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Environment International Oct 2020Organophosphate esters (OPEs) are increasingly used as flame retardants and plasticizers in various products. In vivo and in vitro studies suggest that OPEs can affect...
BACKGROUND
Organophosphate esters (OPEs) are increasingly used as flame retardants and plasticizers in various products. In vivo and in vitro studies suggest that OPEs can affect metabolic health but the human evidence is lacking.
OBJECTIVES
We analyzed data from the U.S. National Health and Nutrition Examination Survey, 2011-2014, to examine the associations between urinary OPE metabolites and metabolic syndrome (MetS) and its components in adults.
METHODS
We included a total of 1157 adults aged ≥20 years who had information on urinary OPE metabolites, components of MetS and essential covariates in the current analyses. MetS was composed of hyperglycemia, hypertension, hypertriglyceridemia, low high-density cholesterol, and central obesity. Binary logistic regression and weighted quantile sum (WQS) regression were used to assess the associations of individual OPE metabolites and OPEs mixture with MetS and its components. All analyses were conducted in men and women separately. Potential effect modification by age, serum total testosterone (TT) level and menopause status were also examined via stratified analyses as well as by testing the significance of the interaction term with exposure.
RESULTS
After adjusting for confounders, bis(2-chloroethyl) phosphate (BCEP) and bis(1,3-dichloro-2-propyl) phosphate (BDCPP) were positively associated with MetS in a dose-dependent manner (P-trend = 0.02 and 0.02 for BCEP and BDCPP, respectively) in all men. Meanwhile, increasing quartiles of DPHP was positively associated with hyperglycemia (P-trend = 0.03), but DBUP was inversely associated with central obesity (P-trend = 0.02). WQS analyses in all men found that OPEs mixture (OPEs index) was positively associated with MetS [odds ratio (OR) for OPEs index: 1.65; 95%CI :1.21, 2.24], hyperglycemia (OR:1.47; 95%CI:1.09,2.00), and central obesity (OR:1.36; 95%CI:1.01,1.83). Although there was no significant interaction between exposure and effect modifiers, stratified analyses in men suggested that significant associations were mainly limited to those aged < 60 years or those with TT < 437 ng/dL (the median level in men). By contrast, the associations with MetS and its components were sparse and inconsistent in women except for the positive association between OPEs index and central obesity.
CONCLUSIONS
In this cross-sectional study, exposure to OPEs was positively associated with elevated odds of MetS and individual components in men, especially among those aged <60 years or those with relatively low TT level. But the associations were less apparent in women except for the consistent positive association of OPEs mixture with central obesity. Nevertheless, these results need to be interpreted with caution and should be confirmed in future studies, ideally with multiple urine samples collected prospectively to improve the exposure measurement of OPEs.
Topics: Adult; Cross-Sectional Studies; Esters; Female; Flame Retardants; Humans; Male; Metabolic Syndrome; Middle Aged; Nutrition Surveys; Organophosphates
PubMed: 32679393
DOI: 10.1016/j.envint.2020.105941 -
South African Medical Journal =... Feb 2023The illegal practice of combining organophosphates (OPs) with other compounds such as carbamates and pyrethroids, creating 'streetpesticides', is common in South Africa....
The illegal practice of combining organophosphates (OPs) with other compounds such as carbamates and pyrethroids, creating 'streetpesticides', is common in South Africa. These agents contain mostly unknown quantities of unregulated toxins and contribute to atypicaland unpredictable clinical presentations following human ingestion. We present such a case in a patient with intentional rodenticideingestion. The initial presentation in the emergency department was a classic cholinergic toxidrome, and clinical resolution was achievedafter provision of atropine. This was followed 12 hours later by an acute decompensation resulting from an apparent sympatheticallydriven episode of autonomic instability and acute pulmonary oedema requiring immediate respiratory and haemodynamic support. In ourdiscussion, we explore this secondary decompensation and suggest various pathophysiological explanations for this atypical clinical coursefollowing what had appeared to be OP poisoning. The patient was discharged home after a total of 6 days in hospital.
Topics: Humans; South Africa; Atropine; Pyrethrins; Carbamates; Organophosphates
PubMed: 36757073
DOI: 10.7196/SAMJ.2023.v113i2.16832 -
Environmental Health Perspectives Apr 2023Organophosphate esters (OPEs) are common endocrine-disrupting chemicals, and OPE exposure may be associated with type 2 diabetes (T2D). However, greater knowledge...
Association between Organophosphate Ester Exposure and Insulin Resistance with Glycometabolic Disorders among Older Chinese Adults 60-69 Years of Age: Evidence from the China BAPE Study.
BACKGROUND
Organophosphate esters (OPEs) are common endocrine-disrupting chemicals, and OPE exposure may be associated with type 2 diabetes (T2D). However, greater knowledge regarding the biomolecular intermediators underlying the impact of OPEs on T2D in humans are needed to understand biological etiology.
OBJECTIVES
We explored the associations between OPE exposure and glycometabolic markers among older Chinese adults 60-69 years of age to elucidate the underlying mechanisms using a multi-omics approach.
METHODS
This was a longitudinal panel study comprising 76 healthy participants 60-69 years of age who lived in Jinan city of northern China. The study was conducted once every month for 5 months, from September 2018 to January 2019. We measured a total of 17 OPEs in the blood, 11 OPE metabolites in urine, and 4 glycometabolic markers (fasting plasma glucose, glycated serum protein, fasting insulin, and homeostatic model assessment for insulin resistance). The blood transcriptome and serum/urine metabolome were also evaluated. The associations between individual OPEs and glycometabolic markers were explored. An adverse outcome pathway (AOP) was established to determine the biomolecules mediating the associations.
RESULTS
Exposure to five OPEs and OPE metabolites (trimethylolpropane phosphate, triphenyl phosphate, tri-iso-butyl phosphate, dibutyl phosphate, and diphenyl phosphate) was associated with increased levels of glycometabolic markers. The mixture effect analysis further indicated the adverse effect of OPE mixtures. Multi-omics analyses revealed that the endogenous changes in the transcriptional and metabolic levels were associated with OPE exposure. The putative AOPs model suggested that triggers of molecular initiation events (e.g., insulin receptor and glucose transporter type 4) with subsequent key events, including disruptions in signal transduction pathways (e.g., phosphatidylinositol 3-kinase/protein kinase B and insulin secretion signaling) and biological functions (glucose uptake and insulin secretion), may constitute the diabetogenic effects of OPEs.
DISCUSSION
OPEs are associated with the elevated risk of T2D among older Chinese adults 60-69 years of age. Implementing OPE exposure reduction strategies may help reduce the T2D burden among these individuals, if the relationship is causal. https://doi.org/10.1289/EHP11896.
Topics: Aged; Humans; Middle Aged; China; Diabetes Mellitus, Type 2; East Asian People; Esters; Flame Retardants; Insulin Resistance; Organophosphates; Phosphates
PubMed: 37042841
DOI: 10.1289/EHP11896 -
Current HIV/AIDS Reports Apr 2020Combination antiretroviral therapy (cART) has had dramatic effects on morbidity and mortality for persons living with HIV (PLWH). Despite significant progress in... (Review)
Review
PURPOSE OF REVIEW
Combination antiretroviral therapy (cART) has had dramatic effects on morbidity and mortality for persons living with HIV (PLWH). Despite significant progress in treatment efficacy, tolerability, and reducing pill burden, new agents are needed to address issues of resistance, drug-drug interactions, end organ disease, and adherence. This review covers novel ART agents recently approved or in development.
RECENT FINDINGS
Capsid inhibitors (CAI) demonstrate high potency and potential for extended-duration dosing in pre-clinical trials. While previous maturation inhibitors (MI) were hampered by issues of drug resistance, a recent phase IIa trial for a second-generation MI demonstrated promising antiviral activity. A phase I trial to evaluate a transdermal implant of islatravir, a nucleoside reverse transcriptase translocation inhibitor (NRTTI), maintained concentrations above the target pharmacokinetic threshold at 12 weeks. The attachment inhibitor fostemsavir is available in the USA for compassionate use in multi-drug-resistant (MDR) HIV. New antiretroviral agents show promise for both extended-duration dosing and MDR HIV.
Topics: Anti-HIV Agents; Capsid; Capsid Proteins; Deoxyadenosines; Drug Discovery; Drug Therapy, Combination; HIV Fusion Inhibitors; HIV Infections; Humans; Organophosphates; Piperazines; Reverse Transcriptase Inhibitors
PubMed: 32052271
DOI: 10.1007/s11904-020-00486-2 -
Clinical Pharmacokinetics Apr 2022Tedizolid is an oxazolidinone antibiotic with high potency against Gram-positive bacteria and currently prescribed in bacterial skin and skin-structure infections. The... (Review)
Review
Tedizolid is an oxazolidinone antibiotic with high potency against Gram-positive bacteria and currently prescribed in bacterial skin and skin-structure infections. The aim of the review was to summarize and critically review the key pharmacokinetic and pharmacodynamic aspects of tedizolid. Tedizolid displays linear pharmacokinetics with good tissue penetration. In in vitro susceptibility studies, tedizolid exhibits activity against the majority of Gram-positive bacteria (minimal inhibitory concentration [MIC] of ≤ 0.5 mg/L), is four-fold more potent than linezolid, and has the potential to treat pathogens being less susceptible to linezolid. Area under the unbound concentration-time curve (fAUC) related to MIC (fAUC/MIC) was best correlated with efficacy. In neutropenic mice, fAUC/MIC of ~ 50 and ~ 20 induced bacteriostasis in thigh and pulmonary infection models, respectively, at 24 h. The presence of granulocytes augmented its antibacterial effect. Hence, tedizolid is currently not recommended for immunocompromised patients. Clinical investigations with daily doses of 200 mg for 6 days showed non-inferiority to twice-daily dosing of linezolid 600 mg for 10 days in patients with acute bacterial skin and skin-structure infections. In addition to its use in skin and skin-structure infections, the high pulmonary penetration makes it an attractive option for respiratory infections including Mycobacterium tuberculosis. Resistance against tedizolid is rare yet effective antimicrobial surveillance and defining pharmacokinetic/pharmacodynamic targets for resistance suppression are needed to guide dosing strategies to suppress resistance development.
Topics: Animals; Anti-Bacterial Agents; Humans; Mice; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Oxazolidinones; Tetrazoles
PubMed: 35128625
DOI: 10.1007/s40262-021-01099-7 -
Archives of Toxicology May 2022
Topics: Nerve Agents; Organophosphates
PubMed: 35267066
DOI: 10.1007/s00204-022-03273-7 -
International Journal of Molecular... Aug 2022Organophosphates (OPs) are toxic chemicals produced by an esterification process and some other routes. They are the main components of herbicides, pesticides, and... (Review)
Review
Organophosphates (OPs) are toxic chemicals produced by an esterification process and some other routes. They are the main components of herbicides, pesticides, and insecticides and are also widely used in the production of plastics and solvents. Acute or chronic exposure to OPs can manifest in various levels of toxicity to humans, animals, plants, and insects. OPs containing insecticides were widely used in many countries during the 20th century, and some of them continue to be used today. In particular, 36 OPs have been registered in the USA, and all of them have the potential to cause acute and sub-acute toxicity. Renal damage and impairment of kidney function after exposure to OPs, accompanied by the development of clinical manifestations of poisoning back in the early 1990s of the last century, was considered a rare manifestation of their toxicity. However, since the beginning of the 21st century, nephrotoxicity of OPs as a manifestation of delayed toxicity is the subject of greater attention of researchers. In this article, we present a modern view on the molecular pathophysiological mechanisms of acute nephrotoxicity of organophosphate compounds.
Topics: Animals; Herbicides; Humans; Insecticides; Organophosphates; Organophosphorus Compounds; Pesticides
PubMed: 36012118
DOI: 10.3390/ijms23168855 -
Molecules (Basel, Switzerland) Feb 2020Biomimetic molecular design is a promising approach for generating functional biomaterials such as cell membrane mimetic blood-compatible surfaces, mussel-inspired... (Review)
Review
Biomimetic molecular design is a promising approach for generating functional biomaterials such as cell membrane mimetic blood-compatible surfaces, mussel-inspired bioadhesives, and calcium phosphate cements for bone regeneration. Polyphosphoesters (PPEs) are candidate biomimetic polymer biomaterials that are of interest due to their biocompatibility, biodegradability, and structural similarity to nucleic acids. While studies on the synthesis of PPEs began in the 1970s, the scope of their use as biomaterials has increased in the last 20 years. One advantageous property of PPEs is their molecular diversity due to the presence of multivalent phosphorus in their backbones, which allows their physicochemical and biointerfacial properties to be easily controlled to produce the desired molecular platforms for functional biomaterials. Polyphosphodiesters (PPDEs) are analogs of PPEs that have recently attracted interest due to their strong affinity for biominerals. This review describes the fundamental properties of PPDEs and recent research in the field of macromolecular bone therapeutics.
Topics: Animals; Biocompatible Materials; Biomimetic Materials; Bone Regeneration; Calcification, Physiologic; Cell Differentiation; Esters; Humans; Materials Testing; Nanoparticles; Organophosphates; Osteoblasts
PubMed: 32050545
DOI: 10.3390/molecules25030758 -
ChemMedChem Jun 2020Phosphoantigens (pAgs) are small phosphorus-containing molecules that stimulate Vγ9Vδ2 T cells with sub-nanomolar cellular potency. Recent work has revealed that these... (Review)
Review
Phosphoantigens (pAgs) are small phosphorus-containing molecules that stimulate Vγ9Vδ2 T cells with sub-nanomolar cellular potency. Recent work has revealed that these compounds work through binding to the transmembrane immunoglobulin butyrophilin 3A1 (BTN3A1) within its intracellular B30.2 domain. Engagement of BTN3A1 is critical to the formation of an immune synapse between cells that contain pAgs and the Vγ9Vδ2 T cells. This minireview summarizes the structure-activity relationships of pAgs and their implications to the mechanisms of butyrophilin 3 activation leading to Vγ9Vδ2 T cell response.
Topics: Antigens, CD; Binding Sites; Butyrophilins; Humans; Intraepithelial Lymphocytes; Ligands; Molecular Structure; Organophosphates; Protein Binding; Protein Domains; Structure-Activity Relationship
PubMed: 32453919
DOI: 10.1002/cmdc.202000198 -
Chemical Research in Toxicology Sep 2022Exposure to organophosphorus pesticides (OP) can have chronic adverse effects that are independent of inhibition of acetylcholinesterase, the classic target for acute OP...
Exposure to organophosphorus pesticides (OP) can have chronic adverse effects that are independent of inhibition of acetylcholinesterase, the classic target for acute OP toxicity. In pure proteins, the organophosphorus pesticide chlorpyrifos oxon induces a cross-link between lysine and glutamate (or aspartate) with loss of water. Tubulin is particularly sensitive to OP-induced cross-linking. Our goal was to explore OP-induced cross-linking in a complex protein sample, MAP-rich tubulin from and to test 8 OP for their capacity to promote isopeptide cross-linking. We treated 100 μg of MAP-rich tubulin with 100 μM chlorpyrifos, chlorpyrifos oxon, methamidophos, paraoxon, diazinon, diazoxon, monocrotophos, or dichlorvos. Each sample was separated using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and stained with Coomassie blue. Five gel slices (at about 30, 50, 150, and 300 kDa, and the top of the separating gel) were removed from the lanes for each of the eight OP samples and from untreated control lanes. These gel slices were subjected to in-gel trypsin digestion. MSMS fragmentation spectra of the tryptic peptides were examined for isopeptide cross-links. Sixteen spectra yielded convincing evidence for isopeptide cross-linked peptides. Ten were from the chlorpyrifos oxon reaction, 1 from dichlorvos, 1 from paraoxon, 1 from diazinon, and 3 from diazoxon. It was concluded that catalysis of protein cross-linking is a general property of organophosphorus pesticides and pesticide metabolites. Data are available via ProteomeXchange with identifier PXD034529.
Topics: Acetylcholinesterase; Aspartic Acid; Chlorpyrifos; Diazinon; Dichlorvos; Glutamates; Lysine; Monocrotophos; Organophosphorus Compounds; Paraoxon; Peptides; Pesticides; Sodium Dodecyl Sulfate; Trypsin; Tubulin; Water
PubMed: 36048166
DOI: 10.1021/acs.chemrestox.2c00194