Long-term safety and impact of immune recovery in heavily treatment-experienced adults receiving fostemsavir for up to 5 years in the phase 3 BRIGHTE study.

Introduction: Fostemsavir is a gp120-directed attachment inhibitor approved for heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. We provide detailed week 240 safety results from the BRIGHTE study and evaluate the impact of immune recovery on safety outcomes. Methods: The phase 3 BRIGHTE trial is ongoing; data for this analysis were collected from the first participant's first visit (February 23, 2015) through the last participant's last visit for week 240 (March 22, 2021). Safety endpoints were assessed in participants who received fostemsavir + optimized background therapy. In participants with baseline CD4+ T-cell count <200 cells/mm3, exposure-adjusted adverse event (AE) rates were assessed among subgroups with or without CD4+ T-cell count ≥200 cells/mm3 at any time during 48-week analysis periods through week 192. Results: Through a median of 258 weeks (range, 0.14-319) of treatment, discontinuations due to AEs occurred in 30/371 (8%) participants. Serious AEs were reported in 177/371 (48%) participants, including 16 drug-related events in 13 (4%) participants. Thirty-five (9%) deaths occurred, primarily related to AIDS or acute infections. COVID-19-related events occurred in 25 (7%) participants; all resolved without sequelae. Among participants with baseline CD4+ T-cell count <200 cells/mm3, 122/162 (75%) achieved CD4+ T-cell count ≥200 cells/mm3 at week 192. Exposure-adjusted AE rates were markedly lower among participants achieving CD4+ T-cell count ≥200 cells/mm3 at any time vs those sustaining <200 cells/mm3. No new AIDS-defining events were reported after week 48 in participants with CD4+ T-cell count ≥200 cells/mm3. Conclusions: Cumulative safety findings through the BRIGHTE 240-week interim analysis are consistent with other trials in HTE participants with advanced HIV-1 and comorbid disease. Reduced rates of AIDS-defining events and AEs were observed in participants with immunologic recovery on fostemsavir-based treatment. Clinical trial number: NCT02362503, https://clinicaltrials.gov/study/NCT02362503.

Early childhood exposure to environmental phenols and parabens, phthalates, organophosphate pesticides, and trace elements in association with attention deficit hyperactivity disorder (ADHD) symptoms in the CHARGE study.

BACKGROUND: A growing body of literature investigated childhood exposure to environmental chemicals in association with attention-deficit/hyperactivity disorder (ADHD) symptoms, but limited studies considered urinary mixtures of multiple chemical classes. This study examined associations of concurrent exposure to non-persistent chemicals with ADHD symptoms in children diagnosed with autism spectrum disorder (ASD), developmental delay (DD), and typical development (TD). METHODS: A total of 549 children aged 2-5 years from the Childhood Autism Risks from Genetics and Environment (CHARGE) case-control study were administered the Aberrant Behavior Checklist (ABC). This study focused on the ADHD/noncompliance subscale and its two subdomains (hyperactivity/impulsivity, inattention). Sixty-two chemicals from four classes (phenols/parabens, phthalates, organophosphate pesticides, trace elements) were quantified in child urine samples, and 43 chemicals detected in > 70% samples were used to investigate their associations with ADHD symptoms. Negative binomial regression was used for single-chemical analysis, and weighted quantile sum regression with repeated holdout validation was applied for mixture analysis for each chemical class and all chemicals. The mixture analyses were further stratified by diagnostic group. RESULTS: A phthalate metabolite mixture was associated with higher ADHD/noncompliance scores (median count ratio [CR] = 1.10; 2.5th, 97.5th percentile: 1.00, 1.21), especially hyperactivity/impulsivity (median CR = 1.09; 2.5th, 97.5th percentile: 1.00, 1.25). The possible contributors to these mixture effects were di-2-ethylhexyl phthalate (DEHP) metabolites and mono-2-heptyl phthalate (MHPP). These associations were likely driven by children with ASD as these were observed among children with ASD, but not among TD or those with DD. Additionally, among children with ASD, a mixture of all chemicals was associated with ADHD/noncompliance and hyperactivity/impulsivity, and possible contributors were 3,4-dihydroxy benzoic acid, DEHP metabolites, MHPP, mono-n-butyl phthalate, and cadmium. CONCLUSIONS: Early childhood exposure to a phthalate mixture was associated with ADHD symptoms, particularly among children with ASD. While the diverse diagnostic profiles limited generalizability, our findings suggest a potential link between phthalate exposure and the comorbidity of ASD and ADHD.

Effects of additional oral fosravuconazole l-lysine ethanolate therapy following inadequate response to initial treatment for onychomycosis: A multicenter, randomized controlled trial.

Onychomycosis, a superficial fungal infection, develops when dermatophytes infect nail plate and beds. Fosravuconazole l-lysine ethanolate (F-RVCZ), a fourth-generation azole antifungal agent with potent antifungal activity and few drug interactions, was highly effective in a clinical trial, with a complete cure rate of 59.4% at 48 weeks after treatment initiation. However, some patients were not completely cured. To achieve a higher complete cure rate, additional therapy needs to be examined. We aimed to examine (i) the criteria for additional F-RVCZ therapy in patients with an inadequate response to initial F-RVCZ treatment for onychomycosis; (ii) the timing of additional therapy; and (iii) the effects of additional treatment. This was a multicenter, open-label, three-arm randomized clinical trial. Patients with onychomycosis were orally administered an approved dose of F-RVCZ for 12 weeks, and its efficacy was assessed at week 24. Patients who demonstrated ≥55% reduction in nail involvement ratio at week 24 were included in Group X and followed up. Patients with <55% reduction were randomly assigned to follow-up (Group A) or additional treatment (Group B) groups. The complete cure rate at week 72 in Group X was 73.3%. In Groups A and B, the complete cure rates were 29.6% and 46.7%, respectively, and were significantly different (P = 0.0414, odds ratio 2.08). During the study, 63 adverse drug reactions were recorded in 59 of the 318 patients (18.6%), for which a causal relationship with F-RVCZ could not be ruled out. In Group B, three of 75 patients (4.0%) experienced three adverse drug reactions, all observed during additional treatment; none were serious. A high complete cure rate is possible without additional F-RVCZ treatment when nail involvement decreases by ≥55% at week 24; however, when the reduction is <55% at week 24, additional F-RVCZ treatment should be considered to improve the cure rate.

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.

Chronic Epilepsy and Mossy Fiber Sprouting Following Organophosphate-Induced Status Epilepticus in Rats.

Organophosphate (OP) compounds are highly toxic and include pesticides and chemical warfare nerve agents. OP exposure inhibits the acetylcholinesterase enzyme, causing cholinergic overstimulation that can evolve into status epilepticus (SE) and produce lethality. Furthermore, OP-induced SE survival is associated with mood and memory dysfunction and spontaneous recurrent seizures (SRS). In male Sprague-Dawley rats, we assessed hippocampal pathology and chronic SRS following SE induced by administration of OP agents paraoxon (2 mg/kg, s.c.), diisopropyl fluorophosphate (4 mg/kg, s.c.), or O-isopropyl methylphosphonofluoridate (GB; sarin) (2 mg/kg, s.c.), immediately followed by atropine and 2-PAM. At 1-hour post-OP-induced SE onset, midazolam was administered to control SE. Approximately 6 months after OP-induced SE, SRS were evaluated using video and electroencephalography monitoring. Histopathology was conducted using hematoxylin and eosin (H&E), while silver sulfide (Timm) staining was used to assess mossy fiber sprouting (MFS). Across all the OP agents, over 60% of rats that survived OP-induced SE developed chronic SRS. H&E staining revealed a significant hippocampal neuronal loss, while Timm staining revealed extensive MFS within the inner molecular region of the dentate gyrus. This study demonstrates that OP-induced SE is associated with hippocampal neuronal loss, extensive MFS, and the development of SRS, all hallmarks of chronic epilepsy. SIGNIFICANCE STATEMENT: Models of organophosphate (OP)-induced SE offer a unique resource to identify molecular mechanisms contributing to neuropathology and the development of chronic OP morbidities. These models could allow the screening of targeted therapeutics for efficacious treatment strategies for OP toxicities.

Protective Activity of Novel Hydrophilic Synthetic Neurosteroids on Organophosphate Status Epilepticus-induced Chronic Epileptic Seizures, Non-Convulsive Discharges, High-Frequency Oscillations, and Electrographic Ictal Biomarkers.

Nerve agents and organophosphates (OP) are neurotoxic chemicals that induce acute seizures, status epilepticus (SE), and mortality. Long-term neurologic and neurodegenerative effects manifest months to years after OP exposure. Current benzodiazepine anticonvulsants are ineffective in preventing such long-term neurobehavioral and neuropathological changes. New and effective anticonvulsants are needed for OP intoxication, especially for mitigating the long-term sequelae after acute exposure. We developed neurosteroids as novel anticonvulsants and neuroprotectants in OP exposure models. In this study, we evaluated the long-term efficacy of novel synthetic neurosteroids in preventing the development of chronic epilepsy and hyperexcitable ictal events in a rat OP model of SE. Rats were exposed to the OP nerve agent surrogate diisopropylfluorophosphate (DFP), and the experimental groups were treated with the synthetic neurosteroid valaxanolone (VX) or lysaxanolone (LX) 40 minutes post-exposure in conjunction with midazolam. Video-electroencephalography was monitored for two months to assess spontaneous recurrent seizures (SRS), epileptiform discharges, interictal spikes, and high-frequency oscillations (HFOs). Within 60 days of DFP exposure, rats developed chronic epilepsy characterized by frequent SRS, epileptiform discharges, and HFOs. LX treatment was associated with a dose-dependent reduction of epilepsy occurrence and overall seizure burden with a significant decrease in SRS and epileptiform discharges. It also significantly reduced the occurrence of epileptic biomarkers of HFOs and interictal spikes, indicating potential disease-modifying activity. Similarly, the neurosteroid analog VX also significantly attenuated SRS, discharges, HFOs, and ictal events. These results demonstrate the long-term protective effects of synthetic neurosteroids in the OP-exposed post-SE model, indicating their disease-modifying potential to prevent epilepsy and ictal abnormalities. SIGNIFICANCE STATEMENT: The effects of nerve agents and organophosphate (OP) exposure are persistent, and survivors suffer from a number of devastating, chronic neurological dysfunctions. Currently, there is no specific therapy for preventing this disastrous impact of OP exposure. We propose synthetic neurosteroids that activate tonic inhibition provide viable options for preventing the long-term neurological effects of OP intoxication. The results from this study reveal the disease-modifying potential of two novel synthetic neurosteroids in preventing epileptogenesis and chronic epileptic seizures after OP-induced SE.

A Pediatric Rat Model of Organophosphate-Induced Refractory Status Epilepticus: Characterization of Long-Term Epileptic Seizure Activity, Neurologic Dysfunction and Neurodegeneration.

Children are highly vulnerable to the neurotoxic effects of organophosphates (OPs), which can cause neuronal developmental defects, including intellectual disability, autism, epilepsy, and related comorbidities. Unfortunately, no specific pediatric OP neurotoxicity model currently exists. In this study, we developed and characterized a pediatric rat model of status epilepticus (SE) induced by the OP diisopropylfluorophosphate (DFP) and examined its impact on long-term neurological outcomes. Postnatal day 21 rats were exposed to a DFP regimen with standard antidotes. Progressive behavioral deteriorations were assessed over a three-month period. Development of epileptic seizures, ictal discharges, high-frequency oscillations (HFOs), and interictal spikes were monitored by video-electroencephalography recordings. Histology-stereology analysis was performed to assess neurodegeneration, neuroinflammation, and morphologic abnormalities. DFP-exposed, post-SE animals exhibited significantly elevated levels of anxiety and depression than age-matched controls at 1, 2, and 3 months post-exposure. DFP-exposed animals displayed aggressive behavior and a marked decline in object recognition memory, as well as prominent impairment in spatial learning and memory. DFP-exposed animals had striking electrographic abnormalities with the occurrence of displayed epileptic seizures, ictal discharges, HFOs, and interictal spikes, suggesting chronic epilepsy. Neuropathological analysis showed substantially fewer principal neurons and inhibitory interneurons with a marked increase in reactive microglia and neuroinflammation in the hippocampus and other brain regions. DFP-exposed animals also exhibited mossy fiber sprouting indicating impaired network formations. Long-term epileptic seizures and neuropsychiatric functional deficits induced by DFP were consistent with neuropathological defects. Collectively, this pediatric model displays many hallmarks of chronic sequelae reminiscent of children exposed to OPs, suggesting that it will be a valuable tool for investigating pathologic mechanisms and potential treatment strategies to attenuate long-term OP neurotoxicity. SIGNIFICANCE STATEMENT: Millions of children are exposed to organophosphates (OPs) used in agriculture or chemical incidents. This study investigated the long-term impact of neonatal exposure to the OP chemical diisopropylfluorophosphate (DFP) on neurobehavioral and neurodevelopmental outcomes in adulthood. DFP exposure caused long-lasting behavioral abnormalities, epileptic seizures, and bilateral brain defects with an array of neurological sequelae seen in children's OP neurotoxicity. Thus, this model provides a novel tool to explore therapeutic interventions that mitigate long-term neurotoxic effects of children exposed to OP-induced seizures and status epilepticus.

Associations between exposure to organophosphate esters and overactive bladder in U.S. adults: a cross-sectional study.

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, P = 0.34; quartile 3, OR = 1.67, 95% CI, 1.10-2.53, P = 0.02; Q4, OR = 1.75, 95% CI, 1.26-2.43, P = 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.

Time- and region-dependent blood-brain barrier impairment in a rat model of organophosphate-induced status epilepticus.

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.

The Association Between Urinary Concentrations of Organophosphate Metabolites and Asthma-Related Outcomes Among Schoolchildren From Informal Settlements.

Objectives: There is inconsistent evidence on the relationship between pesticide exposure and childhood respiratory outcomes in non-agricultural settings. This study investigated the association between organophosphate (OP) pesticide exposure and asthma-related outcomes in children residing in four informal settlements. Methods: The study was a longitudinal study of 590 schoolchildren, with a 12 months follow-up period. A standardised questionnaire adopted from the International Study of Asthma and Allergies in Childhood was administered to caregivers for child's respiratory symptoms and household characteristics. Spirometry and fractional-exhaled nitric oxide, including a phadiatop test (atopy status) and urinary dialkyl phosphate (DAP) metabolites were measured at baseline and follow-up. DAP metabolites included diethylphosphate (DEP) and dimethyl phosphate (DMP) measured at baseline and follow-up and dimethylthiophosphate (DMTP) measured only at baseline. Results: The mean ages of schoolchildren were 9.9 ± 0.91 years and the overal incidence proportions of new doctor diagnosed asthma was 2.2%. No consistent patterns of increased risk of asthma outcomes with increasing DAP concentrations was found in multivariate analysis. Conclusion: Future studies with longer follow-up periods and repeated OP biomonitoring are recommended.

Untargeted metabolomics reveals the preventive effect of quercetin on nephrotoxicity induced by four organophosphorus pesticide mixtures.

This research aimed to explore the protective effect of quercetin against nephrotoxicity induced by four organophosphate pesticide mixtures (PM) using untargeted metabolomics technology in rat kidneys. Sixty male Wistar rats were randomly divided into six groups: control, low-dose quercetin treated (10 mg/kg bw), high-dose quercetin treated (50 mg/kg bw), PM-treated, and two dosages of quercetin + PM-treated. Metabolomics results showed that 17 differential metabolites were identified in the PM-treated group, and pathway analysis revealed that renal metabolic disorders include purine metabolism, glycerophospholipid metabolism, and vitamin B6 metabolism. When high-dose quercetin and PM-treated were administered to rats concurrently, the intensities of differential metabolites were substantially restored (p < 0.01), suggesting that quercetin can improve renal metabolic disorders caused by organophosphate pesticides (OPs). Mechanistically, quercetin could regulate the purine metabolism disorder and endoplasmic reticulum stress (ERS)-mediated autophagy induced by OPs by inhibiting XOD activity. Moreover, quercetin inhibits PLA2 activity to regulate glycerophospholipid metabolism and it could also exert antioxidant and anti-inflammatory effects to correct vitamin B6 metabolism in rat kidneys. Taken together, the high dose of quercetin (50 mg/kg. bw) has a certain protective effect on OPs-induced nephrotoxicity in rats, which provides a theoretical basis for quercetin against nephrotoxicity caused by OPs.

The regulatory roles of DDIT4 in TDCIPP-induced autophagy and apoptosis in PC12 cells.

Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP) is a commonly used organophosphate-based flame retardant and can bio-accumulate in human tissues and organs. As its structure is similar to that of neurotoxic organophosphate pesticides, the neurotoxicity of TDCIPP has raised widespread concerns. TDCIPP can increase neuronal apoptosis and induce autophagy. However, its regulatory mechanism remains unclear. In this study, we found that the expression upregulation of the DNA Damage-Inducible Transcript 4 (DDIT4) protein, which might play essential roles in TDCIPP-induced neuronal autophagy and apoptosis, was observed in TDCIPP-treated differentiated rat PC12 cells. Furthermore, we determined the protective effect of the DDIT4 suppression on the autophagy and apoptosis induced by TDCIPP using Western blot (WB) and Flow cytometry (FACS) analysis. We observed that TDCIPP treatment increased the DDIT4, the autophagy marker Beclin-1, and the microtubule-associated protein light chain 3-II (LC3II) expressions and decreased the mTOR phosphorylation levels. Conversely, the suppression of DDIT4 expression increased the p-mTOR expression and decreased cell autophagy and apoptosis. Collectively, our results revealed the function of DDIT4 in cell death mechanisms triggered by TDCIPP through the mTOR signaling axis in differentiated PC12 cells. Thus, this study provided vital evidence necessary to explain the mechanism of TDCIPP-induced neurotoxicity in differentiated PC12 cells.

Organophosphate ester exposure among Chinese waste incinerator workers: Urinary levels, risk assessment and associations with oxidative stress.

Organophosphate esters (OPEs), which are frequently used as flame retardants and plasticizers in versatile products, are readily released to the external environment. Although workers at municipal waste incineration plants may be extensively exposed to OPEs, only scarce health monitoring and risk assessments have been conducted in this population. In this study, we investigated the levels of eight metabolites of organophosphate esters (mOPEs) and the oxidative stress marker 8-hydroxy-2-deoxyguanosine (8-OHdG) in urine samples from 73 waste incinerator workers and 97 general residents from Shenzhen, China between September 2016 and June 2017. The overall detection rate of mOPEs was 82.2 %-100 %, and higher concentrations of di-p-cresyl phosphate and chlorinated mOPEs [bis(2-chloroethyl) phosphate (BCEP), bis(1-chloro-2propyl) phosphate (BCIPP), bis(1,3-dichloro-2-propyl) phosphate) (BDCIPP)] were found among incinerator workers than among general residents. The incinerator workers also showed significantly higher levels of 8-OHdG than general residents, but the measured levels of most mOPEs were not significantly correlated with the level of 8-OHdG; this may be because co-exposure to multiple toxic compounds can lead to oxidative stress. Risk assessment using Monte Carlo simulations revealed that 95 % of the incinerator workers were free from non-carcinogenic effects due to OPEs exposure (hazard index = 0.27, 95 % CI: 0.09, 0.77). However, the carcinogenic risk of tris(2-chloroethyl) phosphate (TCEP) for incinerator workers was between 10-6 and 10-4. These results indicate that incinerator workers are extensively exposed to OPEs, and better protective measures need to be implemented.

Exposure to organophosphates in association with the development of insulin resistance: Evidence from in vitro, in vivo, and clinical studies.

Insulin resistance is an underlying condition prior to the development of several diseases, including type 2 diabetes, cardiovascular diseases, cognitive impairment, and cerebrovascular complications. Organophosphates (OPs) are one of several factors thought to induce insulin resistance. Previous studies showed that the exposure to OPs pesticides induced insulin resistance through the impairment of hepatic glucose metabolism, pancreatic damage, and disruption of insulin signaling of both adipose tissues and skeletal muscles. Several studies reported possible mechanisms associated with OPs-induced insulin resistance in different models in in vivo studies including those in adult animals, obese animals, and offspring models, as well as in clinical studies. In addition, pharmacological interventions in OPs-induced insulin resistance have been previously investigated. This review aims to summarize and discuss all the evidence concerning OPs-induced insulin resistance in different models including in vitro, in vivo and clinical studies. The interventions of OPs-induced insulin resistance are also discussed. Any contradictory findings also considered. The information from this review will provide insight for possible therapeutic approaches to OPs-induced insulin resistance in the future.

Time-dependent neuropathology in rats following organophosphate-induced status epilepticus.

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-1ß 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.

[Analysis of Flame Retardants Bis(2,3-dibromopropyl) phosphate and Tris(2,3-dibromopropyl) phosphate in Textile Products by GC-MS].

The use of flame retardants, namely bis(2,3-dibromopropyl) phosphate (BDBPP) and tris(2,3-dibromopropyl) phosphate (TDBPP), in textile products such as curtains, carpets and sleeping clothes is banned in Japan under the 'Act on the Control of Household Products Containing Harmful Substances'. Herein, we developed a GC-MS based method to quantify these compounds with greater accuracy and safety than the current official method. For accurate and sensitive quantification, deuterated compounds, BDBPP-d10 and TDBPP-d15, were used as surrogate standards. In consideration of the safety of the analyst, certain solvents and reagents used for the pretreatment that are carcinogenic or have a risk of explosion were replaced. For the extraction step, benzene was replaced by ethyl acetate, and for the methyl derivatization step, the reagent was changed from a self-prepared solution of diazomethane in ether to a solution of trimethylsilyl diazomethane in hexane, a safe and easy-to-use commercially available reagent. The calibration curves were liner in the range of 0.5-8.0 µg/mL for both methylated BDBPP (BDBPP-Me) and TDBPP. The detection limit was 0.05 µg/g for BDBPP-Me and 0.3 µg/g for TDBPP, which is sufficiently low compared to the current detection limits of 10 µg/g for BDBPP-Me and 8 µg/g for TDBPP. The recoveries in various curtain material were 66-108% and relative standard deviations were 1.2-10.2% when 5 µg BDBPP and TDBPP were added to 0.5 g of samples. Thus, the developed method is applicable to textile products of various materials.

Differences in Knowledge, Awareness, Practice, and Health Symptoms in Farmers Who Applied Organophosphates and Pyrethroids on Farms.

OBJECTIVE: This cross-sectional study aimed to examine farmers' knowledge, awareness, practices regarding pesticide use, and prevalence of health symptoms related to pesticides exposure among farmers who applied organophosphates (OP) and pyrethroids (PY). METHODS: Data regarding demographic variables and health symptoms pertinent to pesticide use was collected from 67 farmers who applied OP and 50 farmers who applied PY using interviews from January to March 2021. RESULTS: The farmers who applied OP had lower knowledge, awareness, and prevention practices regarding pesticide use than those who applied PY. After adjustment of covariate variables, the farmers who applied OP had a significantly higher prevalence of respiratory conditions (OR = 8.29 for chest pain, OR = 6.98 for chest tightness, OR = 27.54 for dry throat, and OR = 5.91 for cough), neurological symptoms (OR = 10.62 for fatigue and OR = 6.76 for paresthesia), and neurobehavioral symptoms (OR = 13.84 for poor concentration, OR = 3.75 for short term memory, and OR = 8.99 for insomnia) related to pesticide exposure than those who applied PY. CONCLUSION: Our findings suggest that OP had a more adverse effect on human health than PY, resulting in a higher prevalence of pesticide-related symptoms. The outcomes of this study have the benefit of providing vital information for all stakeholders with regard to the implementation of safe practices in the utilization of personal protective equipment (PPE) and pesticide use in a health intervention and health promotion program.

Prenatal exposure to organophosphate pesticides and risk-taking behaviors in early adulthood.

INTRODUCTION: Previous studies show evidence for associations of prenatal exposure to organophosphate (OP) pesticides with poorer childhood neurodevelopment. As children grow older, poorer cognition, executive function, and school performance can give rise to risk-taking behaviors, including substance abuse, delinquency, and violent acts. We investigated whether prenatal OP exposure was associated with these risk-taking behaviors in adolescence and young adulthood in a Mexican American cohort. METHODS: We measured urinary dialkyl phosphates (DAPs), non-specific metabolites of OPs, twice (13 and 26 weeks gestation) in pregnant women recruited in 1999-2000 in the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a birth cohort set in a primarily Latino agricultural community in the Salinas Valley, California. We followed up children throughout their childhood and adolescence; at the 18-year visit, adolescent youth (n = 315) completed a computer-based questionnaire which included questions about substance use, risky sexual activity, risky driving, and delinquency and police encounters. We used multivariable models to estimate associations of prenatal total DAPs with these risk-taking behaviors. RESULTS: The prevalence of risk-taking behaviors in CHAMACOS youth ranged from 8.9% for smoking or vaping nicotine to 70.2% for committing a delinquent act. Associations of total prenatal DAPs (geometric mean = 132.4 nmol/L) with risk-taking behavior were generally null and imprecise. Isolated findings included a higher risk for smoking or vaping nicotine within the past 30 days (relative risk [RR] per 10-fold increase in prenatal DAPs = 1.89, 95% CI: 1.00, 3.56) and driving without a license (RR = 1.74, 95% CI: 1.25, 2.42). There were no consistent differences by sex or childhood adversity. DISCUSSION: We did not find clear or consistent evidence for associations of prenatal OP exposure with risk-taking behaviors in adolescence/early adulthood in the CHAMACOS population. Our small sample size may have prevented us from detecting potentially subtle associations of early life OP exposure with these risk-taking behaviors.

Uncovering global-scale risks from commercial chemicals in air.

Commercial chemicals are used extensively across urban centres worldwide1, posing a potential exposure risk to 4.2 billion people2. Harmful chemicals are often assessed on the basis of their environmental persistence, accumulation in biological organisms and toxic properties, under international and national initiatives such as the Stockholm Convention3. However, existing regulatory frameworks rely largely upon knowledge of the properties of the parent chemicals, with minimal consideration given to the products of their transformation in the atmosphere. This is mainly due to a dearth of experimental data, as identifying transformation products in complex mixtures of airborne chemicals is an immense analytical challenge4. Here we develop a new framework-combining laboratory and field experiments, advanced techniques for screening suspect chemicals, and in silico modelling-to assess the risks of airborne chemicals, while accounting for atmospheric chemical reactions. By applying this framework to organophosphate flame retardants, as representative chemicals of emerging concern5, we find that their transformation products are globally distributed across 18 megacities, representing a previously unrecognized exposure risk for the world's urban populations. More importantly, individual transformation products can be more toxic and up to an order-of-magnitude more persistent than the parent chemicals, such that the overall risks associated with the mixture of transformation products are also higher than those of the parent flame retardants. Together our results highlight the need to consider atmospheric transformations when assessing the risks of commercial chemicals.