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Proceedings of the National Academy of... Apr 2022As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as...
As a critical sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays an essential role in immune and vascular systems. There are five S1P receptors, designated as S1PR1 to S1PR5, encoded in the human genome, and their activities are governed by endogenous S1P, lipid-like S1P mimics, or nonlipid-like therapeutic molecules. Among S1PRs, S1PR1 stands out due to its nonredundant functions, such as the egress of T and B cells from the thymus and secondary lymphoid tissues, making it a potential therapeutic target. However, the structural basis of S1PR1 activation and regulation by various agonists remains unclear. Here, we report four atomic resolution cryo-electron microscopy (cryo-EM) structures of Gi-coupled human S1PR1 complexes: bound to endogenous agonist d18:1 S1P, benchmark lipid-like S1P mimic phosphorylated Fingolimod [(S)-FTY720-P], or nonlipid-like therapeutic molecule CBP-307 in two binding modes. Our results revealed the similarities and differences of activation of S1PR1 through distinct ligands binding to the amphiphilic orthosteric pocket. We also proposed a two-step “shallow to deep” transition process of CBP-307 for S1PR1 activation. Both binding modes of CBP-307 could activate S1PR1, but from shallow to deep transition may trigger the rotation of the N-terminal helix of Gαi and further stabilize the complex by increasing the Gαi interaction with the cell membrane. We combine with extensive biochemical analysis and molecular dynamic simulations to suggest key steps of S1P binding and receptor activation. The above results decipher the common feature of the S1PR1 agonist recognition and activation mechanism and will firmly promote the development of therapeutics targeting S1PRs.
Topics: Colitis, Ulcerative; Cryoelectron Microscopy; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Immunosuppressive Agents; Multiple Sclerosis; Organophosphates; Protein Binding; Protein Conformation, alpha-Helical; Sphingosine; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors
PubMed: 35412894
DOI: 10.1073/pnas.2117716119 -
Endocrinology Jun 2023Organophosphate esters (OPEs) are used extensively as flame retardants and plasticizers and are found ubiquitously in the environment and human matrices. Previous...
Organophosphate esters (OPEs) are used extensively as flame retardants and plasticizers and are found ubiquitously in the environment and human matrices. Previous studies suggested that exposure to some of these chemicals may disrupt the homeostasis of female sex hormones and have detrimental effects on female fertility. Here, we determined the effects of OPEs on the function of KGN ovarian granulosa cells. We hypothesized that OPEs alter the steroidogenic ability of these cells by dysregulating the expression of transcripts involved in steroid and cholesterol biosynthesis. KGN cells were exposed for 48 hours to 1 of 5 OPEs (1-50μM): triphenyl phosphate (TPHP), tris(methylphenyl) phosphate (TMPP), isopropylated triphenyl phosphate (IPPP), tert-butylphenyl diphenyl phosphate (BPDP), and tributoxyethyl phosphate (TBOEP), or to a polybrominated diphenyl ether flame retardant, 2,2',4,4' tetrabromodiphenyl ether (BDE-47), in the presence or absence of Bu2cAMP. OPEs increased the basal production of progesterone (P4) and 17β-estradiol (E2) and had either no effect or inhibited Bu2cAMP-stimulated P4 and E2 synthesis; exposure to BDE-47 had no effect. Quantitative real-time polymerase chain reaction (qRT-PCR) analyses revealed that OPEs (≥5μM) increased the basal expression of critical genes (STAR, CYP11A1, CYP19A1, HSD3B2, and NR5A1) involved in steroidogenesis; upon stimulation, the expression of all genes tested was downregulated. An overall inhibition in cholesterol biosynthesis was induced by OPEs, characterized by a downregulation in HMGCR and SREBF2 expression. TBOEP consistently showed the least effect. Therefore, OPEs perturbed steroidogenesis in KGN granulosa cells by targeting the expression of steroidogenic enzymes and cholesterol transporters; these effects may have an adverse impact on female reproduction.
Topics: Humans; Female; Esters; Organophosphates; Granulosa Cells; Flame Retardants; Environmental Monitoring
PubMed: 37288667
DOI: 10.1210/endocr/bqad089 -
International Journal of Molecular... Nov 2020Aptamers are nucleic acid analogues of antibodies with high affinity to different targets, such as cells, viruses, proteins, inorganic materials, and coenzymes.... (Review)
Review
Aptamers are nucleic acid analogues of antibodies with high affinity to different targets, such as cells, viruses, proteins, inorganic materials, and coenzymes. Empirical approaches allow the design of in vitro aptamers that bind particularly to a target molecule with high affinity and selectivity. Theoretical methods allow significant expansion of the possibilities of aptamer design. In this study, we review theoretical and joint theoretical-experimental studies dedicated to aptamer design and modeling. We consider aptamers with different targets, such as proteins, antibiotics, organophosphates, nucleobases, amino acids, and drugs. During nucleic acid modeling and in silico design, a full set of in silico methods can be applied, such as docking, molecular dynamics (MD), and statistical analysis. The typical modeling workflow starts with structure prediction. Then, docking of target and aptamer is performed. Next, MD simulations are performed, which allows for an evaluation of the stability of aptamer/ligand complexes and determination of the binding energies with higher accuracy. Then, aptamer/ligand interactions are analyzed, and mutations of studied aptamers made. Subsequently, the whole procedure of molecular modeling can be reiterated. Thus, the interactions between aptamers and their ligands are complex and difficult to understand using only experimental approaches. Docking and MD are irreplaceable when aptamers are studied in silico.
Topics: Anti-Bacterial Agents; Aptamers, Nucleotide; Computer Simulation; Directed Molecular Evolution; Drug Design; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Organophosphates; Proteins; SELEX Aptamer Technique
PubMed: 33182550
DOI: 10.3390/ijms21228420 -
Environmental Research Sep 2022Organophosphate esters (OPE) are flame retardants and plasticizers used in a wide range of consumer products. Despite their widespread use, few studies have...
Organophosphate esters (OPE) are flame retardants and plasticizers used in a wide range of consumer products. Despite their widespread use, few studies have characterized pediatric exposures. We assessed variability and predictors of OPE exposures in a cohort panel study of 179 predominantly Black school-aged children with asthma in Baltimore City, MD. The study design included up to four seasonal week-long in-home study visits with urine sample collection on days 4 and 7 of each visit (n = 618). We quantified concentrations of 9 urinary OPE biomarkers: bis(2-chloroethyl) phosphate (BCEtp), bis(1-chloro-2-propyl) phosphate, bis(1,3-dichloro-2-propyl) phosphate (BDCPP), di-benzyl phosphate (DBuP), di-benzyl phosphate, di-o-cresylphosphate, di-p-cresylphosphate (DPCP), di-(2-propylheptyl) phthalate (DPHP), 2,3,4,5-tetrabromo benzoic acid. We assessed potential predictors of exposure, including demographic factors, household characteristics, and cleaning behaviors. We calculated Spearman/tetrachoric correlations and intraclass correlation coefficients (ICCs) to examine within-week and seasonal intra-individual variability, respectively. We assessed OPE predictors using linear models for continuous log concentrations (BDCPP and DPHP) and logistic models for odds of detection (BCEtP, DBuP, DPCP), with generalized estimating equations to account for repeated measures. For all OPEs, we observed moderate within-week correlations (r: 0.31-0.63) and weak to moderate seasonal reliability (ICC: 0.18-0.38). BDCPP and DPHP concentrations were higher in the summer compared to other seasons. DPHP concentrations were lower among males than females (%: -53.5%; 95% CI: -62.7, -42.0) and among participants spending >12 h/day indoors compared to ≤12 h (%: -20.7%; 95% CI: -32.2, -7.3). BDCPP concentrations were lower among children aged 8-10 years compared to 5-7 years (%: -39.1%; 95% CI: -55.9, -15.9) and higher among children riding in a vehicle on the day of sample collection compared to those who had not (%: 28.5%; 95% CI: 3.4, 59.8). This study is the first to characterize within-week and seasonal variability and identify predictors of OPE biomarkers among Black school-aged children, a historically understudied population.
Topics: Biomarkers; Child; Esters; Female; Flame Retardants; Humans; Male; Organophosphates; Phosphates; Reproducibility of Results
PubMed: 35346652
DOI: 10.1016/j.envres.2022.113192 -
Current Environmental Health Reports Dec 2019Organophosphate esters (OPEs) are applied to a variety of consumer products, primarily as flame retardants and plasticizers. OPEs can leach out of products over time and... (Review)
Review
PURPOSE OF REVIEW
Organophosphate esters (OPEs) are applied to a variety of consumer products, primarily as flame retardants and plasticizers. OPEs can leach out of products over time and are consequently prevalent in the environment and frequently detected in human biomonitoring studies. Exposure during pregnancy is of particular concern as OPEs have recently been detected in placental tissues, suggesting they may be transferred to the developing infant. Also, studies have now shown that children typically experience higher exposure to several OPEs compared with adults, indicating they may be disproportionately impacted by these compounds. This review summarizes the current literature on reproductive and child health outcomes of OPE exposures and highlights areas for future research.
RECENT FINDINGS
Experimental animal studies demonstrate potential for OPEs to adversely impact health, and a limited number of epidemiologic studies conducted in adult cohorts suggest that OPEs may interfere with the endocrine system. Neurodevelopment is perhaps the most well studied of children's health endpoints, and several studies indicate that prenatal and early life OPE exposures impact both cognitive and behavioral development. Associations have also been reported with reproductive outcomes (e.g., fertilization and pregnancy loss) and with the timing of parturition and preterm birth. Cross-sectional studies also demonstrate associations between OPEs and respiratory health outcomes, allergic disease, and measures of adiposity. An expanding body of research demonstrates that OPEs are associated with adverse reproductive health and birth outcomes, asthma and allergic disease, early growth and adiposity, and neurodevelopment. Still, additional research is urgently needed to elucidate the full impact of OPEs on children's health.
Topics: Adult; Child; Cross-Sectional Studies; Environmental Exposure; Environmental Monitoring; Esters; Female; Flame Retardants; Humans; Maternal Exposure; Organophosphates; Plasticizers; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 31755035
DOI: 10.1007/s40572-019-00258-0 -
Environmental Research Jun 2023Organophosphate esters (OPEs) are used as flame retardants and plasticizers in various consumer products. Limited prior research suggests sex-specific effects of...
Sex-specific effects of prenatal organophosphate ester (OPE) metabolite mixtures and adverse infant birth outcomes in the maternal and developmental risks from environmental and social stressors (MADRES) pregnancy cohort.
BACKGROUND
Organophosphate esters (OPEs) are used as flame retardants and plasticizers in various consumer products. Limited prior research suggests sex-specific effects of prenatal OPE exposures on fetal development. We evaluated overall and sex-specific associations between prenatal OPE exposures and gestational age (GA) at birth and birthweight for gestational age (BW for GA) z-scores among the predominately low-income, Hispanic MADRES cohort.
METHODS
Nine OPE metabolite concentrations were measured in 421 maternal urine samples collected during a third trimester visit (GA = 31.5 ± 2.0 weeks). We examined associations between single urinary OPE metabolites and GA at birth and BW for GA z-scores using linear regression models and Generalized Additive Models (GAMs) and effects from OPE mixtures using Bayesian Kernel Machine Regression (BKMR). We also assessed sex-specific differences in single metabolite analyses by evaluating statistical interactions and stratifying by sex.
RESULTS
We did not find significant associations between individual OPE metabolites and birth outcomes in the full infant sample; however, we found that higher bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) was associated with earlier GA at birth among male infants (p = 0.04), and a nonlinear, inverted U-shape association between the sum of dibutyl phosphate and di-isobutyl phosphate (DNBP + DIBP) and GA at birth among female infants (p = 0.03). In mixtures analysis, higher OPE metabolite mixture exposures was associated with lower GA at birth, which was primarily driven by female infants. No associations were observed between OPE mixtures and BW for GA z-scores.
CONCLUSION
Higher BDCIPP and DNBP + DIBP concentrations were associated with earlier GA at birth among male and female infants, respectively. Higher exposure to OPE mixtures was associated with earlier GA at birth, particularly among female infants. However, we saw no associations between prenatal OPEs and BW for GA. Our results suggest sex-specific impacts of prenatal OPE exposures on GA at birth.
Topics: Pregnancy; Infant, Newborn; Humans; Male; Infant; Female; Bayes Theorem; Organophosphates; Phosphates; Flame Retardants; Esters
PubMed: 36934865
DOI: 10.1016/j.envres.2023.115703 -
Journal of the American Mosquito... Sep 2022Susceptibility to organophosphates was evaluated in 2 populations of Culex quinquefasciatus from the department of Atlantico, Colombia. Bioassays for temephos,...
Susceptibility to organophosphates was evaluated in 2 populations of Culex quinquefasciatus from the department of Atlantico, Colombia. Bioassays for temephos, malathion, and pirimiphos-methyl were performed with 3rd-stage larvae and adult females of Cx. quinquefasciatus from the municipalities of Soledad and Puerto Colombia, following the methods of the World Health Organization and Centers for Disease Control and Prevention, respectively. The median lethal concentration (LC50) and 90% lethal concentration (LC90) resistance ratios (RRLC50 and RRLC90) were determined for each insecticide in the field populations evaluated, using the Cartagena strain as the susceptible control. Relative to LC50 and LC90 of the Cartagena strain, the population from Puerto Colombia was moderately resistant to temephos (RRLC50 5.7-fold) and malathion (RRLC50 8.6-fold, RRLC90 9-fold) and susceptible to pirimiphos-methyl (RRLC50 and RRLC90 < 5-fold). The population from Soledad was susceptible to temephos and pirimiphos-methyl (RRLC50 and RRLC90 < 5-fold) and showed moderate resistance to malathion (RRLC50 7.5-fold). It is important to emphasize that routine monitoring of insecticide resistance in Cx. quinquefasciatus helps us detect resistance early and improve the effectiveness of control strategies.
Topics: Animals; Colombia; Culex; Female; Insecticide Resistance; Insecticides; Larva; Malathion; Organophosphates; Temefos
PubMed: 35839258
DOI: 10.2987/22-7058 -
TheScientificWorldJournal Feb 2006Anticholinesterase compounds, organophosphates (OPs) and carbamates (CMs) are commonly used for a variety of purposes in agriculture and in human and veterinary... (Review)
Review
Anticholinesterase compounds, organophosphates (OPs) and carbamates (CMs) are commonly used for a variety of purposes in agriculture and in human and veterinary medicine. They exert their toxicity in mammalian system primarily by virtue of acetylcholinesterase (AChE) inhibition at the synapses and neuromuscular junctions, leading into the signs of hypercholinergic preponderance. However, the mechanism(s) involved in brain/muscle damage appear to be linked with alteration in antioxidant and the scavenging system leading to free radical-mediated injury. OPs and CMs cause excessive formation of F2-isoprostanes and F4-neuroprostanes, in vivo biomarkers of lipid peroxidation and generation of reactive oxygen species (ROS), and of citrulline, a marker of NO/NOS and reactive nitrogen species (RNS) generation. In addition, during the course of these excitatory processes and inhibition of AChE, a high rate of ATP consumption, coupled with the inhibition of oxidative phosphorylation, compromise the cell's ability to maintain its energy levels and excessive amounts of ROS and RNS may be generated. Pretreatment with N-methyl D-aspartate (NMDA) receptor antagonist memantine, in combination with atropine sulfate, provides significant protection against inhibition of AChE, increases of ROS/RNS, and depletion of high-energy phosphates induced by DFP/carbofuran. Similar antioxidative effects are observed with a spin trapping agent, phenyl-N-tert-butylnitrone (PBN) or chain breaking antioxidant vitamin E. This review describes the mechanisms involved in anticholinesterase-induced oxidative/nitrosative injury in target organs of OPs/CMs, and protection by various agents.
Topics: Animals; Brain; Carbamates; Cholinesterase Inhibitors; Humans; Organophosphates; Oxidative Stress; Oxygen; Reactive Oxygen Species
PubMed: 16518518
DOI: 10.1100/tsw.2006.38 -
Current Genetics May 2016Nε-acetylation is emerging as an abundant post-translational modification of bacterial proteins. Two mechanisms have been identified: one is enzymatic, dependent on an... (Review)
Review
Nε-acetylation is emerging as an abundant post-translational modification of bacterial proteins. Two mechanisms have been identified: one is enzymatic, dependent on an acetyltransferase and acetyl-coenzyme A; the other is non-enzymatic and depends on the reactivity of acetyl phosphate. Some, but not most, of those acetylations are reversed by deacetylases. This review will briefly describe the current status of the field and raise questions that need answering.
Topics: Acetylation; Acetyltransferases; Bacterial Proteins; Humans; Organophosphates; Protein Processing, Post-Translational
PubMed: 26660885
DOI: 10.1007/s00294-015-0552-4 -
Environmental Health Perspectives Nov 2023Evidence of the negative impacts of contemporary use insecticides on sperm concentration has increased over the last few decades; however, meta-analyses on this topic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Evidence of the negative impacts of contemporary use insecticides on sperm concentration has increased over the last few decades; however, meta-analyses on this topic are rare.
OBJECTIVES
This investigation assessed the qualitative and quantitative strength of epidemiological evidence regarding adult exposure to two classes of contemporary use insecticides-organophosphates (OPs) and -methyl carbamates (NMCs)-and sperm concentration using robust and reproducible systematic review and meta-analysis methods.
METHODS
Three scientific databases (PubMed, Scopus, and Web of Science), two U.S. government databases (NIOSHTIC-2 and Science.gov), and five nongovernmental organization websites were searched for relevant primary epidemiological studies published in any language through 11 August 2022. Risk of bias and strength of evidence were evaluated according to Navigation Guide systematic review methodology. Bias-adjusted standardized mean difference effect sizes were calculated and pooled using a three-level, multivariate random-effect meta-analysis model with cluster-robust variance estimation.
RESULTS
Across 20 studies, 21 study populations, 42 effect sizes, and 1,774 adult men, the pooled bias-adjusted standardized mean difference in sperm concentration between adult men more- and less-exposed to OP and NMC insecticides was (95% CI: , ; ). Sensitivity and subgroup analyses explored statistical heterogeneity and validated the model robustness. Although the pooled effect estimate was modified by risk of bias, insecticide class, exposure setting, and recruitment setting, it remained negative in direction across all meta-analyses. The body of evidence was rated to be of moderate quality, with sufficient evidence of an association between higher adult OP and NMC insecticide exposure and lower sperm concentration.
DISCUSSION
This comprehensive investigation found sufficient evidence of an association between higher OP and NMC insecticide exposure and lower sperm concentration in adults. Although additional cohort studies can be beneficial to fill data gaps, the strength of evidence warrants reducing exposure to OP and NMC insecticides now to prevent continued male reproductive harm. https://doi.org/10.1289/EHP12678.
Topics: Humans; Male; Adult; Insecticides; Organophosphates; Semen; Carbamates; Spermatozoa
PubMed: 37966213
DOI: 10.1289/EHP12678