-
The Journal of Biological Chemistry Sep 1999The Escherichia coli ssuEADCB gene cluster is required for the utilization of alkanesulfonates as sulfur sources, and is expressed under conditions of sulfate or...
The Escherichia coli ssuEADCB gene cluster is required for the utilization of alkanesulfonates as sulfur sources, and is expressed under conditions of sulfate or cysteine starvation. The SsuD and SsuE proteins were overexpressed and characterized. SsuE was purified to homogeneity as an N-terminal histidine-tagged fusion protein. Native SsuE was a homodimeric enzyme of M(r) 58,400, which catalyzed an NAD(P)H-dependent reduction of FMN, but it was also able to reduce FAD or riboflavin. The SsuD protein was purified to >98% purity using cation exchange, anion exchange, and hydrophobic interaction chromatography. The pure enzyme catalyzed the conversion of pentanesulfonic acid to sulfite and pentaldehyde and was able to desulfonate a wide range of sulfonated substrates including C-2 to C-10 unsubstituted linear alkanesulfonates, substituted ethanesulfonic acids and sulfonated buffers. SsuD catalysis was absolutely dependent on FMNH(2) and oxygen, and was maximal for SsuE/SsuD molar ratios of 2.1 to 4.2 in 10 mM Tris-HCl, pH 9.1. Native SsuD was a homotetrameric enzyme of M(r) 181,000. These results demonstrate that SsuD is a broad range FMNH(2)-dependent monooxygenase catalyzing the oxygenolytic conversion of alkanesulfonates to sulfite and the corresponding aldehydes. SsuE is the FMN reducing enzyme providing SsuD with FMNH(2).
Topics: Alkanesulfonates; Amino Acid Sequence; Bacterial Proteins; Catalysis; Electrophoresis, Polyacrylamide Gel; Escherichia coli; Escherichia coli Proteins; FMN Reductase; Flavin Mononucleotide; Kinetics; Mixed Function Oxygenases; Models, Chemical; Molecular Sequence Data; NADH, NADPH Oxidoreductases; Protein Conformation; Sequence Alignment
PubMed: 10480865
DOI: 10.1074/jbc.274.38.26639 -
Frontiers in Public Health 2024To investigate the relationships between perfluoroalkyl and polyfluoroalkyl substances (PFASs) exposure and glucose metabolism indices.
OBJECTIVE
To investigate the relationships between perfluoroalkyl and polyfluoroalkyl substances (PFASs) exposure and glucose metabolism indices.
METHODS
Data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 waves were used. A total of 611 participants with information on serum PFASs (perfluorononanoic acid (PFNA); perfluorooctanoic acid (PFOA); perfluoroundecanoic acid (PFUA); perfluorohexane sulfonic acid (PFHxS); perfluorooctane sulfonates acid (PFOS); perfluorodecanoic acid (PFDeA)), glucose metabolism indices (fasting plasma glucose (FPG), homeostasis model assessment for insulin resistance (HOMA-IR) and insulin) as well as selected covariates were included. We used cluster analysis to categorize the participants into three exposure subgroups and compared glucose metabolism index levels between the subgroups. Least absolute shrinkage and selection operator (LASSO), multiple linear regression analysis and Bayesian kernel machine regression (BKMR) were used to assess the effects of single and mixed PFASs exposures and glucose metabolism.
RESULTS
The cluster analysis results revealed overlapping exposure types among people with higher PFASs exposure. As the level of PFAS exposure increased, FPG level showed an upward linear trend ( < 0.001), whereas insulin levels demonstrated a downward linear trend ( = 0.012). LASSO and multiple linear regression analysis showed that PFNA and FPG had a positive relationship (>50 years-old group: = 0.059, < 0.001). PFOA, PFUA, and PFHxS (≤50 years-old group: insulin = -0.194, < 0.001, HOMA-IR = -0.132, = 0.020) showed negative correlation with HOMA-IR/insulin. PFNA (>50 years-old group: insulin = 0.191, = 0.018, HOMA-IR = 0.220, = 0.013) showed positive correlation with HOMA-IR/insulin, which was essentially the same as results that obtained for the univariate exposure-response map in the BKMR model. Association of exposure to PFASs on glucose metabolism indices showed positive interactions between PFOS and PFHxS and negative interactions between PFOA and PFNA/PFOS/PFHxS.
CONCLUSION
Our study provides evidence that positive and negative correlations between PFASs and FPG and HOMA-IR/insulin levels are observed, respectively. Combined effects and interactions between PFASs. Given the higher risk of glucose metabolism associated with elevated levels of PFAS, future studies are needed to explore the potential underlying mechanisms.
Topics: Humans; Middle Aged; Environmental Pollutants; Nutrition Surveys; Bayes Theorem; Fluorocarbons; Alkanesulfonates; Glucose; Insulins; Caprylates; Fatty Acids; Sulfonic Acids
PubMed: 38633237
DOI: 10.3389/fpubh.2024.1370971 -
Journal of Cardiovascular Pharmacology Nov 2020The most common complications in patients with type-2 diabetes are hyperglycemia and hyperlipidemia that can lead to cardiovascular disease. Alleviation of these... (Review)
Review
The most common complications in patients with type-2 diabetes are hyperglycemia and hyperlipidemia that can lead to cardiovascular disease. Alleviation of these complications constitutes the major therapeutic approach for the treatment of diabetes mellitus. Agonists of peroxisome proliferator-activated receptor (PPAR) alpha and PPARγ are used for the treatment of hyperlipidemia and hyperglycemia, respectively. PPARs belong to the nuclear receptors superfamily and regulate fatty acid metabolism. PPARα ligands, such as fibrates, reduce circulating triglyceride levels, and PPARγ agonists, such as thiazolidinediones, improve insulin sensitivity. Dual-PPARα/γ agonists (glitazars) were developed to combine the beneficial effects of PPARα and PPARγ agonism. Although they improved metabolic parameters, they paradoxically aggravated congestive heart failure in patients with type-2 diabetes via mechanisms that remain elusive. Many of the glitazars, such as muraglitazar, tesaglitazar, and aleglitazar, were abandoned in phase-III clinical trials. The objective of this review article pertains to the understanding of how combined PPARα and PPARγ activation, which successfully targets the major complications of diabetes, causes cardiac dysfunction. Furthermore, it aims to suggest interventions that will maintain the beneficial effects of dual PPARα/γ agonism and alleviate adverse cardiac outcomes in diabetes.
Topics: Alkanesulfonates; Animals; Cardiotoxicity; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Energy Metabolism; Glycine; Humans; Hypoglycemic Agents; Oxazoles; PPAR alpha; PPAR gamma; Phenylpropionates; Risk Assessment; Risk Factors; Signal Transduction; Thiophenes
PubMed: 33165133
DOI: 10.1097/FJC.0000000000000891 -
The Science of the Total Environment May 2024No study has examined the association between per- and polyfluoroalkyl substances (PFAS) exposure and chronic obstructive pulmonary disease (COPD) risk. This study aims...
BACKGROUND
No study has examined the association between per- and polyfluoroalkyl substances (PFAS) exposure and chronic obstructive pulmonary disease (COPD) risk. This study aims to explore this relationship.
METHODS
This study enrolled 4541 individuals who had available data on PFAS, COPD, and covariates from NHANES 2007-2018. Serum PFAS including perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) were analyzed, because of high detective rates. Considering the skew distribution of PFAS levels, the natural logarithm-transformed PFAS (Ln-PFAS) was used. Logistic regression analysis, restricted cubic spline (RCS), and weighted quantile sum (WQS) regression were performed to explore the single, nonlinear, and mixed effects. A mediating analysis was used to evaluate the mediated effects of albumin.
RESULTS
Individuals with COPD had higher levels of PFHxS, PFNA, PFOA, and PFOS compared to those without COPD. Ln-PFNA (OR : 1.92, 95 % CI:1.31 to 2.80, P: <0.001; OR : 1.07, 95 % CI: 0.81 to 1.40, P: 0.636) and ln-PFOA (OR : 2.17, 95 % CI:1.38 to 3.41, P: <0.001; OR : 1.49, 95 % CI: 1.08 to 2.05, P: 0.016) were associated with COPD risk especially in males. The interaction between PFNA exposure and sex on COPD risk was significant (P : <0.001). The RCS curve demonstrated the nonlinear relationship between the ln-PFOA (P :0.001), ln-PFNA (P :0.045), and COPD risk in males. WQS analysis showed mixed PFAS exposure was correlated with COPD risk in males (OR: 1.44, 95 % CI:1.18 to 1.75, P: <0.001). Albumin mediated the relationship between PFOA and COPD (mediated proportion: -17.94 %).
CONCLUSION
This study concludes PFOA and PFNA are linked to a higher COPD risk in males, and serum albumin plays a mediating role in the relationship between PFOA and COPD. Thess findings are beneficial for the prevention of COPD. Further studies are required to explore potential mechanisms.
Topics: Male; Female; Humans; Nutrition Surveys; Environmental Pollutants; Serum Albumin; Prevalence; Alkanesulfonic Acids; Fluorocarbons; Alkanesulfonates; Pulmonary Disease, Chronic Obstructive; Caprylates; Fatty Acids
PubMed: 38494022
DOI: 10.1016/j.scitotenv.2024.171742 -
Environment International Jul 2020Exposure to per-/polyfluoroalkyl substances (PFASs) can disrupt endocrine hormones in humans. Prior studies have focused on the harmful effects of the two traditional...
BACKGROUND
Exposure to per-/polyfluoroalkyl substances (PFASs) can disrupt endocrine hormones in humans. Prior studies have focused on the harmful effects of the two traditional per-/polyfluoroalkyl substances (PFASs), perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). Other PFASs, used as the replacements of PFOS and PFOA, are widely and increasingly detected in humans. Whether these replacements influence glucocorticoids and progestogens in newborns remains unknown.
OBJECTIVE
To investigate the associations between exposures of PFOS, PFOA and their replacements and glucocorticoids and progestogens in newborns.
METHODS
We measured the concentrations of 13 PFASs, 3 glucocorticoids (11-deoxycortisol, cortisol and cortisone) and 2 progestogens [progesterone, 17-hydroxyprogesterone (17OHP)] in the cord sera of 374 neonates in a birth cohort from Wuhan, China, between 2013 and 2014. We evaluated the associations of each PFAS with glucocorticoids and progestogens using multiple linear regression models, and multiple comparisons were additionally corrected via false discovery rates (FDR).
RESULTS
Out of the 13 PFASs, 9 were detected in over 95% of cord sera. The Chinese specific PFOS replacement - 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA, trade name F-53B) was positively associated with 13.13% change in cortisol in girls (95% CI = 4.47%, 22.52%, for each IQR increase in 6:2 Cl-PFESA). Seven PFASs had positive associations with the precursor of cortisol, namely 11-deoxycortisol (percent change ranged from 6.41% to 11.24%, for each IQR increase in PFASs). Perfluorobutane sulfonate (PFBS) in cord sera was positively associated with progesterone in the linear model, whereas PFOS and perfluorohexane sulfonate (PFHxS) levels were associated with progesterone in the quartile models. No PFASs were related to 17OHP or cortisone.
CONCLUSIONS
In this study, PFOS, PFOA and/or their replacements were positively associated with progesterone, cortisol and 11-deoxycortisol in newborns. These results suggested that not only PFOS and PFOA, but also other PFASs have potential impacts on glucocorticoids and progestogens in newborns.
Topics: Alkanesulfonates; Alkanesulfonic Acids; Caprylates; China; Environmental Pollutants; Ethers; Female; Fluorocarbons; Glucocorticoids; Humans; Infant, Newborn; Progestins
PubMed: 32474218
DOI: 10.1016/j.envint.2020.105636 -
ELife Mar 2022DNA base damage arises frequently in living cells and needs to be removed by base excision repair (BER) to prevent mutagenesis and genome instability. Both the formation...
DNA base damage arises frequently in living cells and needs to be removed by base excision repair (BER) to prevent mutagenesis and genome instability. Both the formation and repair of base damage occur in chromatin and are conceivably affected by DNA-binding proteins such as transcription factors (TFs). However, to what extent TF binding affects base damage distribution and BER in cells is unclear. Here, we used a genome-wide damage mapping method, -methylpurine-sequencing (NMP-seq), and characterized alkylation damage distribution and BER at TF binding sites in yeast cells treated with the alkylating agent methyl methanesulfonate (MMS). Our data show that alkylation damage formation was mainly suppressed at the binding sites of yeast TFs ARS binding factor 1 (Abf1) and rDNA enhancer binding protein 1 (Reb1), but individual hotspots with elevated damage levels were also found. Additionally, Abf1 and Reb1 binding strongly inhibits BER in vivo and in vitro, causing slow repair both within the core motif and its adjacent DNA. Repair of ultraviolet (UV) damage by nucleotide excision repair (NER) was also inhibited by TF binding. Interestingly, TF binding inhibits a larger DNA region for NER relative to BER. The observed effects are caused by the TF-DNA interaction, because damage formation and BER can be restored by depletion of Abf1 or Reb1 protein from the nucleus. Thus, our data reveal that TF binding significantly modulates alkylation base damage formation and inhibits repair by the BER pathway. The interplay between base damage formation and BER may play an important role in affecting mutation frequency in gene regulatory regions.
Topics: DNA; DNA Damage; DNA Repair; Methyl Methanesulfonate; Transcription Factors
PubMed: 35289750
DOI: 10.7554/eLife.73943 -
Environment International Jul 2023Perfluorohexyl sulfonate (PFHxS) is the third most abundant per- and polyfluoroalkyl substances and its developmental toxicity remains very poorly understood. Here,...
Perfluorohexyl sulfonate (PFHxS) is the third most abundant per- and polyfluoroalkyl substances and its developmental toxicity remains very poorly understood. Here, pregnant mice exposed to PFHxS at human relevant dose showed increased fetal death incidence in the high-dose PFHxS-H group (P < 0.01). Body distribution analyses suggested that PFHxS crossed the placental barrier reaching the fetus in a dose-dependent manner. Histopathological data demonstrated impairment in the placenta with reduced blood sinus volume, placental labyrinth area as well as thickness of labyrinthine layer. Further lipidomic and transcriptomic data together showed that PFHxS exposure caused significant disruption in placental lipid homeostasis, including total lipid accumulation in the placenta, and dysregulation in phospholipid and glycerol lipid metabolism. Gene expression analyses uncovered elevation in key placental fatty acid transporters including fabp2, whereas protein expression showed transporter specific disruptions following exposure. Together, gestational exposure to human relevant level of PFHxS may increase the incidence of fetal deaths and caused placental dysplasia via disruption in lipid metabolism homeostasis. These findings raise the concern regarding the highly prevalent and persistent chemical towards early sensitive developing stages and provide basis for further understanding of its effects on lipid metabolism and underlying mechanisms.
Topics: Humans; Pregnancy; Female; Mice; Animals; Placenta; Alkanesulfonates; Fluorocarbons; Fatty Acids; Homeostasis
PubMed: 37315490
DOI: 10.1016/j.envint.2023.108014 -
Environmental Health Perspectives Jul 2023Nontargeted analysis (NTA) methods identify novel exposures; however, few chemicals have been quantified and interrogated with pregnancy complications.
BACKGROUND
Nontargeted analysis (NTA) methods identify novel exposures; however, few chemicals have been quantified and interrogated with pregnancy complications.
OBJECTIVES
We characterized levels of nine exogenous and endogenous chemicals in maternal and cord blood identified, selected, and confirmed in prior NTA steps, including linear and branched isomers perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), monoethylhexyl phthalate, 4-nitrophenol, tetraethylene glycol, tridecanedioic acid, octadecanedioic acid, and deoxycholic acid. We evaluated relationships between maternal and cord levels and between gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy in a diverse pregnancy cohort in San Francisco.
METHODS
We collected matched maternal and cord serum samples at delivery from 302 pregnant study participants from the Chemicals in Our Bodies cohort in San Francisco. Chemicals were identified via NTA and quantified using targeted approaches. We calculated distributions and Spearman correlation coefficients testing the relationship of chemicals within and between the maternal and cord blood matrices. We used adjusted logistic regression to calculate the odds of GDM and hypertensive disorders of pregnancy associated with an interquartile range increase in maternal chemical exposures.
RESULTS
We detected linear PFOS, PFHxS, octadecanedioic acid, and deoxycholic acid in at least 97% of maternal samples. Correlations ranged between and 0.9. We observed strong correlations between cord and maternal levels of PFHxS, linear PFOS, and branched PFOS (, 0.8, and 0.8, respectively). An interquartile range increase in linear and branched PFOS, tridecanedioic acid, octadecanedioic acid, and deoxycholic acid was associated with increased odds ratio (OR) of GDM [ (95% CI: 0.89, 2.01), 1.24 (95% CI: 0.86, 1.80), 1.26 (95% CI: 0.93, 1.73), 1.24 (95% CI: 0.86, 1.80), and 1.23 (95% CI: 0.87, 1.75), respectively]. Tridecanedioic acid was positively associated with hypertensive disorders of pregnancy [ (95% CI: 0.90, 1.86)].
DISCUSSION
We identified both exogenous and endogenous chemicals seldom quantified in pregnant study participants that were also related to pregnancy complications and demonstrated the utility of NTA to identify chemical exposures of concern. https://doi.org/10.1289/EHP11546.
Topics: Pregnancy; Female; Humans; Cross-Sectional Studies; Cohort Studies; Hypertension, Pregnancy-Induced; Pregnancy Complications; Diabetes, Gestational; Alkanesulfonic Acids; Alkanesulfonates; Fluorocarbons; Deoxycholic Acid; Environmental Pollutants
PubMed: 37466315
DOI: 10.1289/EHP11546 -
Applied and Environmental Microbiology Jul 2020Bacterial alkane metabolism is associated with a number of cellular stresses, including membrane stress and oxidative stress, and the limited uptake of charged ions such...
Bacterial alkane metabolism is associated with a number of cellular stresses, including membrane stress and oxidative stress, and the limited uptake of charged ions such as sulfate. In the present study, the genes and in DR1 cells, which encode an alkanesulfonate monooxygenase and a taurine dioxygenase, respectively, were found to be responsible for hexadecanesulfonate (CSOH) and taurine metabolism, and Cbl was experimentally identified as a potential regulator of and expression. The expression of and occurred under sulfate-limited conditions generated during -hexadecane degradation. Interestingly, expression analysis and knockout experiments suggested that both genes are required to protect cells against oxidative stress, including that generated by -hexadecane degradation and HO exposure. Measurable levels of intracellular hexadecanesulfonate were also produced during -hexadecane degradation. Phylogenetic analysis suggested that and are mainly present in soil-dwelling aerobes within the and classes, which suggests that they function as controllers of the sulfur cycle and play a protective role against oxidative stress in sulfur-limited conditions. and , which play a role in the degradation of organosulfonate, were expressed during -hexadecane metabolism and oxidative stress conditions in DR1. Our study confirmed that hexadecanesulfonate was accidentally generated during bacterial -hexadecane degradation in sulfate-limited conditions. Removal of this by-product by SsuD and TauD must be necessary for bacterial survival under oxidative stress generated during -hexadecane degradation.
Topics: Acinetobacter; Alkanes; Alkanesulfonates; Bacterial Proteins; Hydrogen Peroxide; Mixed Function Oxygenases; Oxidative Stress
PubMed: 32503904
DOI: 10.1128/AEM.00692-20 -
Journal of Bacteriology May 2000The Escherichia coli tauABCD and ssuEADCB gene clusters are required for the utilization of taurine and alkanesulfonates as sulfur sources and are expressed only under...
The Escherichia coli tauABCD and ssuEADCB gene clusters are required for the utilization of taurine and alkanesulfonates as sulfur sources and are expressed only under conditions of sulfate or cysteine starvation. tauD and ssuD encode an alpha-ketoglutarate-dependent taurine dioxygenase and a reduced flavin mononucleotide-dependent alkanesulfonate monooxygenase, respectively. These enzymes are responsible for the desulfonation of taurine and alkanesulfonates. The amino acid sequences of SsuABC and TauABC exhibit similarity to those of components of the ATP-binding cassette transporter superfamily, suggesting that two uptake systems for alkanesulfonates are present in E. coli. Chromosomally located in-frame deletions of the tauABC and ssuABC genes were constructed in E. coli strain EC1250, and the growth properties of the mutants were studied to investigate the requirement for the TauABC and SsuABC proteins for growth on alkanesulfonates as sulfur sources. Complementation analysis of in-frame deletion mutants confirmed that the growth phenotypes obtained were the result of the in-frame deletions constructed. The range of substrates transported by these two uptake systems was largely reflected in the substrate specificities of the TauD and SsuD desulfonation systems. However, certain known substrates of TauD were transported exclusively by the SsuABC system. Mutants in which only formation of hybrid transporters was possible were unable to grow with sulfonates, indicating that the individual components of the two transport systems were not functionally exchangeable. The TauABCD and SsuEADCB systems involved in alkanesulfonate uptake and desulfonation thus are complementary to each other at the levels of both transport and desulfonation.
Topics: ATP-Binding Cassette Transporters; Alkanesulfonates; Biological Transport; Escherichia coli; Escherichia coli Proteins; FMN Reductase; Gene Deletion; Genetic Complementation Test; Mixed Function Oxygenases; Mutagenesis; NADH, NADPH Oxidoreductases; Operon; Oxygenases; Sulfur; Taurine
PubMed: 10781534
DOI: 10.1128/JB.182.10.2687-2695.2000