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1.
Environ Health Perspect ; 130(5): 57002, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35503735

RESUMO

BACKGROUND: Abnormal placental development may result in adverse pregnancy outcomes and metabolic diseases in adulthood; however, it remains unknown whether and how xenobiotics affect human placentation. OBJECTIVES: This study aimed to screen and identify placentation-disrupting chemicals in commonly used organophosphate flame retardants (OPFRs) and, if identified, to investigate potential adverse effects on placentation in relation to adverse pregnancy outcomes and metabolic disorder in offspring in mice. METHODS: We devised a high-throughput immunofluorescence screening assay based on human trophoblast organoids and used it to screen OPFRs that inhibit the proliferation of organoids. One identified chemical was assessed for its effects on placentation by evaluating villous cytotrophoblasts, syncytiotrophoblasts, and extravillous trophoblasts using immunofluorescence and a mitochondrial stress test after 2 d of exposure. A 10-d exposure study was further performed to observe the dynamic effect of the OPFR on the structure of the organoids. RNA-sequencing and western blotting experiments were performed to explore the associated pathways, and a potential binding protein was identified by immunoprecipitation and in vitro kinase activity assays. Animal studies were performed to determine whether the findings in organoids could be replicated in mice and to observe adverse pregnancy outcomes. RESULTS: The proliferation of organoids exposed to three aryl-OPFRs was significantly lower than the proliferation of control organoids. Further analysis demonstrated that one such chemical, 2-ethylhexyl-diphenyl phosphate (EHDPP), disrupted placentation in organoids. Mechanistically, EHDPP interfered with insulin-like growth factor 1 receptor (IGF1R) to inhibit aerobic respiration. Mice exposed to EHDPP at a physiological human concentrations exhibited immature and mature placental disorders, which correlated with fetal growth restriction, implantation failure, stillbirth, and impaired glucose tolerance. CONCLUSIONS: The human trophoblast organoid model showed that the commonly used OPFRs disrupted placentation via IGF1R, indicating that its use may contribute to adverse pregnancy outcomes and metabolic disorders in offspring. https://doi.org/10.1289/EHP10273.


Assuntos
Retardadores de Chama , Adulto , Animais , Feminino , Retardadores de Chama/metabolismo , Retardadores de Chama/toxicidade , Humanos , Camundongos , Organoides , Organofosfatos/metabolismo , Organofosfatos/toxicidade , Placenta , Placentação , Gravidez , Resultado da Gravidez , Trofoblastos
2.
Sci Rep ; 12(1): 4660, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35304560

RESUMO

Tris(1,3-dichloro-2-propyl)phosphate (TDCPP) has been suspected to cause toxicity invertebrates, but its phenotypic effects and the underlying regulatory mechanism have not been fully revealed. Generally, cellular responses tightly control and affect various phenotypes. The scope of the whole organism or cellular toxicological phenotyping, however, has been limited, and quantitative analysis methods using phenotype data have not been fully established. Here, we demonstrated that fluorescence imaging of sub-organelle-based phenomic analysis together with transcriptomic profiling can enable a comprehensive understanding of correlations between molecular and phenomic events. To reveal the cellular response to TDCPP exposure, we obtained three sub-organelle images as fluorescent phenotypes. Transcriptomic perturbation data were measured from the RNA-seq experiment, and both profiling results were analyzed together. Interestingly, organelle phenomic data showed a unique fluorescent intensity increase in the endoplasmic reticulum (ER), and pathway analysis using transcriptomic data also revealed that ER was significantly enriched in gene ontology terms. Following the series of analyses, RNA-seq data also revealed potential carcinogenic effects of TDCPP. Our multi-dimensional profiling approach for organophosphate chemicals can uniquely correlate phenotypic changes with transcriptomic perturbations.


Assuntos
Retardadores de Chama , Fosfatos , Retardadores de Chama/toxicidade , Organelas/metabolismo , Organofosfatos/metabolismo , Compostos Organofosforados/farmacologia , Fenômica , Transcriptoma
3.
Sci Total Environ ; 826: 153989, 2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35192813

RESUMO

Organophosphate flame retardants (OPFRs) have been widely used in consumer products to prevent fire spread. However, once released into the atmospheric environment, they may accumulate in humans and undergo metabolic transformation and excretion by urine. In order to clarify the human exposure to OPFRs, a quick, easy, cheap, effective, rugged, and safe method for the simultaneous determination of urinary OPFRs and their metabolites by ultra-performance liquid chromatography-tandem triple quadrupole mass spectrometry was developed. After the optimization by a single-factor or orthogonal experiment, the satisfactory recovery (87.8-119%), matrix effect (-8.88-9.29%), method quantitation limit (3.66-159 ng/L), and inter-day repeatability (1.24 - 10.6%) of most analytes were achieved in artificial urine samples. Based on a monitoring test by the developed method, we propose that urinary bis(1-chloro-2-propyl) phosphate and di-p-cresyl phosphate could be used to trace human exposure to tris(1-chloro-2-propyl) phosphate and tricresyl phosphate, respectively. Most importantly, this is the first study to reveal that 4-hydroxyphenyl diphenyl phosphate (4-OH-TPHP) was dominantly presented in its conjugated form rather than its free form in urine (p = 0.037). Overall, the obtained results contribute a relatively rapid method to help conduct large-scale urine monitoring for revealing the human exposure and risk of OPFRs.


Assuntos
Retardadores de Chama , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Retardadores de Chama/análise , Humanos , Organofosfatos/metabolismo , Fosfatos , Espectrometria de Massas em Tandem/métodos
4.
J Hazard Mater ; 431: 128517, 2022 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-35217347

RESUMO

Organic phosphorus flame retardants (OPFRs), as a new type of emerging contaminant, have drawn great attention over the last few years, due to their wide distribution in aquatic environments and potential toxicities to humans and living beings. Various treatment methods have been reported to remove OPFRs from water or wastewater. In this review, the performances and mechanisms for OPFRs removal with different methods including adsorption, oxidation, reduction and biological techniques are overviewed and discussed. Each technique possesses its advantage and limitation, which is compared in the paper. The degradation pathways of typical OPFRs pollutants, such as Cl-OPFRs, alkyl OPFRs and aryl OPFRs, are also reviewed and compared. The degradation of those OPFRs depends heavily upon their structures and properties. Furthermore, the implications and future perspectives in such area are discussed. The review may help identify the research priorities for OPFRs remediation and understand the fate of OPFRs during the treatment processes.


Assuntos
Poluentes Ambientais , Retardadores de Chama , Retardadores de Chama/metabolismo , Humanos , Organofosfatos/metabolismo , Fósforo , Água
5.
Environ Int ; 160: 107081, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35021149

RESUMO

As an important organophosphate flame retardant, tris(1-chloro-2-propyl)phosphate (TCPP) is ubiquitous in the environment leading to inevitable human exposure. However, there is a paucity of information regarding its acute/chronic effects on obesity, lipid homeostasis, and hepatocellular carcinoma, especially regarding the underlying molecular mechanisms in humans. Herein, we investigated the effects of TCPP exposure (5-25 mg/L) on lipid homeostasis in larval and adult zebrafish (Danio rerio). TCPP exposure caused remarkable lipid-metabolism dysfunction, which was reflected in obesity and excessive lipid accumulation in zebrafish liver. Mechanistically, TCPP induced the over-expression of adipogenesis genes and suppressed the expression of fatty-acid ß-oxidation genes. Consequently, excess lipid synthesis and deficient expenditure triggered oxidative damage and an inflammation response by disrupting the antioxidant system and over-expressing proinflammatory cytokine. Based on high-throughput transcriptome sequencing, we found that TCPP exposure led to enrichment of several pathways involved in lipid metabolism and inflammation, as well as several genes related to pathways of cancer. Notably, increasing expressions of Ki-67 and 53BP1 proteins, which are reliable biomarkers for recognition and risk prediction of cellular proliferation in cancer cells, were observed in liver tissues of adult zebrafish. These results imply that chronic TCPP exposure triggers a potential risk of hepatocellular carcinogenesis (HCC) progression. Collectively, these findings offer new insights into our mechanistic understanding for the health effects of organophosphorus flame retardants on humans.


Assuntos
Carcinoma Hepatocelular , Retardadores de Chama , Neoplasias Hepáticas , Animais , Retardadores de Chama/metabolismo , Retardadores de Chama/toxicidade , Inflamação , Larva , Metabolismo dos Lipídeos , Organofosfatos/metabolismo , Organofosfatos/toxicidade , Compostos Organofosforados , Estresse Oxidativo , Fosfatos/metabolismo , Peixe-Zebra/metabolismo
6.
ACS Appl Mater Interfaces ; 14(2): 2881-2892, 2022 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-34985854

RESUMO

Cascade catalysis that combines chemical catalysis and biocatalysis has received extensive attention in recent years, especially the integration of metal nanoparticles (MNPs) with enzymes. However, the compatibility between MNPs and enzymes, and the stability of the integrated nanocatalyst should be improved to promote the application. Therefore, in this study, we proposed a strategy to space-separately co-immobilize MNPs and enzymes to the pores and surface of a highly stable covalent organic framework (COF), respectively. Typically, Pd NPs that were prepared by in situ reduction with triazinyl as the nucleation site were distributed in COF (Tz-Da), and organophosphorus hydrolase (OPH) was immobilized on the surface of Tz-Da by a covalent method to improve its stability. The obtained integrated nanocatalyst Pd@Tz-Da@OPH showed high catalytic efficiency and reusability in the cascade degradation of organophosphate nerve agents. Furthermore, the versatility of the preparation strategy of COF-based integrated nanocatalyst has been preliminarily expanded: (1) Pd NPs and OPH were immobilized in the triazinyl COF (TTB-DHBD) with different pore sizes for cascade degradation of organophosphate nerve agent and the particle size of MNPs can be regulated. (2) Pt NPs and glucose oxidase were immobilized in COF (Tz-Da) to obtain an integrated nanocatalyst for efficient colorimetric detection of phenol.


Assuntos
Arildialquilfosfatase/metabolismo , Materiais Biocompatíveis/metabolismo , Nanopartículas Metálicas/química , Estruturas Metalorgânicas/metabolismo , Agentes Neurotóxicos/metabolismo , Organofosfatos/metabolismo , Arildialquilfosfatase/química , Biocatálise , Materiais Biocompatíveis/química , Teste de Materiais , Estruturas Metalorgânicas/química , Estrutura Molecular , Agentes Neurotóxicos/química , Organofosfatos/química , Paládio/química , Paládio/metabolismo
7.
Angew Chem Int Ed Engl ; 60(52): 26994-27004, 2021 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-34643312

RESUMO

Lysosome-relevant cell death induced by lysosomal membrane permeabilization (LMP) has recently attracted increasing attention. However, nearly no studies show that currently available LMP inducers can evoke immunogenic cell death (ICD) or convert immunologically cold tumors to hot. Herein, we report a LMP inducer named TPE-Py-pYK(TPP)pY, which can respond to alkaline phosphatase (ALP), leading to formation of nanoassembies along with fluorescence and singlet oxygen turn-on. TPE-Py-pYK(TPP)pY tends to accumulate in ALP-overexpressed cancer cell lysosomes as well as induce LMP and rupture of lysosomal membranes to massively evoke ICD. Such LMP-induced ICD effectively converts immunologically cold tumors to hot as evidenced by abundant CD8+ and CD4+ T cells infiltration into the cold tumors. Exposure of ALP-catalyzed nanoassemblies in cancer cell lysosomes to light further intensifies the processes of LMP, ICD and cold-to-hot tumor conversion. This work thus builds a new bridge between lysosome-relevant cell death and cancer immunotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Morte Celular Imunogênica/efeitos dos fármacos , Lisossomos/metabolismo , Neoplasias/tratamento farmacológico , Organofosfatos/uso terapêutico , Fosfatase Alcalina/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Antineoplásicos/efeitos da radiação , Linhagem Celular Tumoral , Desenho de Fármacos , Células HEK293 , Humanos , Radical Hidroxila/metabolismo , Membranas Intracelulares/metabolismo , Luz , Lisossomos/enzimologia , Camundongos , Organofosfatos/síntese química , Organofosfatos/metabolismo , Organofosfatos/efeitos da radiação , Permeabilidade/efeitos dos fármacos
8.
Commun Biol ; 4(1): 1161, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620990

RESUMO

Recent data show that parasites manipulate the physiology of mosquitoes and human hosts to increase the probability of transmission. Here, we investigate phagostimulant activity of Plasmodium-metabolite, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), in the primary vectors of multiple human diseases, Anopheles coluzzii, An. arabiensis, An. gambiae s.s., Aedes aegypti, and Culex pipiens/Culex torrentium complex species. The addition of 10 µM HMBPP to blood meals significantly increased feeding in all the species investigated. Moreover, HMBPP also exhibited a phagostimulant property in plant-based-artificial-feeding-solution made of beetroot juice adjusted to neutral pH similar to that of blood. The addition of AlbuMAXTM as a lipid/protein source significantly improved the feeding rate of An. gambiae s.l. females providing optimised plant-based-artificial-feeding-solution for delivery toxins to control vector populations. Among natural and synthetic toxins tested, only fipronil sulfone did not reduce feeding. Overall, the toxic-plant-based-artificial-feeding-solution showed potential as an effector in environmentally friendly vector-control strategies.


Assuntos
Aedes/fisiologia , Anopheles/fisiologia , Culex/fisiologia , Mosquitos Vetores/fisiologia , Organofosfatos/administração & dosagem , Plasmodium falciparum/química , Aedes/efeitos dos fármacos , Animais , Anopheles/efeitos dos fármacos , Sangue , Culex/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Interações entre Hospedeiro e Microrganismos , Mosquitos Vetores/efeitos dos fármacos , Organofosfatos/metabolismo
9.
Commun Biol ; 4(1): 1076, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34521989

RESUMO

Lysine-selective molecular tweezers are promising drug candidates against proteinopathies, viral infection, and bacterial biofilm. Despite demonstration of their efficacy in multiple cellular and animal models, important questions regarding their mechanism of action, including cell penetrance and intracellular distribution, have not been answered to date. The main impediment to answering these questions has been the low intrinsic fluorescence of the main compound tested to date, called CLR01. Here, we address these questions using new fluorescently labeled molecular tweezers derivatives. We show that these compounds are internalized in neurons and astrocytes, at least partially through dynamin-dependent endocytosis. In addition, we demonstrate that the molecular tweezers concentrate rapidly in acidic compartments, primarily lysosomes. Accumulation of molecular tweezers in lysosomes may occur both through the endosomal-lysosomal pathway and via the autophagy-lysosome pathway. Moreover, by visualizing colocalization of molecular tweezers, lysosomes, and tau aggregates we show that lysosomes likely are the main site for the intracellular anti-amyloid activity of molecular tweezers. These findings have important implications for the mechanism of action of molecular tweezers in vivo, explaining how administration of low doses of the compounds achieves high effective concentrations where they are needed, and supporting the development of these compounds as drugs for currently cureless proteinopathies.


Assuntos
Astrócitos/metabolismo , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Endossomos/metabolismo , Lisina/metabolismo , Lisossomos/metabolismo , Neurônios/metabolismo , Organofosfatos/metabolismo , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos C57BL
10.
Chem Res Toxicol ; 34(8): 1926-1932, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34255498

RESUMO

Novichok (NV) nerve agents were recently added to the list of Schedule 1 chemicals of the Chemical Weapons Convention. There is a well-accepted method for assessment of nerve agent exposure based on mass spectrometric analysis of a nonapeptide with the serine-198 residue modified by the nerve agent, but this approach has not yet been reported for the class of NV agents and requires the availability of reference standards, which may be a limitation for NV agent exposure assessment. Thus, a goal of this study was to first verify the utility of the nonapeptide method for the characterization of human plasma samples exposed in vitro to the NV agents A-230, A-232, and A-234. A second aim was to evaluate the possibility of identifying unknown exposures by applying precursor ion scanning in combination with high resolution mass spectrometry (HRMS). Thus, precursor ion scanning, with a generic fragment ion (m/z 778) of the nonapeptide, was used to pinpoint any modified nonapeptide, while HRMS was used for structural elucidation of the adduct moiety. By this approach, use of HRMS enabled differentiation between adducts of agents with similar molecular masses. A new unique feature that could be exploited for NV nonapeptide analysis was that the modification was released from the peptide during fragmentation in the mass spectrometer and was detected in the low-mass region of the mass spectrum. This low-mass region was extremely informative and contributed to the assignment of the structure of the particular agent used, which is especially important in case no reference materials are available. The presented method is important for verification purposes by the Organisation for Prohibition of Chemical Weapons (OPCW), e.g., in case of investigations of alleged use of NV agents, and for regular forensic investigations.


Assuntos
Butirilcolinesterase/metabolismo , Agentes Neurotóxicos/metabolismo , Organofosfatos/metabolismo , Peptídeos/metabolismo , Exposição Ambiental/análise , Ensaios Enzimáticos , Humanos
11.
Toxicol Lett ; 348: 73-84, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34082026

RESUMO

The ubiquity of organophosphate esters (OPEs) in the environment has triggered research into metabolic pathways of OPEs. Using liquid chromatography coupled with a hybrid quadrupole Orbitrap high-resolution mass spectrometer, a suspect and characteristic fragment ion-based nontarget screening strategy for the identification of unknown OPE metabolites was developed and evaluated. Then, this integrated approach was successfully used for investigation of three newly identified organophosphate esters (NOPEs), namely 2-biphenylol diphenyl phosphate (BPDPP), tris(2-biphenyl) phosphate (TBPHP), and naphthalen-2-yl diphenyl phosphate (NDPHP), in human liver microsomes (HLMs). The results demonstrated that BPDPP, TBPHP, and NDPHP were effectively metabolized by HLMs, with zero-order kinetics (R2 = 0.48-0.94) within the time frame of the assay. The suspected approach identified a considerable number of dearylated phosphate (DP), and hydroxylated metabolites for each of NOPEs after incubation with HLMs for 2 h. In addition, the nontarget approach further identified 9 novel metabolites including 2 epoxide intermediates and 7 oxidative ring-opening compounds, which were first reported in the Phase I metabolism of OPEs. Collectively, this study provided a novel suspect coupled with nontarget screening approach and was successfully used to screen metabolites of three NOPEs. For the first time, we observed direct evidence that oxidative ring-opening might serve as another primary metabolic pathway regarding the metabolism of aryl OPEs.


Assuntos
Organofosfatos/metabolismo , Biotransformação , Cromatografia Líquida , Ésteres/metabolismo , Humanos , Espectrometria de Massas , Microssomos Hepáticos/metabolismo
13.
Chem Commun (Camb) ; 57(53): 6475-6478, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34105548

RESUMO

Engineering of a promiscuous lactonase via semi-rational evolution gave a 1007-fold improvement in its catalytic activity in the degradation of triphenyl phosphate (TPHP). TPHP is a typical bulky organophosphate flame retardant (OPFR) and is widely used in industry. To the best of our knowledge, this is the first artificial enzyme capable of degrading OPFRs.


Assuntos
Hidrolases de Éster Carboxílico/química , Hidrolases de Éster Carboxílico/metabolismo , Domínio Catalítico , Retardadores de Chama/metabolismo , Organofosfatos/metabolismo , Hidrolases de Éster Carboxílico/genética , Engenharia de Proteínas , Especificidade por Substrato
14.
Artigo em Inglês | MEDLINE | ID: mdl-34171608

RESUMO

In analogy to the fluoride-induced regeneration of butyrylcholinesterase (BChE) inhibited by nerve agents a method was developed and optimized for whole blood samples. Compared to the plasma method, regeneration grade was found to be higher for cyclosarin (GF), i-butylsarin from VR, and n-butylsarin from CVX, but lower for sarin (GB), fluorotabun from tabun (GA), and ethylsarin from VX. Regeneration grade of soman (GD) is the same for both matrices because it is released from serum albumin and not from cholinesterases. The method was fully validated for GB and GF to prove selectivity, linearity (n = 6), limit of determination (LOD1), reproducibility (within day (n = 8) and from day to day (n = 8)), effectiveness of extraction, matrix effect, and sample stability (after sample preparation and during three freeze/thaw cycles). The other agents were tested for selectivity, linearity (n = 2), limit of determination, and stability after sample preparation. The method showed high selectivity, good linearity up to the protein's saturation concentration (GB: R2 = 0.9995, GF: 0.9968), and high reproducibility (GB: C.V. 5.9-13.7%, GF: 4.9-10.3%). The limits of determination (calculated from the spiked amount of the original agent) were found with 0.3 ng/mL VX, 0.5 ng/mL GB, 1 ng/mL VR, 0.5 ng/mL GA, 1 ng/mL CVX, and 8 ng/mL GD. In the case of GF, it was found with 4 ng/mL using Isolute ENV + SPE cartridges as for the other analytes and with 2.5 ng/mL using Isolute C8 EC SPE cartridges instead. This method was then applied to a denatured whole blood sample obtained from an individual exposed to GB. While previously only the GB metabolite isopropyl methylphosphonic acid (IMPA) could be detected in this blood sample it was now possible to successfully release GB from the blood proteins by excess fluoride.


Assuntos
Fluoretos/química , Cromatografia Gasosa-Espectrometria de Massas/métodos , Agentes Neurotóxicos/análise , Organofosfatos/sangue , Espectrometria de Massas em Tandem/métodos , Butirilcolinesterase/química , Butirilcolinesterase/metabolismo , Humanos , Limite de Detecção , Modelos Lineares , Agentes Neurotóxicos/química , Agentes Neurotóxicos/metabolismo , Organofosfatos/química , Organofosfatos/metabolismo , Reprodutibilidade dos Testes
15.
Ecotoxicol Environ Saf ; 219: 112342, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34023725

RESUMO

Apoptosis is one of the typical features of liver diseases, therefore molecular targets of hepatic apoptosis and regulatory mechanisms need to be further investigated. The caspases play important functions in the execution of apoptosis and many studies have focused on classical caspase-dependent cell death pathways. However, other types of cell death pathways (such as mitochondrial poly (ADP-ribose) polymerase-1 (PARP1) pathway) are suggested to be also as important as the caspase-mediated pathways in reflection of early toxic effects in hepatocytes, which requires additional research. In this work, an approach integrated in silico and in vitro was used to investigate the underlying toxicological mechanisms of hepatocyte apoptosis through the PARP1 dependent cell death pathway induced by triphenyl phosphate (TPP). Docking view showed that TPP could interact with helix αJ to affect the activation of PARP1 as a molecular initial event. In vitro assays suggested some biochemical events downstream of PARP1 activation, such as mitochondrial injury, apoptosis inducing factor (AIF) release, reactive oxygen species (ROS) production, and DNA damage. Moreover, the apoptosis was alleviated when cells were pretreated with PJ34 hydrochloride (PARP1 inhibitor), suggesting the mitochondrial PARP1 dependent pathway played a pivotal role in L02 cells apoptosis. This study indicated that PARP1 was an important molecular target in this process. And it also helped to understand the mechanism of hepatocytes apoptosis, early hepatic toxicity, and even liver diseases.


Assuntos
Organofosfatos/toxicidade , Poli(ADP-Ribose) Polimerases/química , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Morte Celular/efeitos dos fármacos , Simulação por Computador , Dano ao DNA , Ésteres , Hepatócitos/metabolismo , Humanos , Mitocôndrias/metabolismo , Simulação de Acoplamento Molecular , Organofosfatos/metabolismo , Espécies Reativas de Oxigênio/metabolismo
16.
J Pharmacokinet Pharmacodyn ; 48(5): 655-669, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34013454

RESUMO

Pre-exposure prophylaxis (PrEP) containing antiretrovirals tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) can reduce the risk of acquiring HIV. Concentrations of intracellular tenofovir-diphosphate (TFV-DP) measured in dried blood spots (DBS) have been used to quantify PrEP adherence; although even under directly observed dosing, unexplained between-subject variation remains. Here, we wish to identify patient-specific factors associated with TFV-DP levels. Data from the iPrEX Open Label Extension (OLE) study were used to compare multiple covariate selection methods for determining demographic and clinical covariates most important for drug concentration estimation. To allow for the possibility of non-linear relationships between drug concentration and explanatory variables, the component selection and smoothing operator (COSSO) was implemented. We compared COSSO to LASSO, a commonly used machine learning approach, and traditional forward and backward selection. Training (N = 387) and test (N = 166) datasets were utilized to compare prediction accuracy across methods. LASSO and COSSO had the best predictive ability for the test data. Both predicted increased drug concentration with increases in age and self-reported adherence, the latter with a steeper trajectory among Asians. TFV-DP reductions were associated with increasing eGFR, hemoglobin and transgender status. COSSO also predicted lower TFV-DP with increasing weight and South American countries. COSSO identified non-linear relationships between log(TFV-DP) and adherence, weight and eGFR, with differing trajectories for some races. COSSO identified non-linear log(TFV-DP) trajectories with a subset of covariates, which may better explain variation and enhance prediction. Future research is needed to examine differences identified in trajectories by race and country.


Assuntos
Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/prevenção & controle , Adenina/análogos & derivados , Adenina/metabolismo , Adenina/uso terapêutico , Adulto , Feminino , Humanos , Masculino , Adesão à Medicação , Organofosfatos/metabolismo , Organofosfatos/uso terapêutico , Profilaxia Pré-Exposição/métodos , Tenofovir/metabolismo , Tenofovir/uso terapêutico , Pessoas Transgênero
17.
Environ Toxicol Chem ; 40(7): 1992-2004, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33818814

RESUMO

Although the distribution of 8:2 polyfluoroalkyl phosphate diester (8:2 diPAP) in aquatic environments has been reported, details on its uptake, tissue specificity, and elimination in bivalve mollusks remain to be clarified. The present study is the first report on the accumulation and elimination of 8:2 diPAP in mussels (Mytilus galloprovincialis). The tissue-specific accumulation and depuration of 8:2 diPAP and its metabolites were investigated via semistatic seawater exposure (8:2 diPAP at a nominal concentration of 10 µg/L), through water-borne exposure with static daily renewal over a 72-h exposure period and a 360-h depuration period. The digestive gland was found to be the target organ where accumulation and biotransformation primarily occur. The bioaccumulation factor values (mL/g dry wt) in different organs were in the following order: digestive gland (1249) > adductor muscle (315) > gills (289) > gonad (82.9) > mantle (33.0). Moreover, the distribution of 8:2 diPAP among tissues may be related to the total protein content. The 8:2 diPAP tended to be excreted in feces. The compounds 8:2 fluorotelomer carboxylic acid, 8:2 fluorotelomer unsaturated carboxylic acid, 7:3 fluorotelomer carboxylic acid, perfluorooctanoic acid, and perfluoroheptanoic acid were detected and quantified as phase I metabolites, and the concentration of all phase I metabolites relative to the 8:2 diPAP concentration (72 h) was 0.304 mol%. A phase II metabolite, 8:2 fluorotelomer alcohol conjugated with sulfate, was detected but not quantitated in the digestive gland. A biotransformation pathway of 8:2 diPAP in M. galloprovincialis was proposed on the basis of the results obtained in the present study and previous studies. These findings improve our understanding of the accumulation of perfluorocarboxylic acids in bivalve mollusks. Environ Toxicol Chem 2021;40:1992-2004. © 2021 SETAC.


Assuntos
Mytilus , Animais , Biotransformação , Mytilus/metabolismo , Organofosfatos/metabolismo , Fosfatos , Distribuição Tecidual
18.
Can J Microbiol ; 67(5): 349-357, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33769090

RESUMO

Arbuscular mycorrhizal (AM) fungi play an important role in the acquisition of phosphorus (P) by plants. The external hyphae of AM fungi function as an extension of plant roots and may downregulate related functions in the roots. It is not clear whether the ability of AM fungi to mineralize organic P affects root phosphatase activities. A pot experiment was conducted to investigate the effect of Funneliformis mosseae on soil organic P mineralization under phytate application and to explore root phosphatase activities, P uptake, and growth in Camellia oleifera Abel. The plants and their growth substrates were harvested 4 and 8 months after planting. The results showed that organic P application had no effect on the total dry mass of nonmycorrhizal plants, but differences in dry mass under P application were observed in mycorrhizal plants in both harvests. Inoculation with F. mosseae increased soil acid phosphatase, phytase, and alkaline phosphatase activities and reduced the soil organic P content. Mycorrhizal plants had higher root activity, shoot and root P contents and root acid phosphatase and phytase activities than nonmycorrhizal plants irrespective of organic P application. In conclusion, AM fungi enhanced the mineralization of soil organic P and positively affect root phosphatase activities.


Assuntos
Camellia/metabolismo , Camellia/microbiologia , Fungos/enzimologia , Organofosfatos/análise , Fósforo/análise , Microbiologia do Solo , Camellia/crescimento & desenvolvimento , Interações entre Hospedeiro e Microrganismos , Micorrizas/enzimologia , Organofosfatos/metabolismo , Fósforo/metabolismo , Raízes de Plantas/microbiologia , Solo/química , Simbiose
19.
Cardiovasc Res ; 117(9): 2016-2029, 2021 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-33576771

RESUMO

Calcification of the arterial wall and valves is an important part of the pathophysiological process of peripheral and coronary atherosclerosis, aortic stenosis, ageing, diabetes, and chronic kidney disease. This review aims to better understand how extracellular phosphates and their ability to be retained as calcium phosphates on the extracellular matrix initiate the mineralization process of arteries and valves. In this context, the physiological process of bone mineralization remains a human model for pathological soft tissue mineralization. Soluble (ionized) calcium precipitation occurs on extracellular phosphates; either with inorganic or on exposed organic phosphates. Organic phosphates are classified as either structural (phospholipids, nucleic acids) or energetic (corresponding to phosphoryl transfer activities). Extracellular phosphates promote a phenotypic shift in vascular smooth muscle and valvular interstitial cells towards an osteoblast gene expression pattern, which provokes the active phase of mineralization. A line of defense systems protects arterial and valvular tissue calcifications. Given the major roles of phosphate in soft tissue calcification, phosphate mimetics, and/or prevention of phosphate dissipation represent novel potential therapeutic approaches for arterial and valvular calcification.


Assuntos
Artérias/metabolismo , Calcinose/metabolismo , Doenças das Valvas Cardíacas/metabolismo , Valvas Cardíacas/metabolismo , Organofosfatos/metabolismo , Osteogênese , Fosfatos/metabolismo , Calcificação Vascular/metabolismo , Animais , Artérias/efeitos dos fármacos , Artérias/patologia , Conservadores da Densidade Óssea/uso terapêutico , Calcinose/tratamento farmacológico , Calcinose/patologia , Quelantes/uso terapêutico , Doenças das Valvas Cardíacas/tratamento farmacológico , Doenças das Valvas Cardíacas/patologia , Valvas Cardíacas/efeitos dos fármacos , Valvas Cardíacas/patologia , Humanos , Osteogênese/efeitos dos fármacos , Calcificação Vascular/tratamento farmacológico , Calcificação Vascular/patologia
20.
J Agric Food Chem ; 69(4): 1283-1290, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33464890

RESUMO

The substantial application of organophosphate triesters (tri-OPEs) may lead to a concentration escalation of their major metabolites, organophosphate diesters (di-OPEs) in animal-derived and plant-derived animal protein supplement feeds (APFs). APFs are major food for raised animals and may bring OPEs into the food supply. In the present study, the concentrations of Σ8di-OPEs in animal-derived and plant-derived APFs were in the range of 1.98-182 ng/g dw (average: 39.2 ng/g dw). Meat meal had the highest average concentrations of di-OPEs (52.1 ng/g dw), followed by blood meal (49.9 ng/g), feather meal (23.3 ng/g dw), and plant-derived feeds (18.3 ng/g dw). The concentrations of di-OPEs were at the same order of magnitude as those of tri-OPEs in APFs. Bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) was the major contributor in blood meal, feather meal, and plant-derived APFs, while dimethyl phosphate dominated in meat meal. The ratios of di-OPEs/tri-OPEs (Rdi/tri) displayed large variability, ranging from 0 for the bis(2-chloroethyl) phosphate-tris(2-chloroethyl) phosphate pair to 175 for the BDCIPP-tris(1,3-dichloroisopropyl) phosphate pair, which indicated that the metabolism capacities and environmental sources for di-OPEs are diverse in APFs. Different Rdi/tri between APFs and similar food matrices implied that di-OPEs may have different environmental sources. The similar Rdi/tri values for some of the di-/tri-OPE pairs among APFs and dust samples indicated that dust may be a direct exogenous source of OPE exposure in some APF matrices. Future studies should simultaneously focus on tri- and di-OPEs, together of which may reflect the actual exposure to OPEs through the food supply.


Assuntos
Ração Animal/análise , Ésteres/análise , Aditivos Alimentares/análise , Organofosfatos/análise , Animais , China , Ésteres/metabolismo , Plumas/química , Retardadores de Chama/análise , Aditivos Alimentares/metabolismo , Abastecimento de Alimentos , Organofosfatos/metabolismo
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