat. Further investigations are needed to quantify in a more detailed way the influence of dietary habits on PFOA exposure.

Comparative steroidogenic effects of hexafluoropropylene oxide trimer acid (HFPO-TA) and perfluorooctanoic acid (PFOA): Regulation of histone modifications

As a widely used alternative to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been detected in the environment and humans; however, little is known regarding its male reproductive toxicity. To compare the effects of HFPO-TA on steroid hormone synthesis with PFOA, we exposed Leydig cells (MLTC-1) to non-lethal doses (0.1, 1, and 10 μM) of PFOA and HFPO-TA for 48 h. It was found that the levels of steroid hormones, 17α-hydroxyprogesterone (OHP), androstenedione (ASD), and testosterone (T) were significantly increased in 1 and 10 μM of PFOA and HFPO-TA groups, with greater elevation being observed in the HFPO-TA groups than in the PFOA groups at 10 μM. We further showed that the two rate-limiting steroidogenic genes (Star and Cyp11a1) were up-regulated, while Hsd3b, Cyp17a1, and Hsd17b were down-regulated or unchanged after PFOA/HFPO-TA exposure. Moreover, PFOA exposure significantly up-regulated histone H3K4me1/3 and H3K9me1, while down-regulated H3K4me2 and H3K9me2/3 levels. By contrast, H3K4me2/3 and H3K9me2/3 were enhanced, while H3K4me1 and H3K9me1 were repressed after HFPO-TA treatment. It was further confirmed that H3K4me1/3 were increased and H3K9me2 was decreased in Star and Cyp11a1 promoters by PFOA, while HFPO-TA increased H3K4me2/3 and decreased H3K9me1 in the two gene promoters. Therefore, we propose that low levels of PFOA/HFPO-TA enhance the expression of Star and Cyp11a1 by regulating H3K4 and H3K9 methylation, thus stimulating the production of steroid hormones in MLTC-1 cells. Collectively, HFPO-TA exhibits stronger effects on steroidogenesis compared to PFOA, which may be ascribed to the distinct regulation of histone modifications. These data suggest that HFPO-TA does not appear to be a safer alternative to PFOA on the aspect of male reproductive toxicity.

Association of Combined Per- and Polyfluoroalkyl Substances and Metals with Chronic Kidney Disease.

Background: Exposure to environmental pollutants such as metals and Per- and Polyfluoroalkyl Substances (PFAS) has become common and increasingly associated with a decrease in the estimated Glomerular Filtration Rate (eGFR), which is a marker often used to measure chronic kidney disease (CKD). However, there are limited studies involving the use of both eGFR and the urine albumin creatinine ratio (uACR), which are more comprehensive markers to determine the presence of CKD and the complexity of pollutant exposures and response interactions, especially for combined metals and PFAS, which has not been comprehensively elucidated. Objective: This study aims to assess the individual and combined effects of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), Cadmium (Cd), Mercury (Hg), and Lead (Pb) exposure on CKD using data from the National Health and Nutritional Examination Survey (NHANES) 2017-2018. Methods: We employed the use of bivariate logistic regression and Bayesian Kernel Machine Regression (BKMR) in our analysis of the data. Results: Logistic regression results revealed a positive association between PFOA and CKD. Our BKMR analysis revealed a non-linear and bi-phasic relationship between the metal exposures and CKD. In our univariate exposure-response function plot, Cd and Hg exhibited a U and N-shaped interaction, which indicated a non-linear and non-additive relationship with both low and high exposures associated with CKD. In addition, the bivariate exposure-response function between two exposures in a mixture revealed that Cd had a U-shaped relationship with CKD at different quantiles of Pb, Hg, PFOA, and PFOS, indicating that both low and high levels of Cd is associated with CKD, implying a non-linear and complex biological interaction. Hg's interaction plot demonstrated a N-shaped association across all quantiles of Cd, with the 75th quantile of Pb and the 50th and 75th quantiles of PFOA and PFOS. Furthermore, the PIP results underscored Cd's consistent association with CKD (PIP = 1.000) followed by Hg's (PIP = 0.9984), then PFOA and PFOS with a closely related PIP of 0.7880 and 0.7604, respectively, and finally Pb (PIP = 0.6940), contributing the least among the five environmental pollutants on CKD, though significant. Conclusions: Our findings revealed that exposure to environmental pollutants, particularly Hg and Cd, are associated with CKD. These findings highlight the need for public health interventions and strategies to mitigate the cumulative effect of PFAS and metal exposure and elucidate the significance of utilizing advanced statistical methods and tools to understand the impact of environmental pollutants on human health. Further research is needed to understand the mechanistic pathways of PFAS and metal-induced kidney injury and CKD, and longitudinal studies are required to ascertain the long-term impact of these environmental exposures.

A novel method to derive a human safety limit for PFOA by gene expression profiling and modelling.

Perfluorooctanoic acid (PFOA) is a persistent environmental contaminant that can accumulate in the human body due to its long half-life. This substance has been associated with liver, pancreatic, testicular and breast cancers, liver steatosis and endocrine disruption. PFOA is a member of a large group of substances also known as "forever chemicals" and the vast majority of substances of this group lack toxicological data that would enable their effective risk assessment in terms of human health hazards. This study aimed to derive a health-based guidance value for PFOA intake (ng/kg BW/day) from in vitro transcriptomics data. To this end, we developed an in silico workflow comprising five components: (i) sourcing in vitro hepatic transcriptomics concentration-response data; (ii) deriving molecular points of departure using BMDExpress3 and performing pathway analysis using gene set enrichment analysis (GSEA) to identify the most sensitive molecular pathways to PFOA exposure; (iii) estimating freely-dissolved PFOA concentrations in vitro using a mass balance model; (iv) estimating in vivo doses by reverse dosimetry using a PBK model for PFOA as part of a quantitative in vitro to in vivo extrapolation (QIVIVE) algorithm; and (v) calculating a tolerable daily intake (TDI) for PFOA. Fourteen percent of interrogated genes exhibited in vitro concentration-response relationships. GSEA pathway enrichment analysis revealed that "fatty acid metabolism" was the most sensitive pathway to PFOA exposure. In vitro free PFOA concentrations were calculated to be 2.9% of the nominal applied concentrations, and these free concentrations were input into the QIVIVE workflow. Exposure doses for a virtual population of 3,000 individuals were estimated, from which a TDI of 0.15ng/kg BW/day for PFOA was calculated using the benchmark dose modelling software, PROAST. This TDI is comparable to previously published values of 1.16, 0.69, and 0.86ng/kg BW/day by the European Food Safety Authority. In conclusion, this study demonstrates the combined utility of an "omics"-derived molecular point of departure and in silico QIVIVE workflow for setting health-based guidance values in anticipation of the acceptance of in vitro concentration-response molecular measurements in chemical risk assessment.

Evaluation of ecological impacts with ferrous iron addition in constructed wetland under perfluorooctanoic acid stress

In this study, ferrous ion (Fe(II)) had the potential to promote ecological functions in constructed wetlands (CWs) under perfluorooctanoic acid (PFOA) stress. Concretely, Fe(II) at 30 mg/L and 20–30 mg/L even led to 11.37% increase of urease and 93.15–243.61% increase of nitrite oxidoreductase respectively compared to the control. Fe(II) promotion was also observed on Nitrosomonas, Nitrospira, Azospira, and Zoogloea by 1.00–6.50 folds, which might result from higher expression of nitrogen fixation and nitrite redox genes. These findings could be explanation for increase of ammonium removal by 7.47–8.75% with Fe(II) addition, and reduction of nitrate accumulation with 30 mg/L Fe(II). Meanwhile, both Fe(II) stimulation on PAOs like Dechloromonas, Rhodococcus, Mesorhizobium, and Methylobacterium by 1.58–2.00 folds, and improvement on chemical phosphorus removal contributed to higher total phosphorus removal efficiency under high-level PFOA exposure. Moreover, Fe(II) raised chlorophyll content and reduced the oxidative damage brought by PFOA, especially at lower dosage. Nevertheless, combination of Fe(II) and high-level PFOA caused inhibition on microbial alpha diversity, which could result in decline of PFOA removal (by 4.29–12.83%). Besides, decrease of genes related to nitrate reduction demonstrated that enhancement on denitrification was due to nitrite reduction to N2 pathways rather than the first step of denitrifying process.

A structural basis for the activation of peroxisome proliferator-activated receptor gamma (PPARγ) by perfluorooctanoic acid (PFOA)

Perfluorooctanoic acid (PFOA) is a widespread environmental pollutant of the perfluoroalkyl substance (PFAS) class that is extremely resistant to environmental and metabolic degradation, leading to bioaccumulation. PFOA exposure has been linked to many health effects including endocrine disruption and metabolic dysregulation, but our understanding of the molecular mechanisms resulting in these outcomes remains incomplete. One target affected by PFOA is the ligand regulated nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) which plays a critical role in controlling metabolic homeostasis through regulating processes such as adipogenesis, glucose homeostasis, inflammation and osteogenesis. It has been previously established that PFOA activates PPARγ through binding to the PPARγ ligand binding domain (PPARγ LBD) leading to increased expression of PPARγ controlled target genes. However, the mechanism by which PFOA achieves this has remained elusive. Here, we employed a combination of X-ray crystallography and fluorescence polarization assays to provide a structural basis for PFOA mediated activation of PPARγ via binding to the PPARγ LBD. Using X-ray crystallography, the cocrystal structure of the PPARγ LBD:PFOA complex was solved. This revealed that PFOA occupies three distinct sites, two within the PPARγ LBD and one within the activation function 2 (AF2) on the protein surface. Structural comparison of PFOA binding with previously reported PPARγ:ligand complexes supports that PFOA activates PPARγ by a partial agonist mechanism at micromolar concentrations. Fluorescence polarization assays also revealed that PFOA binding to the AF2 is unlikely to occur in a cellular context and confirmed that PFOA behaves as a partial agonist in vitro, weakly recruiting a coactivator peptide to the AF2 of the PPARγ LBD. This discovery provides an advancement in understanding PFOA mediated regulation of PPARγ, giving new insight regarding regulation of PPARγ by PFAS and PFAS substitutes in general and can be applied to the design and assessment of safer PFAS.

Comparative hepatotoxicity of novel lithium bis(trifluoromethanesulfonyl)imide (LiTFSI, ie. HQ-115) and legacy Perfluorooctanoic acid (PFOA) in male mice: Insights into epigenetic mechanisms and pathway-specific responses

Lithium Bis(trifluoromethanesulfonyl)imide (LiTFSI ie. HQ-115), a polymer electrolyte used in energy applications, has been detected in the environment, yet its health risks and environmental epigenetic effects remain unknown. This study aims to unravel the potential health risks associated with LiTFSI, investigate the role of DNA methylation-induced toxic mechanisms in its effects, and compare its hepatotoxic impact with the well-studied Perfluorooctanoic Acid (PFOA). Using a murine model, six-week-old male CD1 mice were exposed to 10 and 20 mg/kg/day of each chemical for 14 days as 14-day exposure and 1 and 5 mg/kg/day for 30 days as 30-day exposure. Results indicate that PFOA exposure induced significant hepatotoxicity, characterized by liver enlargement, and elevated serum biomarkers. In contrast, LiTFSI exposure showed lower hepatotoxicity, accompanied by mild liver injuries. Despite higher bioaccumulation of PFOA in serum, LiTFSI exhibited a similar range of liver concentrations compared to PFOA. Reduced Representative Bisulfite Sequencing (RRBS) analysis revealed distinct DNA methylation patterns between 14-day and 30-day exposure for the two compounds. Both LiTFSI and PFOA implicated liver inflammatory pathways and lipid metabolism. Transcriptional results showed that differentially methylated regions in both exposures are enriched with cancer/disease-related motifs. Furthermore, Peroxisome proliferator-activated receptor alpha (PPARα), a regulator of lipid metabolism, was upregulated in both exposures, with downstream genes indicating potential oxidative damages. Overall, LiTFSI exhibits distinct hepatotoxicity profiles, emphasizing the need for comprehensive assessment of emerging PFAS compounds.

Association between prenatal exposure to per- and polyfluoroalkyl substances and infant anthropometry: A prospective cohort study

BackgroundPer- and polyfluoroalkyl substances (PFAS) are a group of synthetic organic chemicals with potential endocrine-disrupting effects, and have been found to impair the physical growth of offspring in both experimental and epidemiological studies. We aimed to investigate the effects of prenatal PFAS exposure on repeated measurements of multiple anthropometric indicators in infants. MethodPFAS were measured in serum samples collected from pregnant women at 12–16 gestational weeks. We calculated z-scores for the weight-for-age (WAZ), weight-for-length (WLZ), head circumference-for-age (HCZ), arm circumference-for-age (ACZ), triceps skinfold-for-age (TSZ), and subscapular skinfold-for-age (SSZ) at birth, 6 months, and 12 months of age according to the child growth standards of the World Health Organization (WHO) for anthropometric indicators. A total of 964 mother–infant pairs were included. A multivariate linear regression was performed to examine the associations between prenatal PFAS concentrations and anthropometric indicators at each time point. A generalized estimating equation (GEE) model was used to examine the longitudinal effects of PFAS exposure on repeated measurements of anthropometric indicators. Ultimately, a Bayesian kernel machine regression (BKMR) model was used to assess the joint effects of the PFAS mixture on anthropometric indicators. ResultsIn GEE models, perfluorododecanoic acid (PFDoA) in the high tertile group was associated with increased WAZ/WLZ, with β values (95% confidence intervals (CI)) of 0.12 (0.00, 0.23) and 0.18 (0.03, 0.32), respectively. Perfluorononanoic acid (PFNA) was associated with increased ACZ in the middle and high tertile groups. The BKMR models also presented the associations of the PFAS mixture with increased WAZ/WLZ throughout infancy, with more profound effects in females. Meanwhile, a pattern of inverse associations was observed between the perfluorooctanoic acid (PFOA) concentrations in the high tertile group and decreased WAZ, WLZ, and HCZ in males. In addition, the associations between PFAS and increased TSZ/SSZ at birth were identified by both linear regression and BKMR models. ConclusionPrenatal PFAS exposure (PFNA and PFDoA) was associated with increased infant anthropometry, especially in female infants, while prenatal PFOA exposure was associated with decreased weight, and head and arm circumference in male infants. The findings indicate that prenatal PFAS exposure may impair the growth trajectory of offspring.

Early-life perfluorooctanoic acid exposure disrupts the function of dopamine transporter protein with glycosylation changes implicating the links between decreased dopamine levels and disruptive behaviors in larval zebrafish

Exposure to perfluorooctanoic acid (PFOA) during early embryonic development is associated with the increased risk of developmental neurotoxicity and neurobehavioral disorders in children. In our previous study, we demonstrated that exposure to PFOA affected locomotor activity and disrupted dopamine-related gene expression in zebrafish larvae. Consequently, we continue to study the dopaminergic system with a focus on dopamine levels and dopamine's effect on behaviors in relation to PFOA exposure. In the present study, we found a decrease in dopamine levels in larval zebrafish. We studied the dopamine transporter (DAT) protein, which is responsible for regulating dopamine levels through the reuptake of dopamine in neuronal cells. We demonstrated that exposure to PFOA disrupted the glycosylation process of DAT, inhibited its uptake function, and induced endoplasmic reticulum (ER) stress in dopaminergic cells. Besides, we conducted a light-dark preference test on larval zebrafish and observed anxiety/depressive-like behavioral changes following exposure to PFOA. Dopamine is one of the most prominent neurotransmitters that significantly influences human behavior, with low dopamine levels being associated with impairments such as anxiety and depression. The anxiety-like response in zebrafish larvae exposure to PFOA implies the link with the reduced dopamine levels. Taken together, we can deduce that glycosylation changes in DAT lead to dysfunction of DAT to regulate dopamine levels, which in turn alters behavior in larval zebrafish. Therefore, alternation in dopamine levels may play a pivotal role in the development of anxiety/depressive-like behavioral changes induced by PFOA.

Integrated evidence of transcriptional, metabolic, and intestinal microbiota changes in Ruditapes philippinarum due to perfluorooctanoic acid-induced immunotoxicity

Perfluorooctanoic acid (PFOA) is a toxic pollutant that bioaccumulates and is a significant public health concern due to its ubiquitous and persistent occurrence in global environments. Few studies have evaluated the adverse effects of PFOA on immune system, and this is particularly true for mollusks. Here, the PFOA-associated effects on immune system were evaluated in Ruditapes philippinarum using integrated analysis of metabolomes, microbiomes, and transcriptomes, providing evidence for possible mechanisms related to immunotoxicity. PFOA exposure caused clear variation in several important metabolites related to immune regulatory function within the haemolyph from R. philippinarum, while also altering key metabolic pathways, including those of lipids, unsaturated fatty acids (UFAs), and bile acids (BAs). After exposure to PFOAs, intestinal bacterial communities also clearly changed, with the predominant microflora becoming Mycoplasma and Bacteroidetes that are related to intestinal inflammation. Molecular analyses provided consistent results, wherein the expression of immune-related genes was significantly altered. Integration of the multi-‘omics’ analyses suggested that the TLR/MyD88/NF-kB pathway, along with PI3K-Akt-mTOR pathway, PPAR-mediated lipid metabolism and the autophagy signaling pathway, likely play important roles in initiating immunotoxic effects in R. philippinarum after PFOA exposure. These results provide further evidence that PFOA exposure can lead to immunologic dysfunction and also provide new insights into the mechanisms of PFAS alteration of bivalve immune function.

Operating performance of sequential batch system with calcium-modified basalt fiber bio-nest exposed to two typical perfluoroalkyl compounds (PFOA and PFBA)

The effects of per- and polyfluoroalkyl substances (PFASs) on the application of sequential batch system with basalt fiber as a biological carrier material have been rarely reported. This study explored the decontamination performance, extracellular polymeric substances (EPS) and microbial community structure of sequencing batch system with calcium-modified basalt fiber (Ca-MBF) bio-nest exposed to perfluorooctanoic acid (PFOA) and perfluorobutyric acid (PFBA). The results showed that 0.5 mg/L PFOA and PFBA both inhibited nitrification by 24.67 % and 19.47 %, while promoted denitrification by 16.54 % and 11.15 %, respectively. Overall, compared to PFBA, PFOA inhibited the removal of total nitrogen (TN) and total phosphorus (TP) by 11.27 % and 9.49 %, respectively. Further analysis of EPS showed that under PFOA exposure, the total EPS and polysaccharide (PS) content decreased by 34.57 % and 40.78 %, respectively. In addition, PFOA and PFBA exhibited a phenomenon of initially promoting by 89.21 % and 55.29 %, and subsequently inhibiting on protein (PN) content by 50.22 % and 51.37 %, respectively. Analyses of Illumina Miseq sequencing showed that PFOA and PFBA exposure for 50 days both inhibited the richness and diversity of microbial communities, and the inhibitory effect of PFOA was greater than that of PFBA. In addition, PFOA and PFBA respectively domesticated the resistant bacteria Meganema and Acinetobacter. These results may provide valuable information for ecological restoration and biodegradation of PFOA and PFBA.

Insight into the differential toxicity of PFOA and PFBA based on a 3D-cultured MDA-MB-231 cell model

Perfluoroalkyl substances (PFASs) are a category of high-concerned emerging contaminants which are suspected to correlate with various human adverse health outcomes including tumors. It is also a question whether short-chain PFASs are qualified alternatives under the regulation of long-chain PFASs. In this study, a three-dimensional (3D) culture system based on Gelatin methacrylate (GelMA) hydrogel matrix was used to investigate the impacts of 120-h perfluorooctanoic acid (PFOA) and perfluorobutanoic acid (PFBA) exposure of MDA-MB-231 cells. The results showed that PFOA exposure promoted the proliferation, migration, and invasion of MDA-MB-231 cells in an environmentally relevant concentration range (0.1 to 10 μM), exhibiting a clear malignant-promoting risk. In contrast, PFBA only showed a trend to induce non-invasive cell migration. Hippo/YAP signaling pathway was identified as the contributor to the differences between the two PFASs. PFOA but PFBA reduced YAP phosphorylation and increased the nuclear content of YAP, which further facilitated abundant key factors of epithelial-mesenchymal transition (EMT) process. Our results provided a new idea for the carcinogenicity of PFOA using a 3D-based paradigm. Although the effects by PFBA were much milder than PFOA in the current test duration, the cell model suitable for longer exposure is still necessary to better assess the safety of alternative short-chain PFASs.

Elevated levels of serum per- and poly-fluoroalkyl substances (PFAS) in contact lens users of U.S. young adults

Despite evidence indicating the presence of per- and poly-fluoroalkyl substances (PFAS) in contact lenses (CL), it remains unclear whether CL use increases PFAS exposure in the general population. We aimed to determine whether CL users have higher serum concentrations of PFAS than non-users, using data of 1660 adults aged 20–39 years participating in the National Health and Nutrition Examination Survey 1999–2000 and 2003–2008. We classified the individuals into CL users and non-users using the record of vision correction types during a vision test. Serum concentrations of six individual PFAS were measured, and the overall PFAS burden was calculated by item response theory scoring. Survey-weighted linear models were used to compare serum PFAS levels between CL users and non-users after adjusting for covariates. Distributions of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) concentrations were compared with reference values (e.g., human biomonitoring [HBM]-II values) indicating potential for adverse health effects. Survey-weighted linear models revealed that covariate-adjusted serum PFOA concentration was higher in CL users (geometric mean [GM]: 3.68 ng/mL; 95% CI: 3.00, 4.50) than in non-users (GM: 3.27 ng/mL; 95% CI: 2.81, 3.80; p = 0.02). Similarly, CL users had a significantly higher serum PFHxS concentration (GM: 1.58 ng/mL; 95% CI: 1.13, 2.20) than non-users (GM: 1.30 ng/mL; 95% CI: 1.10, 1.66; p = 0.03). CL users also had a significantly higher overall burden of PFAS than non-users. The differences in PFAS concentrations between CL users and non-users were more pronounced in females than in males. Moreover, a larger proportion of lens users (4.5%), compared to non-users (3.9%), had PFOA concentrations above the HBM-II, where adverse health effects are expected from PFOA exposure. This study suggests that CL use in general U.S. young adults may contribute significantly to PFAS body burden, which can potentially lead to public health problem.

In vitro evaluation of the carcinogenic potential of perfluorinated chemicals.

Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are the major components of long-chain per- and polyfluorinated alkyl substances (PFAS), known for their chemical stability and environmental persistence. Even if PFOA and PFOS have been phased out or are limited in use, they still represent a concern for human and environmental health. Several studies have been performed to highlight the toxicological behavior of these chemicals and their mode of action (MoA). Data suggested the causal association between PFOA or PFOS exposure and carcinogenicity in humans, but the outcomes of epidemiological studies showed some inconsistency. Moreover, the hypothesized MoA based on animal studies is considered not relevant for human cancer. In order to improve the knowledge on PFAS toxicology and contribute to the weight of evidence for the regulatory classification of PFAS, we used the BALB/c 3T3 cell transformation assay (CTA), an in vitro model under consideration to be included in an integrated approach to testing and assessment for non-genotoxic carcinogens (NGTxCs). PFOS and PFOA were tested at several concentrations by using a validated experimental protocol. Our results demonstrated that PFOA is not able to induce cell transformation, whereas PFOS exposure led to a concentration-related increase of type-III foci. Malignant foci formation is triggered at PFOS concentrations equal to or higher than 50 ppm. It is not directly associated with cytotoxicity or proliferation induction. The divergent CTA outcomes suggest that different molecular events could be responsible for the toxicological profiles of PFOS and PFOA, which were not completely captured in our study.

Determination of Perfluorooctanoic Acid (PFOA) in the Indoor Dust Matter of the Sicily (Italy) Area: Analysis and Exposure Evaluations.

Perfluorooctanoic acid (PFOA) in environmental matrices is increasingly being studied due to its environmental persistence, global occurrence, bioaccumulation, and associated human health risks. Some indoor environments can significantly impact the health of occupants due to pollutants in indoor air and household dust. To investigate the potential exposure of individuals to PFOA in specific confined environments, this study reports an analytical method and results concerning the determination of PFOA in household dust, used as a passive sampler. To the best of our knowledge, this paper represents one of the first studies concerning PFOA concentrations in indoor dust collected in the south of Italy, within the European region. A total of twenty-three dust samples were collected from two different areas of Sicily (Palermo and Milena), extracted, and analyzed by an UHPLC-QTOF-MS/MS system. Finally, PFOA exposure was estimated using a new index (Indoor PFOA Exposure Index, IPEX) that incorporates the PFOA levels in dust, exposure time, and the correlation between the PFOA in dust and blood. It was then compared across four different exposure groups, revealing that PFOA exposure for people working in chemistry laboratories was evaluated to be ten times higher than the exposure for homemakers.

Perfluorooctanoic Acid (PFOA) Exposure Compromises Fertility by Affecting Ovarian and Oocyte Development.

PFOA, a newly emerging persistent organic pollutant, is widely present in various environmental media. Previous reports have proved that PFOA exposure can accumulate in the ovary and lead to reproductive toxicity in pregnant mice. However, the potential mechanism of PFOA exposure on fertility remains unclear. In this study, we explore how PFOA compromises fertility in the zebrafish. The data show that PFOA (100 mg/L for 15 days) exposure significantly impaired fertilization and hatching capability. Based on tissue sections, we found that PFOA exposure led to ovarian damage and a decrease in the percentage of mature oocytes. Moreover, through in vitro incubation, we determined that PFOA inhibits oocyte development. We also sequenced the transcriptome of the ovary of female zebrafish and a total of 284 overlapping DEGs were obtained. Functional enrichment analysis showed that 284 overlapping DEGs function mainly in complement and coagulation cascades signaling pathways. In addition, we identified genes that may be associated with immunity, such as LOC108191474 and ZGC:173837. We found that exposure to PFOA can cause an inflammatory response that can lead to ovarian damage and delayed oocyte development.

Perfluorooctanoic acid (PFOA) exposure induces renal filtration and reabsorption disorders via down-regulation of aquaporins

Perfluorooctanoic acid (PFOA) exposure is associated with kidney dysfunction, however the exact mechanisms by which PFOA induces nephrotoxicity and the specific involvement of aquaporins (AQPs) in kidney tissue remains unclear. In this study, adult male Sprague-Dawley (SD) rats were exposed to PFOA by oral gavage for 28 days and compared with controls. Body weight, water intake and urine volume were recorded daily. At the end of the experiment, blood and kidney samples were collected, and serum urea, creatine and uric acid levels were assessed. The renal expression levels of water channel proteins AQP1, AQP3, AQP2 and p-AQP2 (Ser256) were observed by immunohistochemical staining, and the corresponding transcription levels were detected by Western blot and qRT-PCR. The results showed that PFOA exposure inhibited weight gain and increased water intake, urine volume, kidney weight and renal visceral index. PASM staining and transmission electron microscopy revealed pathological thickening of the glomerular capsule and basement membrane. Serum urea levels were increased, while serum creatine levels were decreased compared to controls. Additionally, the expression levels of AQP1, AQP3, AQP2 and p-AQP2 in kidney tissues were decreased, and the phosphorylation of AQP2 at Ser256 was inhibited. In conclusion, we demonstrate that PFOA exposure can damage the renal filtration barrier and reduce the expression level of AQPs in renal tissues, leading to renal filtration and reabsorption disorders.

Metastatic effects of perfluorooctanoic acid (PFOA) on Drosophila melanogaster with metabolic reprogramming and dysrhythmia in a multigenerational exposure scenario

Perfluorooctanoic acid (PFOA) exposure correlated with various cancers and their mortality. Its persistence in the environment made its long-term multigenerational influences of significant concerns. However, it remained unanswered whether its multigenerational exposure could influence metastasis which contributes ~90 % to cancer mortality. In the present study, long-term effects of PFOA were measured in Drosophila melanogaster over 3 consecutive generations. In the morning-eclosed (AM) adult flies, PFOA significantly promoted tumor invasion rates and distances which increased over generations. Regarding metabolic reprogramming, PFOA disturbed the expressions of Glut1 and Pdk1, activities and contents of FASN1 (fatty acid synthase), ACC (acetyl-CoA carboxylase) and SREBP1 (sterol regulatory element binding protein). Regarding antioxidant responses, PFOA exposure generated provoked oxidative stress via H2O2 and stimulated antioxidants including glutathione (GSH), catalase (CAT), melatonin, serotonin and cortisol, with downregulations on PI3K/AKT pathways and upregulations on MAPK ones. The biochemical and molecular effects altered over generations. In the afternoon-eclosed (PM) adult flies, the metastasis of PFOA was more deteriorated than in AM adults. The significant influences of dysrhythmia were also observed in the multigenerational effects of PFOA on the metabolism reprogramming and antioxidant responses. The effects on rhythm-regulating gene expressions and protein levels explained the dysrhythmia and also indicated close interactions among metabolism reprogramming, antioxidant responses and rhythm regulation. Environmental implicationNumerous emerging per- and polyfluoroalkyl substances (PFASs) are being detected. Meanwhile, the toxicities of the emerging PFASs still depend on the progress of legacy PFASs for the continuity of scientific studies. As one legacy PFAS, perfluorooctanoic acid (PFOA) exposure correlated with various cancers and their mortality. Its persistence in the environment made its long-term multigenerational influences of significant concerns. However, it remained unanswered whether its multigenerational exposure could influence metastasis which contributes ~90 % to cancer mortality. The present study performed PFOA exposure for 3 consecutive generations. Results showed that the metastasis by PFOA increased over generations, and it was further deteriorated by dysrhythmia. Further analysis demonstrated the interactive involvement of metabolism reprogramming, antioxidant responses and rhythm regulation. The findings of the present study would highlight considerate points for studying the toxicities of emerging PFASs.

Inulin alleviates perfluorooctanoic acid-induced intestinal injury in mice by modulating the PI3K/AKT/mTOR signaling pathway

Perfluorooctanoic acid (PFOA) is a widely used industrial compound that has been found to induce intestinal toxicity. However, the underlying mechanisms have not been fully clarified and effective interventions are rarely developed. Inulin, a prebiotic, has been used as a supplement in human daily life as well as in gastrointestinal diseases and metabolic disorders. In this study, male mice were exposed to PFOA with or without inulin supplementation to investigate the enterotoxicity and potential intervention effects of inulin. Mice were administered PFOA at 1 mg/kg/day, PFOA with inulin at 5 g/kg/day, or Milli-Q water for 12 weeks. Histopathological analysis showed that PFOA caused colon shortening, goblet cell reduction, and inflammatory cell infiltration. The expression of the tight junction proteins ZO-1, occludin and claudin5 significantly decreased, indicating impaired barrier function. According to the RNA-sequencing analysis, PFOA exposure resulted in 917 differentially expressed genes, involving 39 significant pathways, such as TNF signaling and cell cycle pathways. In addition, the protein expression of TNF-α, IRG-47, cyclinB1, and cyclinB2 increased, while Gadd45γ, Lzip, and Jam2 decreased, suggesting the involvement of the TNF signaling pathway, cell cycle, and cell adhesion molecules in PFOA-associated intestinal injury. Inulin intervention alleviated PFOA-induced enterotoxicity by activating the PI3K/AKT/mTOR signaling pathway and increasing the protein expression of Wnt1, β-catenin, PI3K, Akt3, and p62, while suppressing MAP LC3β, TNF-α, and CyclinE expression. These findings suggested that PFOA-induced intestinal injury, including inflammation and tight junction disruption, was mitigated by inulin through modifying the PI3K/AKT/mTOR signaling pathways. Our study provides valuable insights into the enterotoxic effects of PFOA and highlights the potential therapeutic role of inulin.