13 research outputs found

    Nickel(II) Inhibits Tet-Mediated 5‑Methylcytosine Oxidation by High Affinity Displacement of the Cofactor Iron(II)

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    Ten-eleven translocation (Tet) family proteins are Fe­(II)- and 2-oxoglutarate-dependent dioxygenases that regulate the dynamics of DNA methylation by catalyzing the oxidation of DNA 5-methylcytosine (5mC). To exert physiologically important functions, redox-active iron chelated in the catalytic center of Tet proteins directly involves the oxidation of the multiple substrates. To understand the function and interaction network of Tet dioxygenases, it is interesting to obtain high affinity and a specific inhibitor. Surprisingly, here we found that natural Ni­(II) ion can bind to the Fe­(II)-chelating motif (HXD) with an affinity of 7.5-fold as high as Fe­(II). Consistently, we further found that Ni­(II) ion can displace the cofactor Fe­(II) of Tet dioxygenases and inhibit Tet-mediated 5mC oxidation activity with an estimated IC<sub>50</sub> of 1.2 μM. Essentially, Ni­(II) can be used as a high affinity and selective inhibitor to explore the function and dynamics of Tet proteins

    Formula for conferring degree to 8 pupils

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    Perfluoroalkyl chemicals (PFCs) are stable man-made compounds with many industrial and commercial uses. Concern has been raised that they may exert deleterious effects, especially on lipid regulation. We aimed to assess exposure to perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and seven other PFCs in occupational workers from a fluorochemical plant and nearby community residents, and to investigate the association between PFOA and serum biomarkers. Serum biomarkers included not only biochemical parameters, such as lipids and enzymes, but also circulating microRNAs (miRNAs). Samples were analyzed by high-pressure liquid chromatography/tandem mass spectrometry (HPLC-MS/MS). Circulating miRNA levels were detected by quantitative polymerase chain reaction (PCR). Analyses were conducted by correlation and linear regression. We detected PFOS, PFOA, perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) in all samples. The median levels of serum PFOA and PFOS were 284.34 ng/mL and 34.16 ng/mL in residents and 1635.96 ng/mL and 33.46 ng/mL in occupational participants, respectively. To our knowledge, we found for the first time that PFOA was negatively associated with high-density lipoprotein cholesterol (HDL-C) in workers using linear regression after adjusting for potential confounders. Circulating miR-26b and miR-199a-3p were elevated with serum concentration of PFOA. Although the limitations of small sample size and the cross-sectional nature of the current study constrained causal inferences, the observed associations between PFOA and these serum biomarkers warrant further study

    Hepatotoxic Effects of Hexafluoropropylene Oxide Trimer Acid (HFPO-TA), A Novel Perfluorooctanoic Acid (PFOA) Alternative, on Mice

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    As an alternative to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been increasingly used for fluoropolymer manufacture in recent years. Its growing detection in environmental matrices and wildlife raises considerable concern about its potential health risks. Here we investigated the effects of HFPO-TA on mouse liver following 28 days of exposure to 0.02, 0.1, or 0.5 mg/kg/d of HFPO-TA via oral gavage. Results showed that HFPO-TA concentrations increased to 1.14, 4.48, and 30.8 μg/mL in serum and 12.0, 32.2, and 100 μg/g in liver, respectively. Liver injury, including hepatomegaly, necrosis, and increase in alanine aminotransferase activity, was observed. Furthermore, total cholesterol and triglycerides decreased in the liver in a dose-dependent manner. Liver transcriptome analysis revealed that 281, 1001, and 2491 genes were differentially expressed (fold change ≥2 and FDR < 0.05) in the three treated groups, respectively, compared with the control group. KEGG enrichment analysis highlighted the PPAR and chemical carcinogenesis pathways in all three treatment groups. Protein levels of genes involved in carcinogenesis, such as AFP, p21, Sirt1 C-MYC, and PCNA, were significantly increased. Compared with previously published toxicological data of PFOA, HFPO-TA showed higher bioaccumulation potential and more serious hepatotoxicity. Taken together, HFPO-TA does not appear to be a safer alternative to PFOA

    Integrated Proteomic and miRNA Transcriptional Analysis Reveals the Hepatotoxicity Mechanism of PFNA Exposure in Mice

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    Perfluoroalkyl chemicals (PFASs) are a class of highly stable man-made compounds, and their toxicological impacts are currently of worldwide concern. Administration of perfluorononanoic acid (PFNA), a perfluorocarboxylic acid (PFCA) with a nine carbon backbone, resulted in dose-dependent hepatomegaly in mice (0, 0.2, 1, and 5 mg/kg body weight, once a day for 14 days) and an increase in hepatic triglycerides (TG) and total cholesterol (TCHO) in the median dose group as well as serum transaminases in the high dose group. Using isobaric tags for relative and absolute quantitation (iTRAQ), we identified 108 (80 up-regulated, 28 down-regulated) and 342 hepatic proteins (179 up-regulated, 163 down-regulated) that exhibited statistically significant changes (at least a 1.2-fold alteration and <i>P</i> < 0.05) in the 1 and 5 mg/kg/d PFNA treatment groups, respectively. Sixty-six proteins (54 up-regulated, 12 down-regulated) significantly changed in both of the two treatment groups. Among these 54 up-regulated proteins, most were proteins related to the lipid metabolism process (31 proteins). The mRNA analysis results further suggested that PFNA exposure not only resulted in a fatty acid oxidation effect but also activated mouse liver genes involved in fatty acid and cholesterol synthesis. Additionally, three (2 down-regulated, 1 up-regulated) and 30 (14 down-regulated, 16 up-regulated) microRNAs (miRNAs) exhibited at least a 2-fold alteration (<i>P</i> < 0.05) in the 1 and 5 mg/kg/d PFNA treatment groups, respectively, Three miRNAs (up-regulated: miR-34a; down-regulated: miR-362-3p and miR-338-3p) significantly changed in both of the two treatment groups. The repression effect of miR-34a on fucosyltransferase 8 (Fut8) and lactate dehydrogenase (Ldha) was confirmed by luciferase activity assay and Western blot analysis. The results implied that PFNA exerted a hepatic effect, at least partially, by miRNAs mediated post-translational protein repression

    Hepatotoxic Effects of Hexafluoropropylene Oxide Trimer Acid (HFPO-TA), A Novel Perfluorooctanoic Acid (PFOA) Alternative, on Mice

    No full text
    As an alternative to perfluorooctanoic acid (PFOA), hexafluoropropylene oxide trimer acid (HFPO-TA) has been increasingly used for fluoropolymer manufacture in recent years. Its growing detection in environmental matrices and wildlife raises considerable concern about its potential health risks. Here we investigated the effects of HFPO-TA on mouse liver following 28 days of exposure to 0.02, 0.1, or 0.5 mg/kg/d of HFPO-TA via oral gavage. Results showed that HFPO-TA concentrations increased to 1.14, 4.48, and 30.8 μg/mL in serum and 12.0, 32.2, and 100 μg/g in liver, respectively. Liver injury, including hepatomegaly, necrosis, and increase in alanine aminotransferase activity, was observed. Furthermore, total cholesterol and triglycerides decreased in the liver in a dose-dependent manner. Liver transcriptome analysis revealed that 281, 1001, and 2491 genes were differentially expressed (fold change ≥2 and FDR < 0.05) in the three treated groups, respectively, compared with the control group. KEGG enrichment analysis highlighted the PPAR and chemical carcinogenesis pathways in all three treatment groups. Protein levels of genes involved in carcinogenesis, such as AFP, p21, Sirt1 C-MYC, and PCNA, were significantly increased. Compared with previously published toxicological data of PFOA, HFPO-TA showed higher bioaccumulation potential and more serious hepatotoxicity. Taken together, HFPO-TA does not appear to be a safer alternative to PFOA

    Prenatal and Neonatal Exposure to Perfluorooctane Sulfonic Acid Results in Changes in miRNA Expression Profiles and Synapse Associated Proteins in Developing Rat Brains

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    We previously identified a number of perfluorooctane sulfonic acid (PFOS)-responsive transcripts in developing rat brains using microarray analysis. However, the underlying mechanisms and functional consequences remain unclear. We hypothesized that microRNAs (miRNAs), which have emerged as powerful negative regulators of mRNA and protein levels, might be responsible for PFOS-induced mRNA changes and consequent neural dysfunctions. We used eight miRNA arrays to profile the expression of brain miRNAs in neonatal rats on postnatal days (PND) 1 and 7 with maternal treatment of 0 (Control) and 3.2 mg/kg of PFOS feed from gestational day 1 to PND 7, and subsequently examined six potentially altered synapse-associated proteins to evaluate presumptive PFOS-responsive functions. Twenty-four brain miRNAs on PND 1 and 17 on PND 7 were significantly altered with PFOS exposure (<i>P</i> < 0.05), with miR-466b, -672, and -297, which are critical in neurodevelopment and synapse transmission, showing a more than 5-fold reduction. Levels of three synapse-involved proteins, NGFR, TrkC, and VGLUT2, were significantly decreased with no protein up-regulated on PND 1 or 7. Perfluorooctane sulfonic acid might affect calcium actions during synapse transmission in the nervous system by interfering with SYNJ1, ITPR1, and CALM1 via their targeting miRNAs. Our results indicated that miRNA had little direct regulatory effect on the expression of mRNAs and synapse-associated proteins tested in the developing rat brain exposed to PFOS, and it seems that the PFOS-induced synaptic dysfunctions and changes in transcripts resulted from a combinatory action of biological controllers and processes, rather than directed by one single factor

    Proteomic Analysis of Mouse Testis Reveals Perfluorooctanoic Acid-Induced Reproductive Dysfunction via Direct Disturbance of Testicular Steroidogenic Machinery

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    Perfluorooctanoic acid (PFOA) is a ubiquitous environmental pollutant suspected of being an endocrine disruptor; however, mechanisms of male reproductive disorders induced by PFOA are poorly understood. In this study, male mice were exposed to 0, 0.31, 1.25, 5, and 20 mg PFOA/kg/day by oral gavage for 28 days. PFOA significantly damaged the seminiferous tubules and reduced testosterone and progesterone levels in the testis in a dose-dependent manner. Furthermore, PFOA exposure reduced sperm quality. We identified 93 differentially expressed proteins between the control and the 5 mg/kg/d PFOA treated mice using a quantitative proteomic approach. Among them, insulin like-factor 3 (INSL3) and cytochrome P450 cholesterol side-chain cleavage enzyme (CYP11A1) as Leydig-cell-specific markers were significantly decreased. We examined in detail the expression patterns of CYP11A1 and associated genes involved in steroidogenesis in the mouse testis. PFOA inhibited the mRNA and protein levels of CYP11A1 and the mRNA levels of 17β-hydroxysteroid dehydrogenase (17β-HSD) in a dose-dependent manner. Moreover, <i>in vitro</i> study showed the reduction in progesterone levels was accompanied by decreased expression of CYP11A1 in cAMP-stimulated mLTC-1 cells. Our findings indicate that PFOA exposure can impair male reproductive function, possibly by disturbing testosterone levels, and CPY11A1 may be a major steroidogenic enzyme targeted by PFOA

    Sex Differences in Transcriptional Expression of FABPs in Zebrafish Liver after Chronic Perfluorononanoic Acid Exposure

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    Perfluorononanoic acid (PFNA), a nine carbon backbone of perfluorinated acids (PFAAs), has wide production applications and is found in environmental matrices as a contaminant. To understand the adverse effects of PFNA, adult male and female zebrafish were exposed to differing PFNA dosages (0, 0.01, 0.1, and 1.0 mg/L) for 180 days using a flow-through exposure system. Results showed body weight, body length, and hepatosomatic index (HSI) decreased in both sexes. The HPLC-MS/MS analysis found that PFNA concentrations were higher in male livers than in female livers with increasing significance in a dose-dependent manner. Total cholesterol levels increased in the livers of both sexes, whereas triglyceride (TG) levels increased in males and decreased in females. With the exception of FABP1b, the transcriptional expression levels of fatty acid binding proteins (FABPs) were up-regulated in males and down-regulated in females. A similar trend between sexes occurred for peroxisome proliferator-activated receptors (PPARs) and Ccaat-enhancer-binding proteins (C/EBPs), which may be the upstream regulatory elements of FABPs. The results indicated that PFNA exposure caused opposite adverse effects on liver TG levels between the sexes in zebrafish possibly due to the opposite expression of FABPs and its upstream genes

    Occurrence and Tissue Distribution of Novel Perfluoroether Carboxylic and Sulfonic Acids and Legacy Per/Polyfluoroalkyl Substances in Black-Spotted Frog (<i>Pelophylax nigromaculatus</i>)

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    Research on perfluoroalkyl substances (PFASs) continues to grow. However, very little is known about these substances in amphibians. Here we report for the first time on the occurrence, tissue distribution, and bioaccumulation of two novel PFASs, chlorinated polyfluorinated ether sulfonic acid (6:2 Cl-PFESA) and hexafluoropropylene oxide trimer acid (HFPO-TA), in the black-spotted frog (<i>Pelophylax nigromaculatus</i>) from China. Frogs from cities with large-scale fluorochemical industries had significantly greater liver ∑PFAS levels (mean 54.28 ng/g in Changshu; 31.22 ng/g in Huantai) than those from cities without similar industry (9.91 ng/g in Zhoushan; 7.68 ng/g in Quzhou). Females had significantly lower liver PFAS levels than males, and older frogs tended to have lower PFAS levels than younger frogs. Skin, liver, and muscle contributed nearly 80% to the whole body burden of 6:2 Cl-PFESA in males, whereas the female ovary alone accounted for 58.4%. These results suggest substantial maternal transfer of 6:2 Cl-PFESA to eggs, raising concern regarding its developmental toxicity on frogs and other species. The bioaccumulation factor results (6:2 Cl-PFESA > PFOS; HFPO-TA > PFOA) suggest a stronger accumulative potential in the black-spotted frog for these alternative substances compared to their predecessors. Future studies on their toxicity and ecology risk are warranted

    First Report on the Occurrence and Bioaccumulation of Hexafluoropropylene Oxide Trimer Acid: An Emerging Concern

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    Here, we report on the occurrence of a novel perfluoroalkyl ether carboxylic acid, ammonium perfluoro-2-[(propoxy)­propoxy]-1-propanoate (HFPO-TA), in surface water and common carp (<i>Cyprinus carpio</i>) collected from the Xiaoqing River and in residents residing near a fluoropolymer production plant in Huantai County, China. Compared with the levels upstream of the Xiaoqing River, HFPO-TA concentrations (5200–68500 ng/L) were approximately 120–1600-times higher downstream after receiving fluoropolymer plant effluent from a tributary. The riverine discharge of HFPO-TA was estimated to be 4.6 t/yr, accounting for 22% of total PFAS discharge. In the wild common carp collected downstream from the point source, HFPO-TA was detected in the blood (median: 1510 ng/mL), liver (587 ng/g ww), and muscle (118 ng/g ww). The log BCF<sub>blood</sub> of HFPO-TA (2.18) was significantly higher than that of PFOA (1.93). Detectable levels of HFPO-TA were also found in the sera of residents (median: 2.93 ng/mL). This is the first report on the environmental occurrence and bioaccumulation of this novel chemical. Our results indicate an emerging usage of HFPO-TA in the fluoropolymer manufacturing industry and raise concerns about the toxicity and potential health risks of HFPO-TA to aquatic organisms and humans
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