Effects Of Polyfluoroalkyl Substances Research Articles

Single-cell transcriptomics reveal the microenvironment landscape of perfluorooctane sulfonate-induced liver injury in female mice

Epidemic and animal studies have reported that perfluoroalkyl and polyfluoroalkyl substances (PFASs) are strongly associated with liver injury; however, to date, the effects of PFASs on the hepatic microenvironment remain largely unknown. In this study, we established perfluorooctane sulfonic acid (PFOS)–induced liver injury models by providing male and female C57BL/6 mice with water containing PFOS at varying doses for 4 weeks. Hematoxylin and eosin staining revealed that PFOS induced liver injury in both sexes. Elevated levels of serum aminotransferases including those of alanine aminotransferase and aspartate transaminase were detected in the serum of mice treated with PFOS. Female mice exhibited more severe liver injury than male mice. We collected the livers from female mice and performed single-cell RNA sequencing. In total, 36,529 cells were included and grouped into 10 major cell types: B cells, granulocytes, T cells, NK cells, monocytes, dendritic cells, macrophages, endothelial cells, fibroblasts, and hepatocytes. Osteoclast differentiation was upregulated and the T cell receptor signaling pathway was significantly downregulated in PFOS-treated livers. Further analyses revealed that among immune cell clusters in PFOS-treated livers, Tcf7+CD4+T cells were predominantly downregulated, whereas conventional dendritic cells and macrophages were upregulated. Among the fibroblast subpopulations, hepatic stellate cells were significantly enriched in PFOS-treated female mice. CellphoneDB analysis suggested that fibroblasts interact closely with endothelial cells. The major ligand–receptor pairs between fibroblasts and endothelial cells in PFOS-treated livers were Dpp4_Cxcl12, Ackr3_Cxcl12, and Flt1_complex_Vegfa. These genes are associated with directing cell migration and angiogenesis. Our study provides a general framework for understanding the microenvironment in the livers of female mice exposed to PFOS at the single-cell level.

Influence of firefighting fluorosynthetic film forming foam on soil microbocenosis

Per- and polyfluoroalkyl substances (PFASs) are a group of over 5000 different chemicals that are used in a wide range of industrial applications and consumer products. Perfluoroalkyl substances have unique properties, such as high chemical stability and surface activity, which leads to their widespread use in medicine, science and everyday life. Aqueous film forming foams (AFFFs) are complex proprietary formulations that contain percent levels of PFASs as well as solvents and hydrocarbon surfactants which, when combined, afford AFFF the functionality required for its purpose. Firefighting foams, such as AFFF, are used primarily to control fires involving flammable liquids such as fuel and oil. AFFF suppresses fire by producing a film over the fuel/oil fire that effectively starves the fire of oxygen. The carbon-fluorine bond makes these compounds extremely strong and stable. This chemical and thermal stability allows these substances to persist in the environment without breaking down. While biological effects of single PFAS have been studied, the effects of PFAS-containing mixtures, such as AFFF, are unknown. The environmental effects of firefighting foam pollutants are generally considered in terms of their toxicity and their biodegradability. Firefighting foams have been found to have a negative impact on the environment (e.g. can remove oxygen from aquatic environment in turn killing aquatic fauna). The effect of PFAS on the microorganisms is not sufficiently studied. To date, there are few studies on the structure and dynamics of microbes in the presence of per- and polyfluoroalkyl substances. Moreover, the results are contradictory. In this regard, it is important to study the impact of various PFAS chemicals on the microorganisms. The article presents the results of the effect study of a fluorosynthetic film forming foam, the main component of which is perfluorinated organic acid, on soil microorganisms, namely ammonifiers, oligonitrophils and nitrogen-fixing microorganisms, yeasts and molds, actinobacteria, and cellulose-degrading bacteria. It was accomplished by plating a sample of the soil that has been serially diluted in water and enumeration of colony forming units (CFU) per gram of soil. The number of soil microorganisms was counted two weeks and three months after contamination with a fluorosynthetic film forming foam. The control sample was unpolluted soil. The sample of soil (1.0 g) was mixed and suspended with a 10 ml of water in a tube for isolation and enumeration of microorganisms. The sample was shaken vigorously to separate organisms from the colloidal material surrounding soil particles. Obtained suspension was serially diluted from 10-2 to 10-6. Aliquot of each dilution was plated onto suitable agar medium. Meat-peptone agar, wort agar, starch-ammonia agar, ashby's agar and hutchinson's agar were used to isolate different groups of microorganisms from gray forest soil and to study the effect of film forming foam on them. The plates were incubated at 28 °C for 3–14 days and the results are expressed as CFU per gram of soil. Colonies of bacteria on meat-peptone agar and ashby's medium were counted after 3–4 days, yeasts and fungi on wort agar after 4–5 days and actinobacteria on starch-ammonia medium after 7–10 days. The number of colonies of cellulose-degrading microorganisms was counted after 14 days cultivation. Firefighting fluorosynthetic film forming foam led to the soil microbial community restructuring and a microbial diversity decrease. The study revealed a decrease the number of different groups of soil microorganisms two weeks after the pollution with the firefighting fluorosynthetic film forming foam, in particular ammonifiers by 2 times compared to the control, nitrogen-fixing microorganisms by 2.7 times, actinobacteria by 4.7 times, yeasts and fungi by 2.8 times. Three months after soil contamination with AFFF the number of nitrogen-fixing microorganisms, actinobacteria, yeasts and fungi increased by 1.85, 1.2 and 2.6 times compared to the control respectively. The number of ammonifiers and cellulose-degrading microorganisms decreased by 1.7 and 5.0 times compared to the control respectively.

Exposure to select PFAS and PFAS mixtures alters response to platinum-based chemotherapy in endometrial cancer cell lines

BackgroundExposure to per- and poly-fluoroalkyl substances (PFAS) has been associated with significant alterations in female reproductive health. These include changes in menstrual cyclicity, timing of menarche and menopause, and fertility outcomes, as well as increased risk of endometriosis, all of which may contribute to an increased risk of endometrial cancer. The effect of PFAS on endometrial cancer cells, specifically altered treatment response and biology, however, remains poorly studied. Like other gynecologic malignancies, a key contributor to lethality in endometrial cancer is resistance to chemotherapeutics, specifically to platinum-based agents that are used as the standard of care for patients with advanced-stage and/or recurrent disease.ObjectivesTo explore the effect of environmental exposures, specifically PFAS, on platinum-based chemotherapy response and mitochondrial function in endometrial cancer.MethodsHEC-1 and Ishikawa endometrial cancer cells were exposed to sub-cytotoxic nanomolar and micromolar concentrations of PFAS/PFAS mixtures and were treated with platinum-based chemotherapy. Survival fraction was measured 48-h post-chemotherapy treatment. Mitochondrial membrane potential was evaluated in both cell lines following exposure to PFAS ± chemotherapy treatment.ResultsHEC-1 and Ishikawa cells displayed differing outcomes after PFAS exposure and chemotherapy treatment. Cells exposed to PFAS appeared to be less sensitive to carboplatin, with instances of increased survival fraction, indicative of platinum resistance, observed in HEC-1 cells. In Ishikawa cells treated with cisplatin, PFAS mixture exposure significantly decreased survival fraction. In both cell lines, increases in mitochondrial membrane potential were observed post-PFAS exposure ± chemotherapy treatment.DiscussionExposure of endometrial cancer cell lines to PFAS/PFAS mixtures had varying effects on response to platinum-based chemotherapies. Increased survival fraction post-PFAS + carboplatin treatment suggests platinum resistance, while decreased survival fraction post-PFAS mixture + cisplatin exposure suggests enhanced therapeutic efficacy. Regardless of chemotherapy sensitivity status, mitochondrial membrane potential findings suggest that PFAS exposure may affect endometrial cancer cell mitochondrial functioning and should be explored further.

Per- and polyfluoroalkyl substances (PFAS) exposure in melanoma patients: a retrospective study on prognosis and histological features

Per- and polyfluoroalkyl substances (PFAS) are endocrine disrupting chemicals which could be associated with cancer development, such as kidney and testicular cancers, pancreatic and hepatocellular carcinoma and thyroid tumor. Available scientific literature offers no information on the role of PFAS in melanoma development/progression. Since 1965, a massive environmental contamination by PFAS has occurred in northeastern Italy. This study compared histopathology and prognosis between melanoma patients exposed (n = 194) and unexposed (n = 488) to PFAS. All patients were diagnosed and/or treated for melanoma at the Veneto Oncological Institute and the University Hospital of Padua (Italy) in 1998–2014. Patients were categorized in exposed or unexposed groups according to their home address and the geographical classification of municipalities affected by PFAS contamination as provided by Veneto Government in 2018. Presence of mitoses was found in 70.5% of exposed patients and 58.7% of unexposed patients (p = 0.005). Median follow-up was 90 months (IQR 59–136). 5-year overall survival was 83.7% in exposed patients and 88.0% in unexposed patients (p = 0.20); 5-year disease-specific survival was 88.0% in exposed patients and 90.9% in unexposed patients (p = 0.50); 5-year disease-free survival was 83.8% in exposed patients and 87.3% in unexposed patients (p = 0.20). Adjusting for imbalanced characteristics at baseline (presence of mitoses), survival was not statistically different between exposed and unexposed patients (overall survival: HR 1.10, 95% CI 0.77 to 1.58, p = 0.57; disease-specific survival: HR 0.99, 95% CI 0.62 to 1.59, p = 0.99; disease-free survival: HR 1.10, 95% CI 0.74 to 1.64, p = 0.62). Although the magnitude of PFAS exposure was not quantifiable, our findings suggested that exposure to PFAS was associated with higher level of mitosis in melanoma patients, but this did not translate into a survival difference. Further studies are required to investigate this relationship and all effects of PFAS on prognosis.

Impacts of PFOAC8, GenXC6, and their mixtures on zebrafish developmental toxicity and gene expression provide insight about tumor-related disease

Concerns about per- and polyfluoroalkyl substances (PFASs) have grown in importance in the fields of ecotoxicology and public health. This study aims to compare the potential effects of long-chain (carbon atoms ≥ 7) and short-chain derivatives and their mixtures' exposure according to PFASs-exposed (1, 2, 5, 10, and 20 mg/L) zebrafish's (Danio rerio) toxic effects and their differential gene expression. Here, PFOAC8, GenXC6, and their mixtures (v/v, 1:1) could reduce embryo hatchability and increase teratogenicity and mortality. The toxicity of PFOAC8 was higher than that of GenXC6, and the toxicity of their mixtures was irregular. Their exposure (2 mg/L) caused zebrafish ventricular edema, malformation of the spine, blood accumulation, or developmental delay. In addition, all of them had significant differences in gene expression. PFOAC8 exposure causes overall genetic changes, and the pathways of this transformation were autophagy and apoptosis. More importantly, in order to protect cells from PFOAC8, GenXC6, and their mixtures' influences, zebrafish inhibited the expression of ATPase and Ca2+ transport gene (atp1b2b), mitochondrial function-related regulatory genes (mt-co2, mt-co3, and mt-cyb), and tumor or carcinogenic cell proliferation genes (laptm4b and ctsbb). Overall, PFOAC8, GenXC6, and their mixtures' exposures will affect the gene expression effects of zebrafish embryos, indicating that PFASs may pose a potential threat to aquatic biological safety. These results showed that the relevant genes in zebrafish that were inhibited by PFASs exposure were related to tumorigenesis. Therefore, the effect of PFASs on zebrafish can be further used to study the pathogenesis of tumors.

Effects of legacy and emerging per- and polyfluoroalkyl substances on PPARα/β/γ regulation and osteogenic/adipogenic differentiation

As the primary molecular target, there is still a gap between the peroxisome proliferator-activated receptors (PPARs) regulation and the adverse health effects caused by per- and polyfluoroalkyl substances (PFASs). The effects of PFASs on cellular differentiation regulated by PPARs is likely significant given the association of PFASs exposure with obesity and decreased bone density. Human mesenchymal stem cells (hMSCs) were used as an in vitro model to assess the roles of PPAR subtypes in the multipotent differentiation of hMSCs affected by perfluorooctanesulfonate (PFOS), perfluorooctanoic acid (PFOA) and their replacement compounds. PFASs increased the expression of three PPAR subtypes in proliferating and differentiating hMSCs. Meanwhile, PFOS and PFOA decreased osteogenesis, enhanced adipogenesis, and increased bone turnover in hMSCs. Similarly, PFOA alternatives, hexafluoropropylene oxide dimer acid (HFPO-DA) and hexafluoropropylene oxide trimer acid (HFPO-TA), exhibited similar or even higher potency in affecting stem cell differentiation compared with PFOA. Perfluorohexanesulfonate (PFHxS) inhibited osteogenesis with comparable potency to PFOS. In contrast, 6:2 chlorinated poly-fluoroalkyl ether sulfonate (6:2Cl-PFESA) enhanced osteogenesis. PPARβ expression is significantly positively correlated with osteogenesis and osteoprotegerin (OPG) secretion in 6:2Cl-PFESA treated cells. shRNA knockdown of PPARβ remarkably reversed the osteogenic effects of 6:2Cl-PFESA and enhanced the adipogenic effects of the six chemicals. The results suggested that the adverse effects and relative potency of PFASs on the multipotent differentiation of hMSCs were dependent on the integrated action of the three PPAR subtypes, which facilitates a better understanding of the molecular initiating events of PFASs. The present study may well explain the mechanism of the decreased bone density and increased obesity incidence among those exposed to legacy PFASs, and indicates the necessity of further health risk assessment for the alternatives.

Cell cycle alterations due to perfluoroalkyl substances PFOS, PFOA, PFBS, PFBA and the new PFAS C6O4 on bottlenose dolphin (Tursiops truncatus) skin cell.

Per- and polyfluoroalkyl substances (PFAS) have become ubiquitous environmental contaminants in aquatic ecosystems worldwide. Marine mammals, as top predators, are constantly exposed to several PFAS compounds that accumulate in different tissues. As a proxy to assess cytotoxicity of PFAS in the bottlenose dolphin (Tursiops truncatus), we generated a new immortalized cell line derived from skin samples of bottlenose dolphin. Using high content imaging, we assessed the effects of increasing concentrations of PFOS, PFOA, PFBS, PFBA and C6O4 on cell viability and cell cycle phases. In particular, we classified all cells based on multiple morphometric differences of the nucleus in three populations, named respectively "Normal" (nuclei in G0, S and M phase); "Large" (nuclei showing characteristics of senescence) and "Small" (nuclei with fragmentation and condensed chromatin). Combining this approach with cell cycle analysis we determined which phases of the cell cycle were influenced by PFAS. The results revealed that the presence of PFOS, PFBS and PFBA could increase the number of cells in G0+G1 phase and decrease the number of those in the S phase. Moreover, PFOS and PFBS lowered the fraction of cells in the M phase. Interestingly PFOS, PFBS and PFBA reduced the prevalence of the senescence phenotype ("large" nuclei), suggesting a potential tumorigenic effect. Besides, the presence of PFOS and PFBS correlated also with a significant decrease in the number of "small" nuclei. The C6O4 exposure did not highlighted morphometric alteration or cell cycle modification bottlenose dolphin skin cell nuclei. While the effects of PFAS on cell cycle was clear, no significant change was detected either in term of cell proliferation or of viability. This study fosters the overall knowledge on the cellular effects of perfluoroalkyl substances in marine mammals.

Select Per- and Polyfluoroalkyl Substances (PFAS) Induce Resistance to Carboplatin in Ovarian Cancer Cell Lines.

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants associated with adverse reproductive outcomes including reproductive cancers in women. PFAS can alter normal ovarian function, but the effects of PFAS on ovarian cancer progression and therapy response remain understudied. Ovarian cancer is the most lethal gynecologic malignancy, and a major barrier to effective treatment is resistance to platinum-based chemotherapy. Platinum resistance may arise from exposure to external stimuli such as environmental contaminants. This study evaluated PFAS and PFAS mixture exposures to two human ovarian cancer cell lines to evaluate the ability of PFAS exposure to affect survival fraction following treatment with carboplatin. This is the first study to demonstrate that, at sub-cytotoxic concentrations, select PFAS and PFAS mixtures increased survival fraction in ovarian cancer cells following carboplatin treatment, indicative of platinum resistance. A concomitant increase in mitochondrial membrane potential, measured by the JC-1 fluorescent probe, was observed in PFAS-exposed and PFAS + carboplatin-treated cells, suggesting a potential role for altered mitochondrial function that requires further investigation.

Effects of perfluorooctanoic acid (PFOA) on activated sludge microbial community under aerobic and anaerobic conditions.

Per- and polyfluoroalkyl substances (PFASs) have received increasing attention due to their widespread presence in diverse environments including wastewater treatment plants (WWTPs) and their potential adverse health effects. Perfluorooctanoic acid (PFOA) is one of the most detected forms of PFASs in WWTPs. However, there is still a paucity of knowledge about the effect of PFASs on microorganisms of the key component of WWTP, activated sludge. In this study, lab-scale microcosm experiments were established to evaluate the influences of PFOA on activated sludge microbes under aerobic and anaerobic conditions. The diversity, structure, and microbe-microbe interaction of microbial community were determined by 16S rRNA gene amplicon sequencing and co-occurrence network analysis. After 90days of exposure to PFOA, activated sludge microbial richness decreased under both aerobic and anaerobic conditions. Specifically, under aerobic condition, Rhodopseudomonas (mean relative abundance 3.6%), Flavobacterium (2.4%), and Ignavibacterium (6.6%) were enriched in PFOA-spiked activated sludge compared with that in the unspiked sludge (2.6%, 0.1%, and 1.9%, respectively). By contrast, after 90days of exposure to PFOA, Eubacterium (2.1%), Hyphomicrobium (1.8%), and Methyloversatilis (1.2%) were enriched under anaerobic condition, and more abundant than that in the control sludge (0.4%, 1.5%, and 0.6%, respectively). These genera were the potential PFOA-resistant members. In addition, Azospirillum and Sporomusa were the most connected taxa in PFOA-aerobic and PFOA-anaerobic networks, respectively. Prediction of the functional gene showed that PFOA inhibited some gene expression of sludge microbes, such as transcription, amino acid transport and metabolism, and energy production and conversion. In summary, continued exposure to PFOA induced substantial shifts of the sludge bacterial diversity and composition under both aerobic and anaerobic conditions.

Occurrence of PFASs and its effect on soil bacteria at a fire-training area using PFOS-restricted aqueous film-forming foams

SummaryFire-training areas (FTAs) are an important source of perfluoroalkyl and polyfluoroalkyl substances (PFASs) pollution. However, the effect of PFASs on soil bacterial communities remains limited. Here, we detected the PFASs in soils ranging from 3.4 to 531.7 μg kg−1 dry weight in seven plots at an FTA where PFOS-restricted aqueous film-forming foams (AFFFs) have been used for 6 years. PFOS was still the dominant homologue despite the restriction by Stockholm Convention, but it was almost three orders of magnitude lower than that in previous studies. PFASs played an important role in shaping the bacterial community, and high levels of PFASs (>100 μg kg−1 dw) reduced the biodiversity and connectivity of soil bacteria. The extreme condition-tolerant bacteria were identified as biomarkers at the FTA. Our study provides valuable insights into the effect of PFOS-restricted AFFFs on soil bacterial communities at the FTA.

Perfluoroalkyl Substances and Incident Natural Menopause in Midlife Women: The Mediating Role of Sex Hormones.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been associated with earlier natural menopause; however, the underlying mechanisms are not well understood, particularly the extent to which this relationship is mediated by sex hormones. We analyzed data (1999-2017) on 1,120 premenopausal women from the Study of Women's Health Across the Nation (SWAN). Causal mediation analysis was applied to quantify the degree to which follicle-stimulating hormone (FSH) and estradiol levels could mediate the associations between PFAS and incident natural menopause. Participants with higher PFAS concentrations had shorter times to natural menopause, with a relative survival of 0.82 (95% confidence interval (CI): 0.69, 0.96) for linear perfluorooctane sulfonate (n-PFOS), 0.84 (95% CI: 0.69, 1.00) for sum of branched-chain perfluorooctane sulfonate (Sm-PFOS), 0.79 (95% CI: 0.66, 0.93) for linear-chain perfluorooctanoate (n-PFOA), and 0.84 (95% CI: 0.71, 0.97) for perfluorononanoate (PFNA), comparing the highest tertile of PFAS concentrations with the lowest. The proportion of the effect mediated through FSH was 8.5% (95% CI: -11.7, 24.0) for n-PFOS, 13.2% (95% CI: 0.0, 24.5) for Sm-PFOS, 26.9% (95% CI: 15.6, 38.4) for n-PFOA, and 21.7% (6.8, 37.0) for PFNA. No significant mediation by estradiol was observed. The effect of PFAS on natural menopause may be partially explained by variations in FSH concentrations.

Associations between Novel and Legacy Per- and Polyfluoroalkyl Substances in Human Serum and Thyroid Cancer: A Case and Healthy Population in Shandong Province, East China.

Per- and polyfluoroalkyl substances (PFASs) are widely detected in the environment and may cause adverse human health effects after exposure. Studies on the effect of PFASs on some health end points, including cancer, are still limited and show inconsistent results. In this research, 319 participants were recruited from Shandong Province, East China, consisting of patients with thyroid cancer and healthy controls. Seven novel and legacy PFASs were frequently detected (detection rate > 75%) in the serum samples of the participants. The concentrations of perfluorooctanoic acid (PFOA) were the highest in the case and control groups. Males showed significantly higher concentrations of PFASs than females. Exposure to PFASs was inversely associated with the risk of thyroid cancer. In the control group, we identified significant positive associations between PFASs and free thyroxine (FT4) as well as between PFOA and thyroid stimulating hormone (TSH) in females. A significant negative association between perfluorononanoic acid (PFNA) and triiodothyronine (T3) was observed in males. Our results suggest that exposure to certain PFASs could interfere with thyroid function. To our knowledge, this is the first case-control study demonstrating associations between novel and legacy PFASs in human and thyroid cancer.

PFAS and Potential Adverse Effects on Bone and Adipose Tissue Through Interactions With PPARγ.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are a widely dispersed, broad class of synthetic chemicals with diverse biological effects, including effects on adipose and bone differentiation. PFAS most commonly occur as mixtures and only rarely, if ever, as single environmental contaminants. This poses significant regulatory questions and a pronounced need for chemical risk assessments, analytical methods, and technological solutions to reduce the risk to public and environmental health. The effects of PFAS on biological systems may be complex. Each may have several molecular targets initiating multiple biochemical events leading to a number of different adverse outcomes. An exposure to mixtures or coexposures of PFAS complicates the picture further. This review illustrates how PFAS target peroxisome proliferator-activated receptors. Additionally, we describe how such activation leads to changes in cell differentiation and bone development that contributes to metabolic disorder and bone weakness. This discussion sheds light on the importance of seemingly modest outcomes observed in test animals and highlights why the most sensitive end points identified in some chemical risk assessments are significant from a public health perspective.

Perfluoroalkyl substances and thyroid stimulating hormone levels in a highly exposed population in the Veneto Region

BackgroundPer- and poly-fluoroalkyl substances (PFAS) are persistent and widespread environmental pollutants. People living in Veneto Region (Italy) have been exposed from the late 1970s to 2013 to elevated concentrations of PFAS through drinking water. The effect of PFAS on thyroid function is still controversial and studies focusing on thyroid stimulating hormone (TSH) have shown inconsistent results. The aim of this study was to evaluate the association between serum PFAS and TSH levels and its dose-response relationship in a large population of highly exposed individuals. MethodsA cross-sectional study was conducted on 21,424 individuals aged 14–39 living in the contaminated area. In the main analysis, participants with prevalent thyroid disease and pregnant women were excluded. Serum levels of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexanesulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) were measured. Generalized Additive Models were used to evaluate the association between TSH levels and serum PFAS, using thin plate spline smooth terms to model the potential non-linear relationship. Models were stratified by sex and age group and adjusted for potential confounders. A secondary analysis was conducted to evaluate the association between PFAS with prevalent self-reported thyroid disorders. ResultsWe found no association between TSH and any type of PFAS among adolescents or women. A decrease in TSH concentration was observed in association with an IQR increase in PFHxS and a mild decrease in TSH at low levels of PFOA, PFOS and PFHxS among male adults. Self-reported thyroid disease was more common among women with higher levels of PFNA concentrations, whereas all other PFAS were not associated with thyroid diseases regardless of sex or age. ConclusionsOverall there is no evidence of an association between TSH and PFAS. However, some results are suggestive of a possible inverse association of TSH with PFOA, PFOS and PFHxS among adult males.

Perfluorooctane sulfonate continual exposure impairs glucose-stimulated insulin secretion via SIRT1-induced upregulation of UCP2 expression.

Per- and polyfluoroalkyl substances (PFASs) are environmentally and biologically persistent anthropogenic chemicals linked to adverse health outcomes. Epidemiological data have revealed association between exposure to specific PFAS and disruption of insulin level in bodies. However, the effect of PFASs on insulin secretion and the responsible molecular mechanism are poorly understood. In the present study, we used perfluorooctane sulfonate (PFOS) as a representative PFAS family member to investigate its effect on the insulin secretion in mouse pancreatic β cells (β-TC-6). Our results showed that exposure to PFOS inhibited silent information regulator 1 (SIRT1) activity, and molecular simulation showed PFOS could fit into the pocket overlapped with the nicotinamide adenine dinucleotide (NAD+) binding cavity in SIRT1. PFOS exposure upregulated uncoupling protein 2 (UCP2) expression, and this upregulation was blunted in the presence of Ex-527, a SIRT1 specific inhibitor. The mitochondria membrane potential (ΔΨm), as well as the glucose-induced ATP production and Ca2+ influx decreased under PFOS treatment. PFOS continual exposure (48h) impaired glucose stimulated insulin secretion (GSIS), while the gene expression of insulin was not significantly altered. Importantly, the SIRT1 activator and UCP2 inhibitor could partly reverse the PFOS-induced impairment of GSIS. Taken together, the results suggested that PFOS continual exposure could inhibit SIRT1 activity, and the SIRT1-UCP2 pathway mediated, at least partially, the PFOS induced GSIS impairment.

Serum vaccine antibody concentrations in adults exposed to per- and polyfluoroalkyl substances: A birth cohort in the Faroe Islands

Per- and polyfluoroalkyl substances (PFASs) are highly persistent in the environment and may cause depressed immune function. Previous studies have linked PFAS exposure to lower vaccine responses in children, but research in adults is limited. Therefore, the present study evaluated the associations between exposure to PFASs and serum antibody concentrations in adults vaccinated at age 28 years in the Faroe Islands. PFAS concentrations were determined from cord-blood collected at birth and serum samples collected at ages 7, 14, 22, and 28 years. Serum antibody concentrations against hepatitis type A and B, diphtheria, and tetanus were analyzed from blood samples collected about 6 mo after the first vaccine inoculation at age 28 years. Linear regression models were used to estimate changes in antibody concentration for each doubling of PFAS concentration. Potential effect modification by sex was assessed by including an interaction term between PFAS and sex. Although the 95% confidence intervals contain the null value, inverse trends were observed between serum perfluorooctanoate (PFOA) at ages 14 and 28 years and hepatitis type A antibody (anti-HAV) concentrations, as revealed by an estimated decrease of 0.71 (95% CI: −1.52, 0.09) and 0.24 (95% CI: −0.59, 0.10) signal-to-cutoff ratio for each doubling of exposure, respectively. Inverse trends were also observed between serum PFOA at ages 22 and 28 years and hepatitis type B antibody (anti-HBs) concentration, with an estimated decrease of 21% (95% CI: −42.20%, 7.34%) and of 17% (95% CI: −35.47%, 7.35%) in anti-HBs for each doubling of exposure, respectively. Sex-specific associations with anti-HAV were observed for cord-blood PFASs and serum PFAS concentrations at ages 7 and 14 years. No inverse associations of PFAS exposure were found with diphtheria and tetanus antibody concentrations. Future studies are needed to confirm these findings and further investigate the effects of PFASs on adult immune function.

Serum albumin mediates the effect of multiple per- and polyfluoroalkyl substances on serum lipid levels

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are synthetically manufactured chemicals recognized to be toxic, bioaccumulative, and persistent. Previous studies on PFAS exposure and serum lipid levels have mainly focused on individual PFASs; however, the influence of multiple-PFAS exposure on the serum lipid profile remains unclear. This study was performed to evaluate the combined effects of multiple PFASs on serum lipid levels. Based on the National Health and Nutrition Examination Survey (NHANES) data (2011–2014), we first established a linear regression model to estimate the association between single-PFAS exposure and the serum lipid profile. Then, a weighted quantile sum (WQS) regression model and a Bayesian kernel machine regression (BKMR) model were used to evaluate the effects of multiple-PFAS exposure on the serum lipid profile. A mediating effect model was used to assess how albumin mediates these effects. We found that PFASs were significantly associated with the levels of serum lipids, including high-density lipoprotein (HDL), low-density lipoprotein (LDL) and total cholesterol (TC). The WQS index was significantly correlated with the levels of HDL (β: 2.03, 95% CI: 0.74–3.32, P-value = 0.002), LDL (β: 4.16, 95% CI: 1.07–7.24, P-value = 0.008) and TC (β: 6.54, 95% CI: 3.00–10.1, P-value < 0.001). In the BKMR analysis, our results demonstrated that the effect of PFASs on serum lipids increased significantly when the concentrations of the PFASs were at their 60th percentiles or above compared to those at their 50th percentile. Mediation analysis showed that albumin mediated the effects of selected PFASs on the levels of serum lipids except for triglycerides (TG). PFAS exposure was correlated with the levels of serum lipids, and this correlation was mediated by albumin. Our results suggest that a comprehensive evaluation of multi-PFAS exposure could better characterize real-life exposure compared with single-PFAS exposure.

Perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorononanoic acid (PFNA) increase triglyceride levels and decrease cholesterogenic gene expression in human HepaRG liver cells

Per- and polyfluoroalkyl substances (PFASs) are omnipresent in the environment, food chain, and humans. Epidemiological studies have shown a positive association between serum levels of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), and increased serum cholesterol and, in some cases, also triglyceride levels. However, causality has been questioned, as animal studies, as well as a human trial, showed a decrease in serum cholesterol and no effects or a decrease in plasma triglycerides. To obtain more insight into the effects of PFASs on these processes, the present study investigated the effects of PFOA, PFOS, and perfluorononanoic acid (PFNA) on intracellular triglyceride and cholesterol levels in human HepaRG liver cells. DNA microarray analyses were performed to provide insight into underlying mechanisms. All PFASs induced an increase in cellular triglyceride levels, but had no effect on cholesterol levels. Gene set enrichment analysis (GSEA) of the microarray data indicated that gene sets related to cholesterol biosynthesis were repressed by PFOA, PFOS, and PFNA. Other gene sets commonly affected by all PFAS were related to PERK/ATF4 signaling (induced), tRNA amino-acylation (induced), amino acid transport (induced), and glycolysis/gluconeogenesis (repressed). Moreover, numerous target genes of peroxisome proliferator-activated receptor α (PPARα) were found to be upregulated. Altogether, the present study shows that PFOA, PFOS, and PFNA increase triglyceride levels and inhibit cholesterogenic gene expression in HepaRG cells. In addition, the present study indicates that PFASs induce endoplasmic reticulum stress, which may be an important mechanism underlying some of the toxic effects of these chemicals.

Per‐ and Polyfluoroalkyl Substances (PFAS): Anglers May Be Exposed to Harmful Chemicals in Their Catch

In this review, we focus on per‐ and polyfluoroalkyl substances (PFAS), synthetic compounds used for a variety of applications, including firefighting foam and manufacturing. Recently, researchers have linked human exposure to PFAS to negative health effects. Hundreds of communities are affected by PFAS contamination, which has raised awareness about the toxicity of these chemicals. Most work has focused on characterizing dangers to humans, and the effects of PFAS on the environment are under‐studied. PFAS contamination of surface water can result in bioaccumulation and biomagnification in fishes. Studies have linked PFAS to lower fitness in fishes, and anglers who consume wild fish can have higher exposure to PFAS compared to the general population. These chemicals remain largely unregulated and the public has been unaware of the extent of contamination and their risk to human health until recently. We review known PFAS contamination of wild‐caught fish, and their possible health risk through angler exposure in the Fairbanks North Star Borough, Alaska. The conclusions and recommendations from the case study can be applied to and are useful for PFAS‐contaminated communities nationwide.

Association of polyfluoroalkyl chemical exposure with serum lipids in children

Perfluoroalkyl and polyfluoroalkyl substances (PFASs), as well as polymers of PFASs, have been widely used in commercial applications and have been detected in humans and the environment. Previous epidemiological studies have shown associations between particular PFAS chemicals and serum lipid concentrations in adults, particularly perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). There exists, however, limited information concerning the effect of PFASs have on serum lipids among children. In the present cross-sectional study, 225 Taiwanese children (12–15years of age) were recruited to determine the relationship between serum level PFASs and lipid concentration. Results showed that eight out of ten particular PFASs were detected in the serum of >94% of the participants. Serum PFOS and perfluorotetradecanoic acid (PFTA) levels were at an order of magnitude higher than the other PFASs, with arithmetical means of 32.4 and 30.7ng/ml in boys and 34.2 and 27.4ng/ml in girls, respectively. However, the variation in serum PFTA concentration was quite large. Following covariate adjustment, linear regression models revealed that PFOS, PFOA, and perfluorononanoic acid (PFNA) were positively associated with total cholesterol (TC), low-density lipoprotein (LDL) and triglycerides (TG), particularly for PFOS and PFTA. Quartile analysis, with the lowest exposure quartile as a reference, yielded associations between serum PFTA and elevations in TC (p=0.002) and LDL (p=0.004). Though not statistically significant, high-density lipoprotein (HDL) appeared to decrease linearly across quartiles for PFOS and PFOA exposure. In conclusion, a significant association was observed between serum PFASs and lipid level in Taiwanese children. These findings for PFTA are novel, and emphasize the need to investigate the exposure route and toxicological evidence of PFASs beyond PFOS and PFOA.