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1.
Calcif Tissue Int ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31832726

RESUMO

Osteoporosis (OP) is a multi-factorial bone disease influenced by genetic factors, age, and lifestyles. The aim of this study is to evaluate the genetic correlations between OP and multiple lifestyle-related factors, and explore the genes underlying the detected genetic correlations. Linkage disequilibrium score regression (LDSC) analysis was applied to evaluate the genetic correlations of total body bone mineral density (TB-BMD) of different ages (including 15-30 years, 30-45 years, 45-60 years, and over 60 years) with four common lifestyle/environment-related factors (including serum 25-hydroxyvitamin D, cigarette smoking, alcohol dependence, and caffeine metabolites). Transcriptome-wide association studies (TWAS) of TB-BMD (30-45 years) and smoking were conducted in peripheral blood (PB), whole blood (WB), and adipose tissues. The identified candidate genes were also subjected to gene set enrichment analysis (GSEA). Genetic correlation was only observed between TB-BMD (30-45 years) and cigarette smoking status (P = 0.01, LD score = 0.11 ± 0.04). No significant genetic correlation was detected for other lifestyle/environmental factors, including serum 25-hydroxyvitamin D, alcohol dependence, and caffeine metabolites for TB-BMD within all of the four age groups. TWAS identified 85 genes in PB and 163 genes in WB for TB-BMD, as well as 123 genes in PB and 257 genes in WB for smoking. Multiple common candidate genes shared by both TB-BMD and smoking were detected, such as MAP1LC3B (PTB-BMD-PB = 1.00 × 10-3, Psmoking-PB = 9.62 × 10-3, PTB-BMD-WB = 2.99 × 10-2) and SLC23A3 (PTB-BMD-WB = 1.48 × 10-2, Psmoking-WB = 8.76 × 10-3). GSEA detected one GO terms for TB-BMD (cytosol) in WB, one GO term for smoking (mitochondrion) in PB, and one pathway (oocyte meiosis) for smoking in WB.

2.
Psychiatry Res ; 282: 112639, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31685286

RESUMO

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, but the genetic mechanism of ADHD remains elusive now. METHODS: Tissue specific transcriptome-wide association study (TWAS) of ADHD was performed by FUSION utilizing a genome-wide association study (GWAS) dataset of ADHD (including 20,183 ADHD cases and 35,191 healthy controls) and gene expression reference from brain and blood. Furthermore, the genes identified by TWAS were compared with the differently expressed genes detected by mRNA expression profiles of ADHD rat model and autism spectrum disorders (ASD) patients. Functional enrichment and annotation analysis of the identified genes were performed by DAVID and FUMAGWAS tool. RESULTS: For brain tissue, TWAS identified 148 genes with P value < 0.05, such as TDO2 (PTWAS=4.01×10-2), CHD1L (PTWAS=9.64×10-3) and KIAA0319L (PTWAS=4.05×10-4). Further 11 common genes were examined in the mRNA expression datasets, such as ACSM5 (PTWAS=3.62×10-2, PmRNA=0.005), CCDC24 (PTWAS=1.49×10-2, PmRNA=2.35×10-3) and MVP (PTWAS=5.55×10-3, PmRNA=5.40×10-3). Pathway enrichment analysis of the genes identified by TWAS detected 3 pathways for ADHD, including Other glycan degradation (P value=0.021), Viral myocarditis (P value=0.034) and Endocytosis (P value=0.041). CONCLUSIONS: Through integrating GWAS and mRNA expression data, we identified a group of ADHD-associated genes and pathways, providing novel clues for understanding the genetic mechanism of ADHD.

3.
Ecotoxicol Environ Saf ; : 109958, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31767456

RESUMO

Recently, the action of steroid receptor coactivators (SRCs) has been recognized to be an important molecular initiating event (MIE) in estrogenic adverse outcome pathways (AOPs). However, the role of SRCs in the molecular mechanisms of many highly concerned environmental estrogens remains poorly understood. In this study, the widely studied environmental estrogen, 4-n-nonylphenol (4-n-NP), was used as a typical pollutant to study SRCs recruitment in its estrogenic effects. In MCF7 cell proliferation (E-SCREEN) assay and MVLN cell assay, 4-n-NP showed significant estrogenic potency that involved an increase in estrogen receptor α (ERα), SRC1 and SRC3 transcript levels. Moreover, 4-n-NP was found to induce estrogen response element (ERE)-mediated activity via ERα in MVLN cells. To investigate the mechanism by which SRCs recruitment is induced by 4-n-NP-ERα, a coactivators recruitment assay was performed, and the results showed that 4-n-NP-ERα recruited both SRC1 and SRC3, whereas it failed to recruit SRC2. Similarly, it had no interaction with SRC2 in the ERα-SRC2 two-hybrid yeast assay. This is the first report to investigate the novel MIE of SRCs recruitment in 4-n-NP-ERα-induced estrogenicity. Overall, our results suggest that the action of 4-n-NP on estrogenic effects involves the following MIEs: the activation of ERα, the recruitment of SRC1 and SRC3, and the induction of ERE-mediated activity. The findings also provide valuable insights into the MIE associated with the different SRCs that are recruited in the adverse outcome pathways of environmental estrogens.

4.
PLoS One ; 14(10): e0223900, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622406

RESUMO

This paper presents an experimental study on the applicability of microbial induced carbonate precipitation (MICP) to treat municipal solid waste incineration (MSWI) fly ash with high alkalinity and heavy metal toxicity. The experiments were carried out on fly ashes A and B produced from incineration processes of mechanical grate furnace and circulating fluidized bed, respectively. The results showed that both types of fly ashes contained high CaO content, which could supply sufficient endogenous Ca for MICP treatment. Moreover, S. pasteurii can survive from high alkalinity and heavy metal toxicity of fly ash solution. Further, the unconfined compressive strength (UCS) of MICP treated fly ashes A and B reached 0.385MPa and 0.709 MPa, respectively. The MICP treatment also resulted in a reduction in the leaching toxicity of heavy metals, especially for Cu, Pb and Hg. MICP had a higher solidification and stabilization effect on fly ash B, which has finer particle size and higher Ca content. These findings shone a light on the possibility of using MICP technique as a suitable and efficient tool to treat the MSWI fly ash.

5.
J Hazard Mater ; 384: 120948, 2019 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-31610345

RESUMO

Facile and ultrasensitive detection of Hg2+ in water environment remains challenging. Exonuclease III (Exo-III)-assisted target recycling is one of the most popular amplification strategies. Although the magnesium (II) ions are widely acting as cofactors of Exo-III, we recognized that Mg2+ cofactors would strongly disturb the charge distribution on citrate-stablized gold nanoparticles (in the general sense, unmodified AuNPs) surface, thus generate false positive colorimetric signals. To address this issue, we first put forward the view that the cobalt (II) ions can function as the Exo-III cofactor and successfully construct a novel label-free colorimetric aptasensor for facile and ultrasensitive detection of Hg2+ using Hg2+-triggered Exo-III-assisted signal amplification and unmodified AuNPs as indicators. A hairpin-looped DNA probe was rationally designed with thymine-rich recognition termini and specifically recognized trace Hg2+ by a stable T-Hg2+-T structure. A blue-to-red color change of AuNPs with the addition of Hg2+ provided the quantitative detection of Hg2+ with a limit of detection of 0.2 nM and a linear working range from 0.5 nM to 5.0 nM. The whole testing time for one assay was approximately 40 min. Real water samples, even containing Hg2+ at 1 nM, could be determined by the aptasensor with recovery rates from 97% to 103%.

6.
Sci Total Environ ; 697: 134040, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31476509

RESUMO

Polybrominated biphenyls (PBBs) were widely used as additive brominated flame retardants. Their hydroxylated products (OH-PBBs) have been detected frequently in various marine mammals, causing an increased health risk. Till now, there lacks information on the potential disruption of OH-PBBs toward thyroid hormone receptor (TR) and the molecular characteristics of their interactions remain largely unknown. We herein in vitro and in silico evaluated the disrupting effect of 3,3',5,5'-tetrabromobiphenyl (BB80) and its metabolite 2,2'-dihydroxy- 3,3',5,5'-tetrabromobiphenyl (OH-BB80) toward human TR. The recombinant human TRß two-hybrid yeast assay reveals the moderate antagonistic activity of OH-BB80 with IC20 at 2 µmol/L, while BB80 shows no agonistic or antagonistic activity. OH-BB80 binds at the binding cavity of TRß ligand binding domain (LBD) and forms one hydrogen bond with Phe272. Electrostatic interactions and hydrophobic interactions contribute much to their interactions. The binding of OH-BB80 quenches the intrinsic fluorescence of TRß LBD at static quenching mode. Our study extends knowledge on the endocrine disrupting effect of OH-PBBs and suggests the full consideration of the biotransformation for further health risk assessment of PBBs and related structurally similar emerging contaminants.

7.
Environ Pollut ; 255(Pt 1): 113193, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31521998

RESUMO

Phthalate esters (PAEs), as widely used plasticizers, have been concerned for their possible disruption of estrogen functions via binding to and activating the transcription of estrogen receptors (ERs). Nevertheless, the computational interpretation of the mechanism of ERs activities modulated by PAEs at the molecular level is still insufficient, which hinders the reliable screening of the ERs-active PAEs with high speed and high throughput. To bridge the gap, the in silico simulations considering the effects of coactivators were accomplished to explore the molecular mechanism of action for the purpose of predicting the estrogenic potencies of PAEs. The transcriptional activation functions of human ERα (hERα) modulated by PAEs is predicted via the simulations including binding interaction of PAEs and hERα, conformational changes of PAEs-hERα complexes and recruitment of coactivators. Molecular insight into the diverse estrogen mechanism of action among PAEs with regard to hERα agonists and selective estrogen receptor modulators (SERMs) is provided. Agonist-modulated conformational change of hERα leads to the optimal exposure of its Activation Function 2 (AF-2) surface which, in turn, facilitates the recruitment of coactivators, therefore promoting the transcriptional activation functions of hERα. Conversely, binding interaction of hERα with SERMs among PAEs leads to the conformational change with blocked AF-2 surface, thus preventing the recruitment of coactivators and consequently inhibiting the AF-2 activity. The two-hybrid recombinant yeast is experimentally used for verification. The established in silico evaluation methodology exhibits great promise to speed up the prediction of chemicals which work as hERα agonist or SERMs.

8.
Clin Lab ; 65(9)2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31532105

RESUMO

BACKGROUND: When a new measurement method is introduced into a clinical laboratory, a comparison study is often needed to ensure that the measurement by the existing method is reproducible by the new method with clinical acceptability. The comparison study of ARCHITECT i2000SR analyzer and i-CHROMATM reader analyzer in measuring plasma human chorionic gonadotropin beta subunit (ß-HCG) has not been reported. METHODS: Blood samples for ß-HCG were collected from pregnant women seen at the outpatient clinic, and they were divided into two groups, those below 20 mU/mL or above, due to its wide concentration range in pregnant women. A comparison study was performed according to EP09-A3 guidelines of the National Clinical and Laboratory Standards Institute (NCCLS). ß-HCG's levels measured from the analyzers being compared were inspected on Bland-Altman plot and outliers were identified by Extreme Studentized Deviate (ESD). Correlation analysis was performed using Passing-Bablok model. RESULTS: Passing-Bablok regression analysis showed that slope B 95% CIs (confidence intervals) of the two groups fall outside of 1, indicating there was a proportional difference between the two methods. Both groups had a ratio of less than 95% percent of the values in the ± 1.96 RSD (residual standard deviation) interval, indicating that there might be inconsistencies between the two methods with respect to random differences. According to Bland-Altman analysis, 95% Limit of Agreement (LOA) between the two methods exceeded the clinically acceptable limits. The deviation between these two detecting platforms was beyond clinically acceptable ranges when samples fell within the concentrations of 15,000 - 30,000 and 1.2 - 20 mU/mL. CONCLUSIONS: Measurements of ß-HCG by ARCHITECT i2000SR and i-CHROMATM Reader are consistent and reproducible only at a certain concentration range. Further research is needed to reduce the biases between these two analyzers.

9.
Arthritis Res Ther ; 21(1): 194, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31455417

RESUMO

BACKGROUND: Chondropathies are a group of cartilage diseases, which share some common pathogenetic features. The etiology of chondropathies is still largely obscure now. METHODS: A transcriptome-wide association study (TWAS) was performed using the UK Biobank genome-wide association study (GWAS) data of chondropathies (including 1314 chondropathy patients and 450,950 controls) with gene expression references of muscle skeleton (MS) and peripheral blood (YBL). The candidate genes identified by TWAS were further compared with three gene expression profiles of osteoarthritis (OA), cartilage tumor (CT), and spinal disc herniation (SDH), to confirm the functional relevance between the chondropathies and the candidate genes identified by TWAS. Functional mapping and annotation (FUMA) was used for the gene ontology enrichment analyses. Immunohistochemistry (IHC) was conducted to validate the accuracy of integrative analysis results. RESULTS: Integrating TWAS and mRNA expression profiles detected 84 candidate genes for knee OA, such as DDX20 (PTWAS YBL = 1.79 × 10- 3, fold change (FC) = 2.69), 10 candidate genes for CT, such as SRGN (PTWAS YBL = 1.46 × 10- 3, FC = 3.36), and 4 candidate genes for SDH, such as SUPV3L1 (PTWAS YBL = 3.59 × 10- 3, FC = 3.22). Gene set enrichment analysis detected 73 GO terms for knee OA, 3 GO terms for CT, and 1 GO term for SDH, such as mitochondrial protein complex (P = 7.31 × 10- 5) for knee OA, cytokine for CT (P = 1.13 × 10- 4), and ion binding for SDH (P = 3.55 × 10- 4). IHC confirmed that the protein expression level of DDX20 was significantly different between knee OA cartilage and healthy control cartilage (P = 0.0358). CONCLUSIONS: Multiple candidate genes and GO terms were detected for chondropathies. Our findings may provide a novel insight in the molecular mechanisms of chondropathies.

10.
J Lipid Res ; 60(10): 1765-1775, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31455613

RESUMO

Sterol-regulated HMG-CoA reductase (HMGCR) degradation and SREBP-2 cleavage are two major feedback regulatory mechanisms governing cholesterol biosynthesis. Reportedly, lanosterol selectively stimulates HMGCR degradation, and cholesterol is a specific regulator of SREBP-2 cleavage. However, it is unclear whether other endogenously generated sterols regulate these events. Here, we investigated the sterol intermediates from the mevalonate pathway of cholesterol biosynthesis using a CRISPR/Cas9-mediated genetic engineering approach. With a constructed HeLa cell line expressing the mevalonate transporter, we individually deleted genes encoding major enzymes in the mevalonate pathway, used lipidomics to measure sterol intermediates, and examined HMGCR and SREBP-2 statuses. We found that the C4-dimethylated sterol intermediates, including lanosterol, 24,25-dihydrolanosterol, follicular fluid meiosis activating sterol, testis meiosis activating sterol, and dihydro-testis meiosis activating sterol, were significantly upregulated upon mevalonate loading. These intermediates augmented both degradation of HMGCR and inhibition of SREBP-2 cleavage. The accumulated lanosterol induced rapid degradation of HMGCR, but did not inhibit SREBP-2 cleavage. The newly synthesized cholesterol from the mevalonate pathway is dispensable for inhibiting SREBP-2 cleavage. Together, these results suggest that lanosterol is a bona fide endogenous regulator that specifically promotes HMGCR degradation, and that other C4-dimethylated sterol intermediates may regulate both HMGCR degradation and SREBP-2 cleavage.

11.
Environ Int ; 132: 105091, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31421388

RESUMO

Establishing biosensors to map a comprehensive picture of potential estrogen-active chemicals remains challenging and must be addressed. Herein, we describe an estrogen receptor (ER)-based evanescent wave fluorescent biosensor by using a triple functional small-molecule-protein conjugate as a signal probe for the determination of estrogenic activities in water samples. The signal probe, consisting of a Cy5.5-labelled streptavidin (STV) moiety and a 17ß-estradiol (E2) moiety, acts simultaneously as signal conversion, signal recognition and signal report elements. When xenoestrogens compete with the E2 moiety of conjugate in binding to the ER, the unbound conjugates are released, and their STV moiety binds with desthiobiotin (DTB) modified on the optical fiber via the STV-DTB affinity interactions. Signal probe detection is accomplished by fluorescence emission induced by an evanescent field, which positively relates with the estrogenic activities in samples. Quantification of estrogenic activity expressed as E2 equivalent concentration (EEQ) can be achieved with a detection limit of 1.05 µg/L EEQ by using three times standard deviation of the mean blank values and a linear calibration range from 20.8 to 476.7 µg/L EEQ. The optical fiber system is robust enough for hundreds of sensing cycles. The biosensor-based determination of estrogenic activities in wastewater samples obtained from a full-scale wastewater treatment plant is consistent with that measured by the two-hybrid recombinant yeast bioassay.

12.
Environ Pollut ; 253: 1-10, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31301531

RESUMO

Organic pollutants in the Arctic seas have been of concern to many researchers; however, the vast dynamic marine water poses challenges to their comprehensive monitoring within appropriate spatial and temporal scales in the Arctic. In this study, on-board passive sampling of organic pollutants using a self-developed device coupled with triolein-embedded cellulose acetate membranes (TECAMs) was performed during an Arctic cruise. The TECAM extracts were used for target analysis of organophosphorus flame retardants (PFRs), and non-target screening of persistent, bioaccumulative, and toxic (PBT) contaminants using two-dimensional gas chromatography with time-of-flight mass spectrometry (GC × GC-TOFMS). Sixteen chemicals were screened out as PBT contaminants from the 1500 features in the non-target analysis and further identified. Consequently, two chlorinated PFRs (tris(chloroisopropyl)phosphate and tris(1,3-dichloroisopropyl)phosphate) and four PBT contaminants (4-tert-butylphenol, 2-isopropylnaphthalene, 1,1,3-trimethyl-3-phenylindane, and 1-phenylnonan-1-one) were accurately quantified, with the temporally and spatially integrated concentrations ranging from 0.83 ng L-1 to 20.82 ng L-1 in the seawaters. Sources and transport of the contaminants were studied, and ocean current transport (West Spitsbergen Current, WSC) and local sources (human settlement, Arctic oil exploitation, and petroleum fuel emissions) were found to contribute to the presence of the different contaminants. Finally, annual transport fluxes of the contaminants from the North Atlantic to the Arctic Ocean by WSC were estimated, and the results indicate that their hazard to the Arctic should be concerned.


Assuntos
Monitoramento Ambiental/métodos , Retardadores de Chama/análise , Organofosfatos/análise , Água do Mar/química , Poluentes Químicos da Água/análise , Regiões Árticas , Poluentes Ambientais/análise , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Svalbard
14.
Aging (Albany NY) ; 11(11): 3704-3715, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175266

RESUMO

BACKGROUND: Schizophrenia is a complex mental disorder. The genetic mechanism of schizophrenia remains elusive now. METHODS: We conducted a large-scale integrative analysis of two genome-wide association studies of schizophrenia with functional annotation datasets of regulatory single-nucleotide polymorphism (rSNP). The significant SNPs identified by the two genome-wide association studies were first annotated to obtain schizophrenia associated rSNPs and their target genes and proteins, respectively. We then compared the integrative analysis results to identify the common rSNPs and their target regulatory genes and proteins, shared by the two genome-wide association studies of schizophrenia. Finally, DAVID tool was used to conduct gene ontology and pathway enrichment analysis of the identified targets genes and proteins. RESULTS: We detected 53 schizophrenia-associated target genes for rSNP, such as FOS (P value = 2.18×10-20), ATXN1 (P value = 5.22×10-21) and HLA-DQA1 (P value = 1.98×10-10). Pathway enrichment analysis identified 24 pathways for transcription factors binding regions, chromatin interacting regions, long non-coding RNAs, topologically associated domains, circular RNAs and post-translational modifications, such as hsa05034:Alcoholism (P value = 2.57×10-7) and hsa04612:Antigen processing and presentation (P value = 6.82×10-8). CONCLUSION: We detected multiple candidate genes, gene ontology terms and pathways for schizophrenia, supporting the functional importance of rSNPs, and providing novel clues for understanding the genetic architecture of schizophrenia.

15.
Cartilage ; : 1947603519858748, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31220921

RESUMO

OBJECTIVE: Epigenetic modifications of DNA are regarded as a crucial factor for understanding the molecular basis of complex phenotypes. This study aims to uncover insight into the epigenetic modifications for Kashin-Beck disease (KBD) by integrating genome-wide association studies (GWAS), methylation quantitative trait loci (meQTLs), and DNA methylation profiles data. DESIGN: The knee articular cartilages of 5 KBD patients and 5 healthy controls were collected for DNA methylation profiling, using Illumina Infinium HumanMethylation450 BeadChip. Mass spectrograph validation of identified differently methylated genes was conducted using independent samples of 4 KBD patients and 3 healthy controls, together with a previous sample of 2743 Han Chinese individuals of GWAS study for KBD and a study of 697 normal subjects for meQTLs annotation datasets. KBD GWAS single nucleotide polymorphisms (SNPs) and normal meQTLs SNPs were integrated with DNA methylation profiles of KBD articular cartilage to identify genetic control (GC) genes of DNA methylation for KBD. Quantitative polymerase chain reaction (qPCR) was performed to validate the mRNA expression of several identified candidate genes. RESULTS: A total of 162 CpG sites, 253 SNPs, and 123 GC genes for KBD were identified. Enrichment analysis detected 642 marked GO terms and 19 KEGG pathways (P < 0.05). Six potential key GC genes were conducted for qPCR experiment (ERG, MN1, MITF, WISP1, TRIO, and NOSTRIN). CONCLUSIONS: The results suggest that GC genes of DNA methylation may lead to the erosion of cartilage in KBD, which may help us in understanding the epigenetic alteration of KBD.

16.
Sci Total Environ ; 679: 221-228, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31082595

RESUMO

As a widely used antiepileptic drug, carbamazepine (CBZ) has been frequently detected in aquatic environments, even in drinking water. Chloramine is a widely used alternative disinfectant due to its low-level formation of regulated disinfection byproducts (DBPs). However, there is previous evidence linking product mixtures of chloraminated CBZ to stronger DNA damage effects than those caused by CBZ itself. The present study further investigated the reaction rate, transformation mechanism and multi-endpoint toxicity of transformation products (TPs) of CBZ treated with NH2Cl under different pH conditions. The results showed that the reaction between CBZ and NH2Cl at pH 8.5, where NH2Cl is stable, is a second-order reaction with a rate of 4.2 M-1 h-1. Compared to both alkaline and acidic conditions, CBZ was quickly degraded at pH 7. This indicated that HOCl produced from NH2Cl hydrolysis is more effective in degrading CBZ than NH2Cl and NHCl2. Furthermore, the concentration variation of four TPs formed during the chloramination of CBZ under different pH conditions was investigate by quantitative analysis, and the transformation pathway from CBZ to 9(10H)-acridone was confirmed. Three of the detected TPs showed cytotoxicity, DNA damage effects or chromosome damage effects. Acridine and 9(10H)-acridone, which accumulated with increasing time, showed higher cytotoxic or genotoxic effects than CBZ itself. In addition, a similar transformation mechanism was observed in real ambient water during simulated chloramination with a low level of CBZ. These results suggested that despite the chloramination of CBZ being slower than chlorination, TPs with higher cytotoxicity or genotoxicity may lead to greater toxic risks.


Assuntos
Carbamazepina/toxicidade , Cloraminas/química , Poluentes Químicos da Água/toxicidade , Aminação , Anticonvulsivantes/química , Anticonvulsivantes/toxicidade , Carbamazepina/química , Citotoxinas/química , Citotoxinas/toxicidade , Desinfecção , Concentração de Íons de Hidrogênio , Cinética , Mutagênicos/química , Mutagênicos/toxicidade , Poluentes Químicos da Água/química
17.
J Environ Sci (China) ; 82: 70-81, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31133271

RESUMO

Surfactants such as alkylphenol polyethoxylates (APEOs) and nonylphenol ethoxylates (NPEOs) are commonly used worldwide, but the majority of these compounds, together with their metabolites, have been reported to induce severe biological toxicity. Here, we evaluated for the first time the cytotoxicity, genotoxicity and mitochondrial damage in Chinese hamster ovary (CHO-K1) cells caused by a novel non-ionic surfactant, vanillin ethoxylates (VAEOs), an alternative to APEOs. In parallel, the same in vitro bioassays were conducted on NPEOs along with their metabolic byproducts 4-nonylphenol (4-NP) and vanillin. The results showed that the cytotoxic potency order was NPEOs > 4-NP > VAEOs>vanillin using CCK-8 assays. Also, 4-NP showed potential direct DNA damage in SOS/umu tests, whereas NPEOs, VAEOs and vanillin showed no positive result with and without S9 addition. In addition, none of the test compounds showed obvious genotoxic effects with low olive tail moment value using comet assays. However, all test compounds were shown to cause mitochondrial impairment by increasing mitochondrial mass and decreasing mitochondrial membrane potential in a concentration-dependent manner. And further analysis of reactive oxygen species (ROS) and mitochondrial superoxide (MNSOD) measurement showed that mitochondrial impairment was induced by oxidative stress with intracellular ROS and MNSOD overproduction. It's worth noting that VAEOs and vanillin cause relative lower cytotoxic, genotoxic and mitochondrial damage effects than NPEOs and 4-NP, indicating that VAEOs have the potential to substitute NPEOs as suitable surfactants. Take together, this study elucidates the toxicity profiles of VAEOs and NPEOs relatively comprehensively, and further toxicity analyses are suggested in the population, community and ecosystem.


Assuntos
Benzaldeídos/toxicidade , Fenóis/toxicidade , Tensoativos/toxicidade , Testes de Toxicidade , Animais , Células CHO , Cricetinae , Cricetulus , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
18.
Heart Vessels ; 34(11): 1882-1888, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31065785

RESUMO

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia characterized by extensive structural, contractile and electrophysiological remodeling. The genetic basis of AF remained elusive until now. Transcriptome-wide association study (TWAS) was conducted by FUSION tool using gene expression weights of 7 tissues combined with a large-scale genome-wide association study (GWAS) dataset of AF, totally involving 8180 AF cases and 28,612 controls. Significant genes identified by TWAS were then subjected to gene ontology (GO) and pathway enrichment analysis. The genome-wide mRNA gene expression profiling of AF was compared with the results of TWAS to detect common genes shared by TWAS and mRNA expression profiling of AF. TWAS detected a group of candidate genes with PTWAS values < 0.05 across the seven tissues for AF, such as CMAH (PTWAS = 3.15 × 10-25 for whole blood), INCENP (PTWAS = 1.77 × 10-22 for artery aorta), CMAHP (PTWAS = 4.57 × 10-20 for artery aorta). Pathway enrichment analysis identified multiple candidate pathways, such as protein K48-linked ubiquitination (P value = 0.0124), positive regulation of leukocyte chemotaxis (P value = 0.0046) and fatty acid degradation (P value = 0.0295). Further comparing the GO results of TWAS and mRNA expression profiling, 2 common GO terms were identified, including actin binding (PTWAS = 0.0446, PmRNA = 7.00 × 10-4) and extracellular matrix (PTWAS = 0.0037, PmRNA = 3.00 × 10-6). We detected multiple novel candidate genes, GO terms and pathways for AF, providing novel clues for understanding the genetic mechanism of AF.

19.
Brief Bioinform ; 2019 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953055

RESUMO

Psychiatric disorders are a group of complex psychological syndromes with high prevalence. It has been reported that gut microbiota has a dominant influence on the risks of psychiatric disorders through gut microbiota-brain axis. We extended the classic gene set enrichment analysis (GSEA) approach to detect the association between gut microbiota and complex diseases using published genome-wide association study (GWAS) and GWAS of gut microbiota summary data. We applied our approach to real GWAS data sets of five psychiatric disorders, including attention deficiency/hyperactive disorder (ADHD), autism spectrum disorder (AUT), bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD). To evaluate the performance of our approach, we also tested the genetic correlations of obesity and type 2 diabetes with gut microbiota. We identified several significant associations between psychiatric disorders and gut microbiota, such as ADHD and genus Desulfovibrio (P = 0.031), order Clostridiales (P = 0.034). For AUT, association signals were observed for genera Bacteroides (P = 0.012) and Desulfovibrio (P = 0.033). Genus Desulfovibrio (P = 0.005) appeared to be associated with BD. For MDD, association signals were observed for genus Desulfovibrio (P = 0.003), order Clostridiales (P = 0.004), family Lachnospiraceae (P = 0.007) and genus Bacteroides (P = 0.007). Genus Desulfovibrio (P = 0.012) and genus Bacteroides (P = 0.038) appeared to be associated with SCZ. Our study results provide novel clues for revealing the roles of gut microbiota in psychiatric disorders. This study also illustrated the good performance of GSEA approach for exploring the relationships between gut microbiota and complex diseases.

20.
Environ Pollut ; 250: 58-67, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30981936

RESUMO

Aryl phosphorus-containing flame retardants (aryl-PFRs) have been frequently detected with increasingly used worldwide as one of alternatives for brominated flame retardants. However, information on their adverse effects on human health and ecosystem is insufficient, with limited study on their molecular mode of action in vitro. In this study, the cytotoxicity, DNA damage, mitochondrial impairment and the involved molecular mechanisms of certain frequently detectable aryl-PFRs, including 2-ethylhexyldiphenyl phosphate (EHDPP), methyl diphenyl phosphate (MDPP), bisphenol-A bis (diphenyl phosphate) (BDP), isodecyl diphenyl phosphate (IDPP), cresyl diphenyl phosphate (CDP) and the structurally similar and widely used organophosphorus pesticide chlorpyrifos (CPF), were evaluated in A549 cells using high-content screening (HCS) system. Aryl-PFRs showed different lethal concentration 50 (LC50) values ranging from 97.94 to 546.85 µM in A549 cells using CCK-8 assay. EHDPP, IDPP, CDP, MDPP and CPF demonstrated an ability to induce DNA damage, evidenced by increased DNA content and S phase-reducing cell cycle arrest effect using fluorophore dye cocktail assay. Additionally, the selected aryl-PFRs induced mitochondrial impairment by the increasing mitochondrial mass and decreasing mitochondrial membrane potential. Moreover, BDP, MDPP, and CDP, which contain short alkyl chains showed their potential oxidative stress with intracellular ROS and mitochondrial superoxide overproduction from an initially relatively low concentration. Additionally, based on the promotion of firefly luminescence in p53-transfected A549 cells, p53 activation was found to be involved in aryl-PFRs-induced DNA damage. Further real-time PCR results showed that all selected aryl-PFRs triggered p53/p21/gadd45ß-, and p53/p21/mdm2-mediated cell cycle pathways, and the p53/bax mediated apoptosis pathway to induce DNA damage and cytotoxic effects. These results suggest that aryl-PFRs (e.g., BDP, MDPP, CDP) cause oxidative stress-mediated DNA damage and mitochondrial impairment, and p53-dependent pathway was involved in the aryl-PFRs-induced DNA damage and cell cycle arrest. In conclusion, this study improves the understanding of PFRs-induced adverse outcomes and the involved molecular mechanism.


Assuntos
Dano ao DNA , Retardadores de Chama/toxicidade , Mitocôndrias/efeitos dos fármacos , Organofosfatos/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Células A549 , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Organofosfatos/química
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