Hexafluoropropylene Oxide Trimer Acid Research Articles

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.

Hexafluoropropylene oxide trimer acid (HFPO-TA) exerts cytotoxic effects on leydig cells via the ER stress/JNK/β-trcp/mcl-1 axis

Hexafluoropropylene oxide trimer acid (HFPO-TA) is an alternative to perfluorooctanoic acid (PFOA) and is widely used in various industries. The effects of HFPO-TA on the male reproductive system and the underlying mechanisms are still not fully understood. In this study, TM3 mouse Leydig cells were used as the main model to evaluate the cytotoxicity of HFPO-TA in vitro. HFPO-TA inhibited the viability and expression of multiple biomarkers of Leydig cells. HFPO-TA also induced Leydig cell apoptosis in a caspase-dependent manner. Moreover, HFPO-TA induced the ubiquitination and degradation of Mcl-1 in a β-TrCP-dependent manner. Further investigations showed that HFPO-TA treatment led to the upregulation of ROS, which activated the ER stress/JNK/β-TrCP axis in Leydig cells. Overall, our study provides novel insights into the cytotoxic effects of HFPO-TA on the male reproductive system.

Legacy and emerging per- and polyfluoroalkyl substances in tissue and toilet paper from China

Per- and polyfluoroalkyl substances (PFASs) have been found in toilet paper in Europe, the United States, and Africa; however, their presence in Chinese household paper has not been investigated. In this study, 21 legacy and 30 emerging PFASs were analyzed in tissue and toilet paper from China, including 48 samples of different origins and materials. Median concentrations of chlorinated polyfluorinated ether sulfonates (Cl-PFESAs), hexafluoropropylene oxide homologs (HFPOs), and p-perfluorous nonenoxybenzenesulfonate (OBS) were 0.32, 0.19, and 0.10 ng/g dry weight (dw), respectively. The detection frequencies (DFs) of Cl-PFESAs and OBS both were greater than 96%, followed by hexafluoropropylene oxide trimer acid (HFPO-TrA, DF: 85%). Notably, the level of HFPO-TrA in one sample was as high as 540 ng/g dw, indicating a potential environmental risk to humans. In addition, the concentrations of Cl-PFESAs in toilet paper were significantly higher than that in tissue (p < 0.05). However, no significant differences were observed in the concentrations of PFASs in tissue and toilet paper from different materials and origins. This suggests that PFASs, particularly emerging PFASs, are widely detected in tissue and toilet paper products across China, and their presence is a potential source of landfill contamination and human exposure.

Exposure to hexafluoropropylene oxide trimer acid (HFPO-TA) impairs 5-HT metabolism by impacting the brain-gut axis in mice

Hexafluoropropylene oxide trimer acid (HFPO-TA) has been found to cause hepatotoxicity, lipotoxicity, and cytotoxicity. However, the effects of HFPO-TA exposure on nervous system toxicity are still unclear. Here, six-week-old male C57BL/6J mice were treated with 2, 20, and 200 μg/L HFPO-TA for six weeks. The untargeted transcriptome analysis was employed to identify differentially expressed mRNAs in the tissue of mouse hippocampi. Then, the levels of neurotransmitters were detected by ELISA analysis in hippocampal and colonic tissues. Real-time quantitative PCR and western blotting analysis were performed to detect the expression of genes associated with modulation of serotonin (5-HT) metabolism and blood-brain barrier. HFPO-TA exposure reduced the mRNA and protein expression of several tight junction protein-coded genes, including Occludin, Claudin-1, and ZO-1, in mice hippocampi, indicating that the blood-brain barrier was disrupted. Moreover, HFPO-TA exposure elevated the expression of neuroinflammatory factors, including TNF-α, IL-6, IL-1β, TGF-α, and TGF-β. Analysis of hippocampal transcriptomics suggested that HFPO-TA exposure would impair 5-HT generation and metabolic pathways. In keeping with this prediction, our findings confirmed that the levels of several neurotransmitters, including tryptophan (TRP), 5-HT, 5-HTP, and 5-HIAA, were all impaired by HFPO-TA exposure in the serum, colon, and hippocampus, as was the colonic and hippocampal expression of TRP and 5-HT metabolism-related genes such as SERT, MAO-A, and IDO. These results suggest that HFPO-TA nervous system toxicity in mice may be partly modulated by the brain-gut axis and that HFPO-TA exposure may negatively impact human mental health.

The key role of hydrophobic forces during the electrocoagulation of perfluorooctanoic acid substitute (HFPO-TA) revealed by the interfacial thermodynamics

Per- and polyfluoroalkyl substances (PFASs) have been widely found in water bodies and may generate negative impacts on the ecosystem. Eectrocoagulation (EC) with a zinc anode is an effective technology to remove PFASs but the dominating interaction forces between zinc flocs and PFASs are still not well elucidated. In this study, we used hexafluoropropylene oxide trimer acid (HFPO-TA), a new perfluorooctanoic acid substitute, as a model to investigate the influence of EC operational parameters on its removal efficiency, including the current density, the pH value, and the electrolyte type. 99 % removal of 40 μM HFPO-TA were achieved in 3-h at optimal conditions. The extended Derjaguin-Landau-Verwey-Overbeek (XDLVO) theory was innovatively applied to reveal the interfacial free energies between zinc flocs and HFPO-TA and other PFASs. It was found that the hydrophobic force can significantly promote the adsorption of HFPO-TA on the surface of zinc flocs and a strong correlation may exist between the calculated total interfacial free energies and the pseudo-first-order kinetic constants of removing PFASs. FT-IR spectra indicated the specific interactions occurring between carboxylate head groups and zinc flocs. These findings advance the mechanistic understanding of PFASs removal by metal flocs and could support the development of electrocoagulation for removing PFASs.

Prenatal exposure to hexafluoropropylene oxide trimer acid (HFPO-TA) disrupts the maternal gut microbiome and fecal metabolome homeostasis

Initially considered a “safe” substitute for perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been extensively used in the production of fluoropolymers for several years, leading to its environmental ubiquity and subsequent discovery of its significant bio-accumulative properties and toxicological effects. However, the specific impact of HFPO-TA on females, particularly those who are pregnant, remains unclear. In the present study, pregnant mice were exposed to 0.63 mg/kg/day HFPO-TA from gestational day (GD) 2 to GD 18. We then determined the potential effects of exposure on gut microbiota and fecal metabolites at GD 12 (mid-pregnancy) and GD 18 (late pregnancy). Our results revealed that, in addition to liver damage, HFPO-TA exposure during the specified window altered the structure and function of cecal gut microbiota. Notably, these changes showed the opposite trends at GD 12 and GD 18. Specifically, at GD 12, HFPO-TA exposure primarily resulted in the down-regulation of relative abundances within genera from the Bacteroidetes and Proteobacteria phyla, as well as associated Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. With extended exposure time, the down-regulated genera within Proteobacteria became significantly up-regulated, accompanied by corresponding up-regulation of human disease- and inflammation-associated pathways, suggesting that HFPO-TA exposure can induce intestinal inflammation and elevate the risk of infection during late pregnancy. Pearson correlation analysis revealed that disturbances in the gut microbiota were accompanied by abnormal fecal metabolite. Additionally, alterations in hormones related to the steroid hormone biosynthesis pathway at both sacrifice time indicated that HFPO-TA exposure might change the steroid hormone level of pregnant mice, but need further study. In conclusion, this study provides new insights into the mechanisms underlying HFPO-TA-induced adverse effects and increases awareness of potential persistent health risks to pregnant females.

Emerging and legacy per- and polyfluoroalkyl substances in Daling River and its estuary, Northern China

Strict restriction on legacy per- and polyfluoroalkyl substances (PFASs) has caused a dramatic increase in production and usage of emerging PFASs over the last decades. However, the environmental behaviors of emerging PFASs is largely unknown in Daling River, Northern China. In this study, the potential sources, sediment-water partitioning and substitution trends of PFASs were investigated in overlying water and sediments from Daling River and its estuary. Perfluorooctane sulfonate and 6:2 fluorotelomer sulfonic acid were major compounds, and sodium p-perfluorous nonenoxybenzene sulfonate was first detected. Firefighting foam manufacturing and fluoropolymer production were the main sources of PFASs. Compared to legacy PFASs (C8), the emerging PFASs (C6 - C9) were more incline to distribute into overlying water. Substitution trends indicated 6:2 fluorotelomer sulfonic acid and hexafluoropropylene oxide trimer acid as the important alternatives of perfluorooctane sulfonate and perfluorooctanoic acid, respectively. The results were meaningful for understanding the environmental behaviors of emerging PFASs.

Adverse effects of gestational exposure to hexafluoropropylene oxide trimer acid (HFPO-TA) homologs on maternal, fetal, and placental health in mice

In an effort to identify and develop potential alternatives for perfluorooctanoic acid (PFOA), PFDMO2HpA and PFDMO2OA have been engineered by reducing the -CF2 content in the molecular structure of hexafluoropropylene oxide trimer acid (HFPO-TA). Yet, despite their subsequent presence in environmental samples, there is a paucity of information regarding their toxicity, particularly on pregnancy. Here, pregnant CD-1 mice were exposed to PFDMO2HpA (0, 0.04, 0.16, 0.63, 2.5, or 10 mg/kg/day) or PFDMO2OA (0, 0.01, 0.04, 0.16, 0.63, or 2.5 mg/kg/day) via oral gavage from gestational days 2 (GD2) to 12 or 18 to evaluate the detrimental effects on dams and embryo-placenta units. Both two chemicals can transfer across the placenta, with a higher transfer ratio in late-pregnancy (GD18) than in mid-pregnancy (GD12), and PFDMO2OA being transferred at a higher rate than PFDMO2HpA. PFDMO2HpA/PFDMO2OA exposure caused maternal hepatotoxicity and fetal hepatomegaly, showing the lowest no-observed-adverse-effect level among all observed endpoints, which were used for calculating their reference dose (13.33 ng/kg/day). In the 2.5 and 10 mg/kg/day PFDMO2HpA groups as well as 2.5 mg/kg/day PFDMO2OA group at GD18, besides the abnormally high abortion rates exceeding 5 %, survival fetal weight was notably reduced (2.33 %, 6.44 %, and 5.59 % decrease relative to corresponding controls, respectively). Concurrently, placentas exhibited significant enlargement following PFDMO2HpA or PFDMO2OA exposure at doses of 0.63 mg/kg/day or higher, resulting in diminished placental efficiency. The deleterious effects of two chemicals on dams, fetuses, and placentas were stronger than that of PFOA or HFPO-DA, suggesting that neither PFDMO2HpA nor PFDMO2OA is suitable PFOA alternative. Bioinformatics analyses revealed significant alterations in the expression of genes involved in inflammation and immunity in the placenta upon exposure to 10 mg/kg/day PFDMO2HpA and 2.5 mg/kg/day PFDMO2OA at GD18, potentially elucidating mechanism behind the observed decrease in placental efficiency and increase in abortion rates after exposure.

Different Life-Stage Exposure to Hexafluoropropylene Oxide Trimer Acid Induces Reproductive Toxicity in Adult Zebrafish (Danio rerio).

As a novel alternative to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been widely used and has caused ubiquitous water pollution. However, its adverse effects on aquatic organisms are still not well known. In the present study, zebrafish at different life stages were exposed to 0, 5, 50, and 100 μg/L of HFPO-TA for 21 days to investigate reproductive toxicity in zebrafish. The results showed that HFPO-TA exposure significantly inhibited growth and induced reproductive toxicity in zebrafish, including a decrease of the condition factor, gonadosomatic index, and the average number of eggs. Histological section observation revealed that percentages of mature oocytes and spermatozoa were reduced, while those of primary oocytes and spermatocytes increased. In addition, exposure to HFPO-TA at three stages induced a significant decrease in the hatching rate, while the heart rate and normal growth rate of F1 offspring were only significantly inhibited for the exposure from fertilization to 21 days postfertilization (dpf). Compared with the exposure from 42 to 63 dpf, the reproductive toxicity induced by HFPO-TA was more significant for the exposure from fertilization to 21 dpf and from 21 to 42 dpf. Expression of the genes for cytochrome P450 A1A, vitellogenin 1, estrogen receptor alpha, and estrogen receptor 2b was significantly up-regulated in most cases after exposure to HFPO-TA, suggesting that HFPO-TA exhibited an estrogen effect similar to PFOA. Therefore, HFPO-TA might disturb the balance of sex steroid hormones and consequently induce reproductive toxicity in zebrafish. Taken together, the results demonstrate that exposure to HFPO-TA at different life stages could induce reproductive toxicity in zebrafish. However, the underlying mechanisms deserve further investigation. Environ Toxicol Chem 2023;42:2490-2500. © 2023 SETAC.

Hexafluoropropylene oxide trimer acid exposure triggers necroptosis and inflammation through the Wnt/β-catenin/NF-κB axis in the liver

Hexafluoropropylene oxide trimer acid (HFPO-TA), an emerging alternative to perfluorooctanoic acid (PFOA), has recently been identified as a significant environmental pollutant. Nevertheless, there is a scarcity of studies regarding the hepatotoxic effects of HFPO-TA. Here, we investigated the types and potential mechanisms of liver damage caused by HFPO-TA. Initially, we validated that the introduction of HFPO-TA resulted in the Wnt/β-catenin signaling (W/β signaling) activation, as well as the induction of necroptosis and inflammation, both in the liver of mice and in HepG2 cells. Subsequently, we established that the W/β signaling mediated the necroptosis and inflammation observed in the liver and HepG2 cells exposed to HFPO-TA. Finally, we demonstrated that the phosphorylated form of NF-κB p65 (p-NF-κB p65) played a role in mediating the necroptosis and inflammation, and its activity could be regulated by the W/β signaling pathway in the liver of mice and HepG2 cells exposed to HFPO-TA. In conclusion, our investigation elucidates the role of HFPO-TA in inducing necroptosis and inflammation in the liver, which is facilitated through the activation of the W/β/NF-κB axis.

Toxicity comparison of perfluorooctanoic acid (PFOA), hexafluoropropylene oxide dimer acid (HFPO-DA), and hexafluoropropylene oxide trimer acid (HFPO-TA) in zebrafish gut

Hexafluoropropylene oxide dimer acid (HFPO-DA) and hexafluoropropylene oxide trimer acid (HFPO-TA) are considered as alternatives to perfluorooctanoic acid (PFOA). In this study, zebrafish were exposed to different concentrations of PFOA, HFPO-DA, and HFPO-TA (5 μg/L and 500 μg/L), and the toxic effects on oxidative damage, inflammation, and cell apoptosis in the gut were compared. Additionally, changes in gut metabolome profiles and microbial community structure were analyzed. The results revealed that exposures to HFPO-DA and HFPO-TA led to lower levels of oxidative damage compared to PFOA exposure. However, all three treatments had comparable effects on inflammation and apoptosis. The main biological pathways affected by all three exposures were lipid metabolism, nucleotide metabolism, amino acid metabolism, and environmental information processing. The effects on metabolome profiles were much higher for HFPO-DA and HFPO-TA compared to PFOA at a concentration of 5 μg/L. At a concentration of 500 μg/L, HFPO-DA and HFPO-TA showed similar effects to PFOA. This study also examined the Pearson correlations between gut microbiota and the toxic effects mentioned above. The abundance of specific apoptosis-related genera differed among the three target chemicals, suggesting they may act differently in inducing apoptosis. The correlations between HFPO-DA and HFPO-TA were mostly similar, which helps explain the similar effects observed in their respective treatment groups on metabolic profiles. Overall, this study indicates that HFPO-DA and HFPO-TA may not be safe alternatives to PFOA and provides valuable insights into their toxic effects and risk assessment in water environments.

Influence of dietary bioactive compounds on the bioavailability and excretion of PFOA and its alternative HFPO-TA: Mechanism exploration

Oral ingestion is considered an important route of human exposure to perfluorooctanoic acid (PFOA) and its alternative hexafluoropropylene oxide trimer acid (HFPO-TA). Bioactive compounds are widely used as dietary supplements and food additives. However, little is known about the influence of dietary bioactive compounds on the bioavailability of PFOA and HFPO-TA. Here, three dietary bioactive compounds, β-carotene, quercetin and curcumin, were selected to study their influence on the relative bioavailability (RBA) of PFOA and HFPO-TA in soil using a mouse model. Compared to the control group (68.7 ± 6.27 %), quercetin and curcumin at medium and high doses (20 and 100 mg/kg/d) significantly (p < 0.05) decreased PFOA RBA to 55.2 ± 4.85–56.4 ± 4.57 % and 48.3 ± 5.49–48.6 ± 5.44 %, respectively. Mechanism study showed that medium- and high-dose quercetin as well as high-dose curcumin increased urinary excretion of PFOA by 33.6–35.6 % and 32.2 % through upregulating renal expression of multidrug resistance protein 2 (Mrp2) (1.52–1.63 folds) and Mrp4 (1.26–1.53 folds), thereby reducing PFOA accumulation. In PFOA-treated groups, quercetin at medium and high doses dramatically downregulated the hepatic expression of organic anion transport polypeptides (Oatp1a6, Oatp1b2), organic anion transport proteins (Oat1, Oat2), and fatty acid binding proteins (FABP4, FABP12), while curcumin at medium and high doses inhibited the hepatic expression of Oatp1a6, Oat1 and Oat2. These downregulated genes may reduce the transport of PFOA from blood to liver, and in turn decrease the PFOA RBA. However, β-carotene, quercetin and curcumin exhibited no significant effect on RBA and excretion of HFPO-TA (p > 0.05). This indicated the different absorption mechanisms between PFOA and HFPO-TA, and further research is warranted. This study provided a novel perspective for establishing environmentally friendly ways to reduce health hazards from per- and polyfluoroalkyl substances (PFASs).

New Insights into the Accumulation, Transport, and Distribution Mechanisms of Hexafluoropropylene Oxide Homologues, Important Alternatives to Perfluorooctanoic Acid, in Lettuce (Lactuca sativa L.).

Hexafluoropropylene oxide (HFPO) homologues, which are important alternatives to perfluorooctanoic acid, have been frequently identified in crops. Although exposure to HFPO homologues via crops may pose non-negligible threats to humans, their impact on crops is still unknown. In this study, the accumulation, transport, and distribution mechanisms of three HFPO homologues in lettuce were investigated at the plant, tissue, and cell levels. More specifically, HFPO trimer acid and HFPO tetramer acid were primarily fixed in roots and hardly transported to shoots (TF, 0.06-0.63). Conversely, HFPO dimer acid (HFPO-DA) tended to accumulate in lettuce shoots 2-264 times more than the other two homologues, thus resulting in higher estimated daily intake values. Furthermore, the dissolved organic matter derived from root exudate enhanced HFPO-DA uptake by increasing its desorption fractions in the rhizosphere. The transmembrane uptake of HFPO homologues was controlled by means of a transporter-mediated active process involving anion channels, with the uptake of HFPO-DA being additionally facilitated by aquaporins. The higher accumulation of HFPO-DA in shoots was attributed to the larger proportions of HFPO-DA in the soluble fraction (55-74%) and its higher abundance in both vascular tissues and xylem sap. Our findings expand the understanding of the fate of HFPO homologues in soil-crop systems and reveal the underlying mechanisms of the potential exposure risk to HFPO-DA.

Hexafluoropropylene oxide trimer acid, a perfluorooctanoic acid alternative, induces cardiovascular toxicity in zebrafish embryos

As an increasingly used alternative to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been widely detected in global water environments. However, little is known regarding its toxic effects on cardiovascular development. Here, zebrafish embryos were treated with egg water containing 0, 60, 120, or 240 mg/L HFPO-TA. Results showed that HFPO-TA treatment led to a significant reduction in both larval survival percentage and heart rate. Furthermore, HFPO-TA exposure caused severe pericardial edema and elongation of the sinus venous to bulbus arteriosus distance (SV-BA) in Tg (myl7: GFP) transgenic larvae, disrupting the expression of genes involved in heart development and thus causing abnormal heart looping. Obvious sprouting angiogenesis was observed in the 120 and 240 mg/L exposed Tg (fli: GFP) transgenic larvae. HFPO-TA treatment also impacted the mRNA levels of genes involved in the vascular endothelial growth factor (VEGF) pathway and embryonic vascular development. HFPO-TA exposure significantly decreased erythrocyte number in Tg (gata1: DsRed) transgenic embryos and influenced gene expression associated with the heme metabolism pathway. HFPO-TA also induced oxidative stress and altered the transcriptional levels of genes related to cell cycle and apoptosis, inhibiting cell proliferation while promoting apoptosis. Therefore, HFPO-TA exposure may induce abnormal development of the cardiovascular and hematopoietic systems in zebrafish embryos, suggesting it may not be a suitable or safe alternative for PFOA.

Trophic behaviors of PFOA and its alternatives perfluoroalkyl ether carboxylic acids (PFECAs) in a coastal food web

With the increasing restrictions and concerns about legacy poly- and perfluoroalkyl substances (PFAS), the production and usage of alternatives, i.e., perfluoroalkyl ether carboxylic acids (PFECAs), have risen recently. However, there is a knowledge gap regarding the bioaccumulation and trophic behaviors of emerging PFECAs in coastal ecosystems. The bioaccumulation and trophodynamics of perfluorooctanoic acid (PFOA) and its substitutes (PFECAs) were investigated in Laizhou Bay, which is located downstream of a fluorochemical industrial park in China. Hexafluoropropylene oxide trimer acid (HFPO-TrA), perfluoro-2-methoxyacetic acid (PFMOAA) and PFOA constituted the dominant compounds in the ecosystem of Laizhou Bay. PFMOAA was dominant in invertebrates, whereas the long-chain PFECAs preferred to accumulate in fishes. The PFAS concentrations in carnivorous invertebrates were higher than those in filter-feeding species. Considering migration behaviors, the ∑PFAS concentrations followed the order oceanodromous fish < diadromous fish < non-migratory fish. The trophic magnification factors (TMFs) of long-chain PFECAs (HFPO-TrA, HFPO-TeA and PFO5DoA) were >1, suggesting trophic magnification potential, while biodilution for short-chain PFECAs (PFMOAA) was observed. The intake of PFOA in seafood may constitute a great threat to human health. More attention should be given to the impact of emerging hazardous PFAS on organisms for the health of ecosystems and human beings.

Hexafluoropropylene oxide trimer acid causes fibrosis in mice liver via mitochondrial ROS/cGAS-STING/NLRP3-mediated pyroptosis.

Hexafluoropropylene oxide trimer acid (HFPO-TA) causes hepatotoxicity, however, its underlying mechanisms have not been conclusively determined. We investigated the effects of HFPO-TA on mice liver after 28 days of orally administered 0 or 0.5mg/kg/d HFPO-TA. Administration of HFPO-TA induced mitochondrial ROS (mtROS) overexpression, cGAS-STING signaling activation, pyroptosis and fibrosis in mice liver. To determine the HFPO-TA-associated hepatotoxic mechanisms, mtROS, cGAS-STING signaling and pyroptosis intervention assays were performed in HFPO-TA-exposed mice liver. First, mtROS was found to be an upstream regulatory target of cGAS-STING signaling, pyroptosis and fibrosis. Second, cGAS-STING signaling was established to be an upstream regulatory mechanism of pyroptosis and fibrosis. Finally, pyroptosis was shown to regulate fibrosis. The above results confirm that HFPO-TA causes mice liver fibrosis via mtROS/cGAS-STING/NLRP3-mediated pyroptosis.

Emerging poly- and perfluoroalkyl substances in water and sediment from Qiantang River-Hangzhou Bay

Many emerging poly- and perfluoroalkyl substances (PFASs) are being used in China, due to the gradual phase out of legacy PFASs. Occurrence and environmental behaviors of emerging PFASs in Chinese fresh water environment are still not well known. In this study, 31 PFASs, including 14 emerging PFASs, were measured in 29 pairs of water and sediment samples from Qiantang River-Hangzhou Bay, an important drinking water resource for cities in Yangtze River basin. Perfluorooctanoate was consistently the predominant legacy PFAS in water (8.8–130 ng/L) and sediment (3.7–49 ng/g dw). Twelve emerging PFASs were detected in water, with the dominance of 6:2 chlorinated polyfluoroalkyl ether sulfonates (6:2 Cl-PFAES; mean 11 ng/L, 0.79–57 ng/L) and 6:2 fluorotelomer sulfonate (6:2 FTS; 5.6 ng/L, < LOD–29 ng/L). Eleven emerging PFASs were found in sediment, and were also dominated by 6:2 Cl-PFAES (mean 4.3 ng/g dw, 0.19–16 ng/g dw) and 6:2 FTS (2.6 ng/g dw, < LOD–9.4 ng/g dw). Spatially, sampling sites closed to the surrounding cities had comparatively higher water concentrations of PFASs. Among emerging PFASs, 8:2 Cl-PFAES (3.0 ± 0.34) had the highest mean field-based log-transformed organic‑carbon normalized sediment-water partition coefficient (log Koc), followed by 6:2 Cl-PFAES (2.9 ± 0.35) and hexafluoropropylene oxide trimer acid (2.8 ± 0.32). p-perfluorous nonenoxybenzene sulfonate (2.3 ± 0.60) and 6:2 FTS (1.9 ± 0.54) had relatively lower mean log Koc values. To our knowledge, this is the most comprehensive study investigating the occurrence and partitioning behaviors of emerging PFASs in Qiantang River.

Uptake and translocation of both legacy and emerging per- and polyfluorinated alkyl substances in hydroponic vegetables

The extensive use of per- and polyfluorinated alkyl substances (PFASs) and their substitutes has resulted in their frequent detections in environmental matrices. However, limited information is known about their uptake into vegetables and health risk through diet, particularly for those emerging alternatives. In this study, a total of 17 PFASs (namely 12 legacy PFASs and 5 of their alternatives) were compared for their accumulation into four staple vegetables (lettuce, Chinese cabbage, chrysanthemum coronarium, and cucumber) in hydroponic system with single PFAS concentration being 10 μg/L, except for 8:2 chlorinated polyfluoroalkyl ether sulfonate (Cl-PFESA) as 0.5 μg/L. The sum concentrations of 17 PFASs in edible parts were in the order of Chinese cabbage leaf (13,456 ng/g) > lettuce leaf (5996 ng/g) > cucumber fruit (4115 ng/g) >chrysanthemum coronarium stem (3999 ng/g). For perfluorooctanoate acid (PFOA) and its alternatives, hexafluoropropylene oxide trimer acid (HFPO-TA) preferentially accumulated in roots than PFOA with root concentration factors being 35.7–99.9. Translocation to edible parts was more remarkable for hexafluoropropylene oxide dimer acid (HFPO-DA) compared with PFOA in lettuce and cucumber. For perfluorooctanesulfonate acid (PFOS) and its alternatives, roots of all the four vegetables were found to more readily accumulate 8:2 Cl-PFESA than PFOS, but 8:2 Cl-PFESA was hardly translocated to the aerial parts. Significantly (p < 0.05) higher edible concentrations of 8:2 and 6:2 fluorotelomer sulfonic acids (FTSA) than that of PFOS were observed for cucumber.

Hexafluoropropylene oxide trimer acid (HFPO-TA) disturbs embryonic liver and biliary system development in zebrafish

Hexafluoropropylene oxide trimer acid (HFPO-TA), a novel alternative to perfluorooctanoic acid (PFOA), has emerged as a potential environmental pollutant. Here, to investigate the toxic effects of HFPO-TA on liver and biliary system development, zebrafish embryos were exposed to 0, 50, 100, or 200 mg/L HFPO-TA from 6 to 120 h post-fertilization (hpf). Results showed that the 50 % lethal concentration (LC50) of HFPO-TA was 231 mg/L at 120 hpf, lower than that of PFOA. HFPO-TA exposure decreased embryonic hatching, survival, and body length. Furthermore, HFPO-TA exerted higher toxicity at the specification stage than during the differentiation and maturation stages, leading to small-sized livers in Tg(fabp10a: DsRed) transgenic larvae and histopathological changes. Significant decreases in the mRNA expression of genes related to liver formation were observed. Alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and direct bilirubin (DBIL) levels were significantly increased. HFPO-TA decreased total cholesterol (TCHO) and triglyceride (TG) activities, disturbed lipid metabolism through the peroxisome proliferator-activated receptor (PPAR) pathway, and induced an inflammatory response. Furthermore, HFPO-TA inhibited intrahepatic biliary development in Tg(Tp1:eGFP) transgenic larvae and interfered with transcription of genes associated with biliary duct development. HFPO-TA reduced bile acid synthesis but increased bile acid transport, resulting in disruption of bile acid metabolism. Therefore, HFPO-TA influenced embryonic liver and biliary system morphogenesis, caused liver injury, and may be an unsafe alternative for PFOA.

Emerging and legacy per-and polyfluoroalkyl substances in the rivers of a typical industrialized province of China: Spatiotemporal variations, mass discharges and ecological risks

Per- and polyfluoroalkyl substances (PFAS) contamination has drawn considerable attention in the rivers of Shandong, China. However, their seasonal variations have not been well addressed due to the geographic scale. Here, surface waters were collected seasonally at estuaries of 13 major rivers in Shandong to investigate the spatiotemporal variations, mass discharges and ecological risks of PFAS. Two novel perfluoroalkyl ether carboxylic acids, hexafluoropropylene oxide-dimer acid (HFPO-DA) and hexafluoropropylene oxide-trimer acid (HFPO-TA), and 10 legacy PFAS were all detectable and their total concentrations (∑PFAS) ranged largely from 23 to 25,400 ng/L. Elevated levels of all target compounds were found in the Xiaoqing River but Majia and Jiaolai Rivers were also of concern. Perfluorooctanoic acid (PFOA) was dominant in all the rivers. Its concentration in the Xiaoqing River estuary increased 6-fold from 2011 to 2014 and reached a plateau during 2014–2020. The nonsignificant seasonality of the PFAS concentrations in rivers with seasonal flows may indicate their different emission patterns (i.e., higher emission in the wet season and lower emission in the dry season). The ratio of maximum to minimum concentration (Cmax/Cmin) was proposed to characterize the influence of local point sources, with Cmax/Cmin ranging from 10 to 14,000. Xiaoqing and Yellow Rivers discharged ∼98% of ∑PFAS flux to the sea, which was estimated to be 28.0 t in 2020. This study raises attention to the industrial emission patterns of PFAS. Further investigations with higher time resolution were needed to understand the emission patterns of PFAS in Shandong.