13 research outputs found
Nickel(II) Inhibits Tet-Mediated 5‑Methylcytosine Oxidation by High Affinity Displacement of the Cofactor Iron(II)
Ten-eleven
translocation (Tet) family proteins are FeÂ(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 NiÂ(II) ion can bind to the FeÂ(II)-chelating
motif (HXD) with an affinity of 7.5-fold as high as FeÂ(II). Consistently,
we further found that NiÂ(II) ion can displace the cofactor FeÂ(II)
of Tet dioxygenases and inhibit Tet-mediated 5mC oxidation activity
with an estimated IC<sub>50</sub> of 1.2 μM. Essentially, NiÂ(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
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
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
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
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
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
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
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>)
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
Here,
we report on the occurrence of a novel perfluoroalkyl ether
carboxylic acid, ammonium perfluoro-2-[(propoxy)Âpropoxy]-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