-
Neurotoxicology Jul 2022Exposure to high levels of a cholinesterase inhibiting organophosphorus (OP) agent often results in seizures that progress to status epilepticus (SE). Survivors of...
Exposure to high levels of a cholinesterase inhibiting organophosphorus (OP) agent often results in seizures that progress to status epilepticus (SE). Survivors of OP-induced SE often display neuropathological consequences the days following SE. In the current study, the temporal profile of neuropathology after SE was investigated in a rat model of diisopropylfluorophosphate (DFP)-induced SE. Adult Sprague-Dawley rats were injected with DFP to induce SE for one hour. Following termination of electrographic SE with urethane (0.8 g/kg, sc), cohorts of rats were euthanized 3, 24 and 48 h later and brain tissue was processed to determine immediate early gene and inflammatory mediator expression as well as blood-brain barrier changes and neurodegeneration. After SE rats displayed a time-dependent upregulation of immediate early genes such as cFos and ΔFosB as well as pro-inflammatory mediators COX-2, IL-1β and IL-6. The profile of positive cFos staining, but not ΔFosB, coincided temporally with heightened brain activity measured by cortical electroencephalography (EEG). Neurodegeneration in limbic brain regions was absent 3 h after SE, but prominent 24 h later and continued to increase 48 h after SE. Serum albumin was detected in the cortex 3 h after SE suggesting early loss of blood brain barrier integrity. However, the blood-brain barrier appeared repaired 48 h after SE. This study demonstrates that following OP-poisoning in rats, immediate early gene expression in the brain precedes neuroinflammation followed by erosion of the blood-brain barrier and neurodegeneration. The study also demonstrates that seizure activity in brain nuclei coincides with cFos expression. Together, these studies give insight into the temporal molecular changes in the brain following organophosphate-induced status epilepticus.
Topics: Animals; Brain; Disease Models, Animal; Isoflurophate; Organophosphate Poisoning; Organophosphates; Rats; Rats, Sprague-Dawley; Status Epilepticus
PubMed: 35500718
DOI: 10.1016/j.neuro.2022.04.010 -
Environmental Science & Technology Jan 2022Occupational exposures to flame retardants (FRs), a class of suspected endocrine-disrupting compounds, are of health concern for firefighters. We sought to characterize...
Organophosphate and Organohalogen Flame-Retardant Exposure and Thyroid Hormone Disruption in a Cross-Sectional Study of Female Firefighters and Office Workers from San Francisco.
Occupational exposures to flame retardants (FRs), a class of suspected endocrine-disrupting compounds, are of health concern for firefighters. We sought to characterize exposure to FR compounds and evaluate their association with thyroid hormone levels, a biomarker of early effect, in female firefighters and office workers in San Francisco. In a cross-sectional study, we measured replacement organophosphate and organohalogen FRs in spot urine samples from firefighters ( = 86) and office workers ( = 84), as well as total thyroxine (T) and thyroid-stimulating hormone in plasma for 84 firefighters and 81 office workers. Median bis(1,3-dichloro-2-propyl)phosphate (BDCPP) levels were 5 times higher in firefighters than office workers. Among firefighters, a doubling of BDCPP was associated with a 2.88% decrease (95% confidence interval -5.28, -0.42) in T. We did not observe significant associations between FRs and T among office workers. In the full group, intermediate body mass index and a college education were associated with higher FR levels. The inverse association observed between FRs and T coupled with the lack of studies on women workers and evidence of adverse health effects from FR exposure─including endocrine disruption and breast cancer risk─warrant further research on occupational exposures and identification of opportunities for exposure reduction.
Topics: Cross-Sectional Studies; Female; Firefighters; Flame Retardants; Humans; Organophosphates; San Francisco; Thyroid Hormones
PubMed: 34902963
DOI: 10.1021/acs.est.1c05140 -
Ecotoxicology and Environmental Safety May 2023Triphenyl phosphate (TPHP) is a widely used organophosphate flame retardant and has biological toxicity. Previous studies showed TPHP can restrain testosterone...
Triphenyl phosphate (TPHP) is a widely used organophosphate flame retardant and has biological toxicity. Previous studies showed TPHP can restrain testosterone biosynthesis in Leydig cells, while the underlying mechanisms remain unclear. In this study, C57BL/6J male mice were exposed to 0, 5, 50, and 200 mg/kg B.W. of TPHP for 30 d by oral, as well as TM3 cells were treated with 0, 50, 100, and 200 μM of TPHP for 24 h. Results showed that TPHP induced testes damage, including spermatogenesis disorders and testosterone synthesis inhibition. Meanwhile, TPHP can cause apoptosis in testicular Leydig cells and TM3 cells, as evidenced by the increased apoptosis rate and decreased Bcl-2/Bax ratio. Moreover, TPHP disrupted mitochondrial ultrastructure of testicular Leydig cells and TM3 cells, reduced healthy mitochondria content and depressed mitochondrial membrane potential of TM3 cells, as well as inhibited mitochondrial fusion proteins mitofusin 1 (Mfn1), mitofusin 2 (Mfn2), and optic atrophy 1 (Opa1) expression, without effect on mitochondrial fission proteins dynamin-related protein 1 (Drp1) and fission 1 (Fis1) in testicular tissue and/or TM3 cells. Then, the mitochondrial fusion promoter M1 was used to pre-treat TPHP-exposed TM3 cells to determine the roles of mitochondrial fusion inhibition in TPHP-induced Leydig cells apoptosis. The results showed M1 pretreatment alleviated the above changes and further mitigated TM3 cells apoptosis and testosterone levels decreased, indicating TPHP induced TM3 cells apoptosis by inhibited mitochondrial fusion. Intriguingly, the intervention experiment of N-acetylcysteine (NAC) showed that TPHP-induced mitochondrial fusion inhibition is ROS dependent, because inhibition of ROS overproduction alleviated mitochondrial fusion inhibition, and subsequently relieved TPHP-induced apoptosis in TM3 cells. In summary, above data revealed that apoptosis is a specific mechanism for TPHP-induced male reproductive toxicity, and that ROS-mediated mitochondrial fusion inhibition is responsible for Leydig cells apoptosis caused by TPHP.
Topics: Mice; Animals; Male; Leydig Cells; Reactive Oxygen Species; Mitochondrial Dynamics; Mice, Inbred C57BL; Apoptosis; Mitochondrial Proteins; Organophosphates; Testosterone
PubMed: 37027944
DOI: 10.1016/j.ecoenv.2023.114876 -
Environmental Health : a Global Access... May 2020Organophosphate esters (OPEs) are synthetic chemicals used as flame retardants and plasticizers in a variety of goods. Despite ubiquitous human exposures and laboratory...
BACKGROUND
Organophosphate esters (OPEs) are synthetic chemicals used as flame retardants and plasticizers in a variety of goods. Despite ubiquitous human exposures and laboratory evidence that prenatal OPE exposures may disrupt offspring metabolism, perinatal studies of OPE health effects are limited. The objectives of this study were to: 1) Determine predictors and reproducibility of urinary OPE biomarker concentrations during pregnancy, and 2) Estimate the relation of prenatal OPE exposures with birth outcomes and cord blood adipokine and insulin concentrations.
METHODS
We analyzed five OPE metabolites in urine samples collected at up to three visits during pregnancy from 90 women enrolled in the ORigins of Child Health And Resilience in Development (ORCHARD) pregnancy cohort in Baltimore, MD from 2017 to 2019. To quantify the variability of metabolite concentrations during pregnancy, we calculated intraclass correlation coefficients (ICCs) for each metabolite using mixed effects regression models. Using self-reported questionnaire data collected during gestation, we assessed possible sociodemographic and environmental/behavioral predictors of each OPE metabolite using generalized estimating equations to account for repeated exposure measures. We ascertained birth outcomes of 76 offspring from medical records, including weight-for-gestational age, length, ponderal index, and gestational age. In a subset of 37 infants, we measured cord blood concentrations of leptin, adiponectin, and insulin. To account for repeated exposure measures, we used linear structural equation models to assess the relations of standard deviation (SD) increases in prenatal OPE metabolite factor scores with continuous birth outcomes and cord blood biomarker concentrations.
RESULTS
ICCs ranged from 0.09 for isopropylphenyl-phenyl phosphate (ip-PPP) to 0.59 for bis(1,3-dichloro-2-propyl) phosphate (BDCIPP). We observed little consistency in environmental or behavioral predictors of OPE exposures, although concentrations were generally lower for samples collected in the afternoon compared to morning and winter compared to other seasons. In adjusted analyses, a SD increase in BDCIPP concentration was associated with a 0.06 g/cm (95% CI: 0.00, 0.12) greater ponderal index. A SD increase in BDCIPP was associated with a 0.37 (95% CI: - 0.62, - 0.13) SD lower insulin concentration and 0.24 (95% CI: - 0.39, - 0.08) SD lower leptin concentration. Other OPEs were not associated with infant outcomes.
CONCLUSIONS
These findings suggest some OPEs may be metabolic disruptors warranting investigation in larger studies.
Topics: Adolescent; Adult; Baltimore; Biomarkers; Environmental Pollutants; Esters; Female; Fetal Blood; Flame Retardants; Humans; Infant, Newborn; Male; Maternal Exposure; Middle Aged; Organophosphates; Plasticizers; Pregnancy; Reproducibility of Results; Urban Population; Young Adult
PubMed: 32448197
DOI: 10.1186/s12940-020-00610-0 -
European Review For Medical and... Jan 2022The organophosphate compounds chlorpyrifos (O, O-diethyl O-[3,5,6-trichloro-2-pyridinyl] phosphorothioate, CPF) and phenyl saligenin phosphate (PSP) have been widely...
OBJECTIVE
The organophosphate compounds chlorpyrifos (O, O-diethyl O-[3,5,6-trichloro-2-pyridinyl] phosphorothioate, CPF) and phenyl saligenin phosphate (PSP) have been widely implicated in developmental neurotoxicity and neurodegeneration. However, the underlying mechanism remains unclear. Transglutaminase (TG)2 is a calcium ion (Ca2+)-dependent enzyme with an important role in neuronal cell outgrowth and differentiation and in neurotoxin activity and is modulated by organophosphates.
MATERIALS AND METHODS
We studied TG2 activity modulation by CPO and PSP during differentiation in C6 glioma cells. We studied the effects of CPO or PSP treatment with or without the TG2 inhibitor Z-DON and identified potential TG2 protein substrates via mass spectrometry.
RESULTS
PSP and CPO did not affect cell viability but affected TG2 activity in differentiating cells. Our results indicate that the organophosphate-induced amine incorporation activity of TG2 may have a direct effect on neuronal outgrowth, differentiation, and cell survival by modifying several essential microtubule proteins, including tubulin. Inhibiting TG2 reduced neurite length but not cell survival.
CONCLUSIONS
TG2 inhibitors can protect against organophosphate-induced neuropathy and could be used for developing novel therapeutic strategies for treating brain cancer and neurodegenerative disorders.
Topics: Animals; Cell Differentiation; GTP-Binding Proteins; Organophosphates; Protein Glutamine gamma Glutamyltransferase 2; Rats; Transglutaminases
PubMed: 35049033
DOI: 10.26355/eurrev_202201_27766 -
Frontiers in Public Health 2023The relationship between exposure to organophosphate esters (OPEs) and the risk of developing overactive bladder (OAB) is uncertain. The purpose of this study is to...
BACKGROUND
The relationship between exposure to organophosphate esters (OPEs) and the risk of developing overactive bladder (OAB) is uncertain. The purpose of this study is to examine the potential link between urinary metabolites of organophosphate esters and OAB.
METHOD
Data from the National Health and Nutrition Examination Survey (NHANES) database of the 2011-2016 cycles were utilized. Four urinary metabolites of organophosphate esters: diphenyl phosphate (DPHP), bis (1,3-dichloro-2-propyl) phosphate (BDCPP), bis (2-chloroethyl) phosphate (BCEP), and dibutyl phosphate (DBUP) were included in the study. Multivariate logistic regression and restricted cubic spline (RCS) were used to evaluate the relationship between urinary OPEs metabolites and OAB. Interaction analysis was conducted on subgroups to confirm the findings.
RESULTS
A total of 3,443 United States (US) adults aged 20 years or older were included in the study, of whom 597 participants were considered to have OAB. After adjusting for potential confounding factors, we found a positive association between DPHP and the risk of overactive bladder. The risk of overactive bladder increased with increasing DPHP concentrations compared with quartile 1 (quartile 2, OR = 1.19, 95% CI, 0.82-1.73, = 0.34; quartile 3, OR = 1.67, 95% CI, 1.10-2.53, = 0.02; Q4, OR = 1.75, 95% CI, 1.26-2.43, = 0.002). However, after dividing the participants by gender, only the female group retained consistent results. Additionally, restricted cubic spline analysis revealed a nonlinear dose-response correlation between DPHP and OAB in female participants. In the subgroup analysis based on age, race, body mass index (BMI), recreational activity, smoking status, drinking status, hypertension, diabetes, and stroke, the interaction analysis revealed that the findings were uniform.
CONCLUSION
Our findings indicate that exposure to DPHP could elevate the risk of OAB in US adult females. Further experimental studies are needed to explore the underlying mechanism in the future.
Topics: Humans; Adult; United States; Female; Cross-Sectional Studies; Nutrition Surveys; Urinary Bladder, Overactive; Organophosphates; Phosphates
PubMed: 38026372
DOI: 10.3389/fpubh.2023.1186848 -
Environmental Research May 2023Exposure to organophosphate (OP) pesticides during pregnancy has been linked to deficiencies of neurobehavioral development in childhood; however, the molecular...
BACKGROUND
Exposure to organophosphate (OP) pesticides during pregnancy has been linked to deficiencies of neurobehavioral development in childhood; however, the molecular mechanisms underlying this association remain elusive. The placenta plays a crucial role in protecting the fetus from environmental insults and safeguarding proper fetal development including neurodevelopment. The aim of our study is to evaluate changes in the placental transcriptome associated with prenatal OP exposure.
METHODS
Pregnant farm workers from two agricultural districts in northern Thailand were recruited for the Study of Asian Women and Offspring's Development and Environmental Exposures (SAWASDEE) from 2017 to 2019. For 254 participants, we measured maternal urinary concentrations of six nonspecific dialkyl phosphates (DAP) metabolites in early, middle, and late pregnancy. In parallel, we profiled the term placental transcriptome from the same participants using RNA-Sequencing and performed Weighted Gene co-expression Network Analysis (WGCNA). Generalized linear regression modeling was used to examine associations of urinary OP metabolites and placental co-expression module eigenvalues.
RESULTS
We identified 21 gene co-expression modules in the placenta. From the six DAP metabolites assayed, diethylphosphate (DEP) and diethylthiophosphate (DETP) were detected in more than 70% of the urine samples. Significant associations between DEP at multiple time points and two specific placental gene modules were observed. The 'black' module, enriched in genes involved in epithelial-to-mesenchymal transition (EMT) and hypoxia, was negatively associated with DEP in early (p = 0.034), and late pregnancies (p = 0.016). The 'lightgreen' module, enriched in genes involved in myogenesis and EMT, was negatively associated with DEP in late pregnancy (p = 0.010). We observed 2 hub genes (CELSR1 and PYCR1) of the 'black' module to be negatively associated with DEP in early and late pregnancies.
CONCLUSIONS
Our results suggest that prenatal OP exposure may disrupt placental gene networks in a time-dependent manner. Such transcriptomic effects may lead to down-stream changes in placental function that ultimately affect the developing fetus.
Topics: Female; Pregnancy; Humans; Gene Regulatory Networks; Pesticides; Organophosphates; Maternal Exposure; Placenta; Organophosphorus Compounds; Insecticides; Environmental Exposure; Phosphates; Prenatal Exposure Delayed Effects
PubMed: 36828252
DOI: 10.1016/j.envres.2023.115490 -
Proceedings of the National Academy of... Oct 2019Insecticides allow control of agricultural pests and disease vectors and are vital for global food security and health. The evolution of resistance to insecticides, such...
Insecticides allow control of agricultural pests and disease vectors and are vital for global food security and health. The evolution of resistance to insecticides, such as organophosphates (OPs), is a serious and growing concern. OP resistance often involves sequestration or hydrolysis of OPs by carboxylesterases. Inhibiting carboxylesterases could, therefore, restore the effectiveness of OPs for which resistance has evolved. Here, we use covalent virtual screening to produce nano-/picomolar boronic acid inhibitors of the carboxylesterase αE7 from the agricultural pest as well as a common Gly137Asp αE7 mutant that confers OP resistance. These inhibitors, with high selectivity against human acetylcholinesterase and low to no toxicity in human cells and in mice, act synergistically with the OPs diazinon and malathion to reduce the amount of OP required to kill by up to 16-fold and abolish resistance. The compounds exhibit broad utility in significantly potentiating another OP, chlorpyrifos, against the common pest, the peach-potato aphid (). These compounds represent a solution to OP resistance as well as to environmental concerns regarding overuse of OPs, allowing significant reduction of use without compromising efficacy.
Topics: Acetylcholinesterase; Animals; Aphids; Carboxylic Ester Hydrolases; Cell Line; Diazinon; Female; HEK293 Cells; Humans; Insecticide Resistance; Insecticides; Malathion; Mice; Mice, Inbred C57BL; Organophosphates
PubMed: 31575743
DOI: 10.1073/pnas.1909130116 -
Molecules (Basel, Switzerland) Mar 2023As a substitute for banned brominated flame retardants (BFRs), the use of organophosphate esters (OPEs) increased year by year with the increase in industrial production... (Review)
Review
As a substitute for banned brominated flame retardants (BFRs), the use of organophosphate esters (OPEs) increased year by year with the increase in industrial production and living demand. It was inevitable that OPEs would be discharged into wastewater in excess, which posed a great threat to the health of human beings and aquatic organisms. In the past few decades, people used various methods to remove refractory OPEs. This paper reviewed the photocatalysis method, the adsorption method with wide applicability, and the biological method mainly relying on enzymolysis and hydrolysis to degrade OPEs in water. All three of these methods had the advantages of high removal efficiency and environmental protection for various organic pollutants. The degradation efficiency of OPEs, degradation mechanisms, and conversion products of OPEs by three methods were discussed and summarized. Finally, the development prospects and challenges of OPEs' degradation technology were discussed.
Topics: Humans; Water; Flame Retardants; Adsorption; Organophosphates; Esters; Environmental Monitoring; China
PubMed: 37049746
DOI: 10.3390/molecules28072983 -
The Science of the Total Environment Aug 2021Contemporary human populations are exposed to elevated concentrations of organophosphate esters (OPEs) and phthalates. Some metabolites have been linked with altered...
BACKGROUND
Contemporary human populations are exposed to elevated concentrations of organophosphate esters (OPEs) and phthalates. Some metabolites have been linked with altered thyroid function, however, inconsistencies exist across thyroid function biomarkers. Research on OPEs is sparse, particularly during pregnancy, when maintaining normal thyroid function is critical to maternal and fetal health. In this paper, we aimed to characterize relationships between OPEs and phthalates exposure and maternal thyroid function during pregnancy, using a cross-sectional investigation of pregnant women nested within the Norwegian Mother, Father, and Child Cohort (MoBa).
METHODS
We included 473 pregnant women, who were euthyroid and provided bio-samples at 17 weeks' gestation (2004-2008). Four OPE and six phthalate metabolites were measured from urine; six thyroid function biomarkers were estimated from blood. Relationships between thyroid function biomarkers and log-transformed concentrations of OPE and phthalate metabolites were characterized using two approaches that both accounted for confounding by co-exposures: co-pollutant adjusted general linear model (GLM) and Bayesian Kernal Machine Regression (BKMR).
RESULTS
We restricted our analysis to common-detect OPE and phthalate metabolites (>94%): diphenyl phosphate (DPHP), di-n-butyl phosphate (DNBP), and all phthalate metabolites. In GLM, pregnant women with summed di-isononyl phthalate metabolites (∑DiNP) concentrations in the 75th percentile had a 0.37 ng/μg lower total triiodothyronine (TT3): total thyroxine (TT4) ratio (95% credible interval: [-0.59, -0.15]) as compared to those in the 25th percentile, possibly due to small but diverging influences on TT3 (-1.99 ng/dL [-4.52, 0.53]) and TT4 (0.13 μg/dL [-0.01, 0.26]). Similar trends were observed for DNBP and inverse associations were observed for DPHP, monoethyl phthalate, mono-isobutyl phthalate, and mono-n-butyl phthalate. Most associations observed in co-pollutants adjusted GLMs were attenuated towards the null in BKMR, except for the case of ∑DiNP and TT3:TT4 ratio (-0.48 [-0.96, 0.003]).
CONCLUSIONS
Maternal thyroid function varied modestly with ∑DiNP, whereas results for DPHP varied by the type of statistical models.
Topics: Bayes Theorem; Child; Cross-Sectional Studies; Environmental Exposure; Environmental Pollutants; Esters; Female; Humans; Maternal Exposure; Norway; Organophosphates; Phthalic Acids; Pregnancy; Thyroid Gland
PubMed: 33839654
DOI: 10.1016/j.scitotenv.2021.146709