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Neurobiology of Disease Oct 2023Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including...
Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication.
Topics: Rats; Animals; Blood-Brain Barrier; Rats, Sprague-Dawley; Organophosphates; Status Epilepticus; Seizures; Brain
PubMed: 37797902
DOI: 10.1016/j.nbd.2023.106316 -
Ecotoxicology and Environmental Safety Apr 2023Whether exposure to organophosphate esters (OPEs) is associated with metabolic dysfunction-associated fatty liver disease (MAFLD) and nonalcoholic fatty liver disease...
Whether exposure to organophosphate esters (OPEs) is associated with metabolic dysfunction-associated fatty liver disease (MAFLD) and nonalcoholic fatty liver disease (NAFLD) remains unclear. A healthy diet is crucial to metabolic health and dietary intake is also an important route for OPEs exposure. However, the joint associations of OPEs, diet quality, and the effect modification by diet quality remain unknown. This study comprised 2618 adults with complete data on 6 urinary OPEs metabolites, 24 h dietary recalls, and definitions of NAFLD and MAFLD from the 2011-2018 National Health and Nutrition Examination Survey cycles. Multivariable binary logistic regression was applied to assess the associations of OPEs metabolites with NAFLD, MAFLD, and components of MAFLD. We also adopted the quantile g-Computation method to examine the associations of OPEs metabolites mixture. Our results revealed that OPEs metabolites mixture and three individual metabolites [i.e., bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), bis(2-chloroethyl) phosphate, and diphenyl phosphate] were significantly and positively associated with NAFLD and MAFLD (P-trend<0.001), with BDCIPP being identified as the dominant metabolite, whereas the 4 diet quality scores were monotonically and inversely associated with both MAFLD and NAFLD (P-trend<0.001). Of note, 4 diet quality scores were by and large negatively associated with BDCIPP, but not with other OPEs metabolites. Joint association analyses revealed that individuals with higher diet quality and lower BDCIPP concentration tend to have lower odds of having MAFLD and NAFLD in comparison with people in the low diet quality and high BDCIPP group, but the associations of BDCIPP were not modified by diet quality. Our findings suggest that certain OPEs metabolites and diet quality exhibited opposing associations with both MAFLD and NAFLD. Individuals adherent to a healthier diet may have a lower level of certain OPEs metabolites, and thus could have lower odds of having NAFLD and MAFLD.
Topics: Humans; Adult; Non-alcoholic Fatty Liver Disease; Nutrition Surveys; Esters; Organophosphates; Diet; Phosphates
PubMed: 36889207
DOI: 10.1016/j.ecoenv.2023.114720 -
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 -
International Journal of Environmental... Sep 2020Childhood wheeze may be related to pesticide exposure, and diet and genetics (Paroxonase; ) may modify the effects of exposure.
BACKGROUND
Childhood wheeze may be related to pesticide exposure, and diet and genetics (Paroxonase; ) may modify the effects of exposure.
METHODS
We analyzed data from the HOME Study, a prospective pregnancy and birth cohort, to examine the association of gestational urinary organophosphate (OP) and pyrethroid (3PBA) metabolite concentrations with child wheeze, forced expiratory volume in one second (FEV1) at ages 4 and 5 years, and wheeze trajectory patterns through age 8 years.
RESULTS
Among 367 singletons, the frequency of wheeze ranged from 10.6% to 24.1% at each measurement age. OP and 3PBA metabolite concentrations were not associated with wheeze at 8 years or from birth to 8 years, but there were three significant interactions: (1) maternal daily fruit and vegetable consumption (less than daily consumption and increasing 3PBA was associated with wheeze at age 8 years, OR = 1.40), (2) maternal allele (CT/TT genotypes and high DE was associated with wheeze at age 8 years, OR = 2.13, 2.74) and (3) alleles (QR/RR genotypes with higher diethylphosphate (DE) and dialkyl phosphate (DAP) were associated with wheeze at age 8 years, OR = 3.84). Pesticide metabolites were not consistently related to FEV1 or wheeze trajectory.
CONCLUSIONS
Gestational OP and 3PBA metabolites were associated with child respiratory outcomes in participants with maternal dietary and genetic susceptibility.
Topics: Aryldialkylphosphatase; Child; Child, Preschool; Female; Humans; Male; Maternal Exposure; Organophosphates; Organophosphorus Compounds; Pesticides; Pregnancy; Prospective Studies; Respiratory Sounds; Respiratory Tract Diseases
PubMed: 33007939
DOI: 10.3390/ijerph17197165 -
Environmental Science & Technology Jan 2021Eleven organophosphate esters (OPEs) were detected in surface water and sediment samples from yearly sampling (2013-2018) in the Canadian Arctic. In water samples,...
Eleven organophosphate esters (OPEs) were detected in surface water and sediment samples from yearly sampling (2013-2018) in the Canadian Arctic. In water samples, ∑chlorinated-OPEs (Cl-OPEs) concentrations exceeded ∑non-chlorinated-OPEs (non-Cl-OPEs) with median concentrations of 10 ng L and 1.3 ng L, respectively. In sediment samples, ∑Cl-OPEs and ∑nonchlorinated-OPEs had median concentrations of 4.5 and 2.5 ng g, respectively. High concentrations of OPEs in samples from the Mackenzie River plume suggest riverine discharge as an OPE source to the Canadian Arctic. The prevalence of OPEs at other sites is consistent with long-range transport. The OPE inventory of the Canadian Arctic Ocean representative of years 2013-2018 was estimated at 450-16,000 tonnes with a median ∑OPE mass of 4100 tonnes with >99% of the OPE inventory estimated to be in the water column. These results highlight the importance of OPEs as water-based Arctic contaminants subject to long-range transport and local sources. The high OPE inventory in the water column of the Canadian Arctic Ocean points to the need for international regulatory mechanisms for persistent and mobile organic contaminants (PMOCs) that are not covered by the risk assessment criteria of the Stockholm Convention.
Topics: Arctic Regions; Canada; China; Environmental Monitoring; Esters; Flame Retardants; Oceans and Seas; Organophosphates
PubMed: 33305563
DOI: 10.1021/acs.est.0c04422 -
Revista Espanola de Quimioterapia :... Sep 2021The most relevant information on the clinical uses of tedizolid from studies published in the last 18 months is presented in this brief review. The most important data... (Review)
Review
The most relevant information on the clinical uses of tedizolid from studies published in the last 18 months is presented in this brief review. The most important data indicate better tolerance and safety profile of long-term therapeutic regimes in off-label indications, such as osteoarticular infections and those caused by mycobacteria. Its lower risk of hazardous interactions compared to linezolid should be emphasized. Furthermore, tedizolid in its combination with rifampicin shows a more favourable way of acting as demonstrated in vitro and in vivo studies. A recent trial also opens the door for its potential use in nosocomial pneumonia caused by Gram-positive bacteria.
Topics: Anti-Bacterial Agents; Humans; Microbial Sensitivity Tests; Organophosphates; Oxazoles; Oxazolidinones; Tetrazoles
PubMed: 34598418
DOI: 10.37201/req/s01.06.2021 -
Nature Communications Aug 2023Resistance to insecticides in Anopheles mosquitoes threatens the effectiveness of malaria control, but the genetics of resistance are only partially understood. We...
Resistance to insecticides in Anopheles mosquitoes threatens the effectiveness of malaria control, but the genetics of resistance are only partially understood. We performed a large scale multi-country genome-wide association study of resistance to two widely used insecticides: deltamethrin and pirimiphos-methyl, using sequencing data from An. gambiae and An. coluzzii from ten locations in West Africa. Resistance was highly multi-genic, multi-allelic and variable between populations. While the strongest and most consistent association with deltamethrin resistance came from Cyp6aa1, this was based on several independent copy number variants (CNVs) in An. coluzzii, and on a non-CNV haplotype in An. gambiae. For pirimiphos-methyl, signals included Ace1, cytochrome P450s, glutathione S-transferases and the nAChR target site of neonicotinoid insecticides. The regions around Cyp9k1 and the Tep family of immune genes showed evidence of cross-resistance to both insecticides. These locally-varying, multi-allelic patterns highlight the challenges involved in genomic monitoring of resistance, and may form the basis for improved surveillance methods.
Topics: Animals; Anopheles; Insecticides; Genome-Wide Association Study; Organophosphates; Pyrethrins
PubMed: 37587104
DOI: 10.1038/s41467-023-40693-0 -
Viruses Aug 2021Human cytomegalovirus (HCMV) uses two major ways for virus dissemination: infection by cell-free virus and direct cell-to-cell spread. Neutralizing antibodies can...
Human cytomegalovirus (HCMV) uses two major ways for virus dissemination: infection by cell-free virus and direct cell-to-cell spread. Neutralizing antibodies can efficiently inhibit infection by cell-free virus but mostly fail to prevent cell-to-cell transmission. Here, we show that the 'molecular tweezer' CLR01, a broad-spectrum antiviral agent, is not only highly active against infection with cell-free virus but most remarkably inhibits antibody-resistant direct cell-to-cell spread of HCMV. The inhibition of cell-to-cell spread by CLR01 was not limited to HCMV but was also shown for the alphaherpesviruses herpes simplex viruses 1 and 2 (HSV-1, -2). CLR01 is a rapid acting small molecule that inhibits HCMV entry at the attachment and penetration steps. Electron microscopy of extracellular virus particles indicated damage of the viral envelope by CLR01, which likely impairs the infectivity of virus particles. The rapid inactivation of viral particles by CLR01, the viral envelope as the main target, and the inhibition of virus entry at different stages are presumably the key to inhibition of cell-free virus infection and cell-to-cell spread by CLR01. Importance: While cell-free spread enables the human cytomegalovirus (HCMV) and other herpesviruses to transmit between hosts, direct cell-to-cell spread is thought to be more relevant for in vivo dissemination within infected tissues. Cell-to-cell spread is resistant to neutralizing antibodies, thus contributing to the maintenance of virus infection and virus dissemination in the presence of an intact immune system. Therefore, it would be therapeutically interesting to target this mode of spread in order to treat severe HCMV infections and to prevent dissemination of virus within the infected host. The molecular tweezer CLR01 exhibits broad-spectrum antiviral activity against a number of enveloped viruses and efficiently blocks antibody-resistant cell-to-cell spread of HCMV, thus representing a novel class of small molecules with promising antiviral activity.
Topics: Antibodies, Neutralizing; Bridged-Ring Compounds; Cell Communication; Cell Line; Cytomegalovirus; Fibroblasts; Foreskin; Humans; Male; Organophosphates; Virus Internalization; Virus Replication
PubMed: 34578265
DOI: 10.3390/v13091685 -
Frontiers in Endocrinology 2024Organophosphate esters (OPEs) may interfere with thyroid function, but the relationship between OPEs and thyroid disease remains unclear. This study aims to elucidate...
Association between urinary organophosphate ester metabolite exposure and thyroid disease risk among US adults: National Health and Nutrition Examination Survey 2011-2014.
BACKGROUND
Organophosphate esters (OPEs) may interfere with thyroid function, but the relationship between OPEs and thyroid disease remains unclear. This study aims to elucidate the relationship between OPEs exposure and thyroid disease risk in the general population in the United States.
METHOD
Data were obtained from the 2011-2014 National Health and Nutrition Examination Survey cycle. All participants were tested for seven OPE metabolites in their urine and answered questions about whether they had thyroid disease through questionnaires. Logistic regression was employed to analyze the association between exposure to individual OPE metabolites and thyroid disease. Weighted Quantile Sum (WQS) regression modeling was utilized to assess exposure to mixed OPE metabolites and risk of thyroid disease. Bayesian kernel machine regression(BKMR) models to analyze the overall mixed effect of OPE metabolites.
RESULT
A total of 2,449 participants were included in the study, 228 of whom had a history of thyroid disease. Bis(1,3-dichloro-2-propyl) phos (BDCPP), Diphenyl phosphate (DPHP) and Bis(2-chloroethyl) phosphate (BCEP) were the top three metabolites with the highest detection rates of 91.75%, 90.77% and 86.57%, respectively. In multivariate logistic regression models, after adjustment for confounding variables, individuals with the highest tertile level of BCEP were significantly and positively associated with increased risk of thyroid disease (OR=1.57, 95% CI=1.04-2.36), using the lowest tertile level as reference. In the positive WQS regression model, after correcting for confounding variables, mixed exposure to OPE metabolites was significantly positively associated with increased risk of thyroid disease (OR=1.03, 95% CI=1.01-1.06), with BCEP and DPHP having high weights. In the BKMR model, the overall effect of mixed exposure to OPE metabolites was not statistically significant, but univariate exposure response trends showed that the risk of thyroid disease decreased and then increased as BCEP exposure levels increased.
CONCLUSION
The study revealed a significant association between exposure to OPE metabolites and an increased risk of thyroid disease, with BCEP emerging as the primary contributor. The risk of thyroid disease exhibits a J-shaped pattern, whereby the risk initially decreases and subsequently increases with rising levels of BCEP exposure. Additional studies are required to validate the association between OPEs and thyroid diseases.
Topics: Adult; Humans; United States; Nutrition Surveys; Bayes Theorem; Flame Retardants; Organophosphates; Thyroid Diseases; Phosphates; Esters
PubMed: 38405137
DOI: 10.3389/fendo.2024.1329247 -
Andes Pediatrica : Revista Chilena de... Oct 2021Accidental or intentional intoxication by organophosphates, which are toxic substances that inhibit acetylcholinesterase, constitutes a serious public health problem...
INTRODUCTION
Accidental or intentional intoxication by organophosphates, which are toxic substances that inhibit acetylcholinesterase, constitutes a serious public health problem worldwide, with a greater impact in developing countries. Chronic intoxication during pregnancy with alterations in neurodevelopment and fetal growth has been described.
OBJECTIVE
To describe an unusual case of transplacentally acquired organophosphorus poisoning, highlighting the clinical presentation, the management with atropine, and the neurological outcome.
CLINICAL CASE
36-weeks premature newborn, whose mother presented acute intentional organophosphorus poisoning 17 hours before birth. The patient was born by emergency C-section, without respiratory distress, with bradycardia, hypotonia, miosis, and bron- chorrhea, as well as clinical signs and laboratory evidence of acute poisoning, with severe metabolic acidosis, and decreased cholinesterase activity. She required advanced resuscitation, management in the Neonatal Intensive Care Unit with invasive ventilation, inotropes, and repeated doses of atropine. She evolved with left hemiparesis and convulsive syndrome that was treated with phenobarbital. She was discharged at 34 days of life with her mother, under custody and supervision of social and family welfare. Treatment and follow-up were suspended until her first year of life when her custody was transferred to an aunt. In neurological control at 18 months, she presented persistence of hemiparesis and speech-language delay, without new seizures.
CONCLUSIONS
Organophosphorus poisoning is very rare in the neonatal period and due to the absence of guidelines for the management of this type of patients its treatment is challenging and must be individualized, multidisciplinary, evaluating the risk and benefit of each intervention.
Topics: Acetylcholinesterase; Atropine; Cholinesterases; Female; Humans; Infant, Newborn; Organophosphate Poisoning; Organophosphates; Pregnancy
PubMed: 35319584
DOI: 10.32641/andespediatr.v92i5.3275