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Ecotoxicology and Environmental Safety Jul 20242-Ethylhexyl diphenyl phosphate (EHDPP) is a representative organophosphorus flame retardant (OPFR) that has garnered attention due to its widespread use and potential...
2-Ethylhexyl diphenyl phosphate (EHDPP) is a representative organophosphorus flame retardant (OPFR) that has garnered attention due to its widespread use and potential adverse effects. EHDPP exhibits cytotoxicity, genotoxicity, developmental toxicity, and endocrine disruption. However, the toxicity of EHDPP in mammalian oocytes and the underlying mechanisms remain poorly understood. Melatonin is a natural free radical scavenger that has demonstrated cytoprotective properties. In this study, we investigated the effect of EHDPP on mouse oocytes in vitro culture system and evaluated the rescue effect of melatonin on oocytes exposed to EHDPP. Our results indicated that EHDPP disrupted oocyte maturation, resulting in the majority of oocytes arrested at the metaphase I (MI) stage, accompanied by cytoskeletal damage and elevated levels of reactive oxygen species (ROS). Nevertheless, melatonin supplementation partially rescued EHDPP-induced mouse oocyte maturation impairment. Results of single-cell RNA sequencing (scRNA-seq) analysis elucidated potential mechanisms underlying these protective effects. According to the results of scRNA-seq, we conducted further tests and found that EHDPP primarily disrupts mitochondrial distribution and function, kinetochore-microtubule (K-MT) attachment, DNA damage, apoptosis, and histone modification, which were rescued upon the supplementation of melatonin. This study reveals the mechanisms of EHDPP on female reproduction and indicates the efficacy of melatonin as a therapeutic intervention for EHDPP-induced defects in mouse oocytes.
Topics: Animals; Melatonin; Mice; Oocytes; Mitochondria; Female; Flame Retardants; Reactive Oxygen Species; Organophosphates; DNA Damage; Apoptosis; Organophosphorus Compounds
PubMed: 38865937
DOI: 10.1016/j.ecoenv.2024.116559 -
PLoS Neglected Tropical Diseases Jun 2024Aedes albopictus, also known as the Asian tiger mosquito, is indigenous to the tropical forests of Southeast Asia. Ae. albopictus is expanding across the globe at...
Aedes albopictus, also known as the Asian tiger mosquito, is indigenous to the tropical forests of Southeast Asia. Ae. albopictus is expanding across the globe at alarming rates, raising concern over the transmission of mosquito-borne diseases, such as dengue, West Nile fever, yellow fever, and chikungunya fever. Since Ae. albopictus was reported in Houston (Harris County, Texas) in 1985, this species has rapidly expanded to at least 32 states across the United States. Public health efforts aimed at controlling Ae. albopictus, including surveillance and adulticide spraying operations, occur regularly in Harris County. Despite rotation of insecticides to mitigate the development of resistance, multiple mosquito species including Culex quinquefasciatus and Aedes aegypti in Harris County show organophosphate and pyrethroid resistance. Aedes albopictus shows relatively low resistance levels as compared to Ae. aegypti, but kdr-mutation and the expression of detoxification genes have been reported in Ae. albopictus populations elsewhere. To identify potential candidate detoxification genes contributing to metabolic resistance, we used RNA sequencing of field-collected malathion-resistant and malathion-susceptible, and laboratory-maintained susceptible colonies of Ae. albopictus by comparing the relative expression of transcripts from three major detoxification superfamilies involved in malathion resistance due to metabolic detoxification. Between these groups, we identified 12 candidate malathion resistance genes and among these, most genes correlated with metabolic detoxification of malathion, including four P450 and one alpha esterase. Our results reveal the metabolic detoxification and potential cuticular-based resistance mechanisms associated with malathion resistance in Ae. albopictus in Harris County, Texas.
Topics: Animals; Malathion; Aedes; Insecticide Resistance; Insecticides; Gene Expression Profiling; Mosquito Vectors; Sequence Analysis, RNA; Transcriptome; Texas; Female; Insect Proteins
PubMed: 38865422
DOI: 10.1371/journal.pntd.0012243 -
Frontiers in Immunology 2024Fostemsavir is a gp120-directed attachment inhibitor approved for heavily treatment-experienced (HTE) adults with multidrug-resistant HIV-1. We provide detailed week 240... (Randomized Controlled Trial)
Randomized Controlled Trial
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/mm, exposure-adjusted adverse event (AE) rates were assessed among subgroups with or without CD4+ T-cell count ≥200 cells/mm 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/mm, 122/162 (75%) achieved CD4+ T-cell count ≥200 cells/mm at week 192. Exposure-adjusted AE rates were markedly lower among participants achieving CD4+ T-cell count ≥200 cells/mm at any time vs those sustaining <200 cells/mm. No new AIDS-defining events were reported after week 48 in participants with CD4+ T-cell count ≥200 cells/mm.
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.
Topics: Humans; Adult; HIV Infections; Female; Male; CD4 Lymphocyte Count; Middle Aged; HIV-1; Anti-HIV Agents; Organophosphates; COVID-19; SARS-CoV-2; Treatment Outcome; Viral Load; Piperazines
PubMed: 38863717
DOI: 10.3389/fimmu.2024.1394644 -
Ecotoxicology and Environmental Safety Jul 2024Roundup®, a prominent glyphosate-based herbicide (GBH), holds a significant position in the global market. However, studies of its effects on aquatic invertebrates,...
Roundup®, a prominent glyphosate-based herbicide (GBH), holds a significant position in the global market. However, studies of its effects on aquatic invertebrates, including molluscs are limited. Pomacea canaliculata, a large freshwater snail naturally thrives in agricultural environments where GBH is extensively employed. Our investigation involved assessing the impact of two concentrations of GBH (at concentrations of 19.98 mg/L and 59.94 mg/L, corresponding to 6 mg/L and 18 mg/L glyphosate) during a 96 h exposure experiment on the intestinal bacterial composition and metabolites of P. canaliculata. Analysis of the 16 S rRNA gene demonstrated a notable reduction in the alpha diversity of intestinal bacteria due to GBH exposure. Higher GBH concentration caused a significant shift in the relative abundance of dominant bacteria, such as Bacteroides and Paludibacter. We employed widely-targeted metabolomics analysis to analyze alterations in the hepatopancreatic metabolic profile as a consequence of GBH exposure. The shifts in metabolites primarily affected lipid, amino acid, and glucose metabolism, resulting in compromised immune and adaptive capacities in P. canaliculata. These results suggested that exposure to varying GBH concentrations perpetuates adverse effects on intestinal and hepatopancreatic health of P. canaliculata. This study provides an understanding of the negative effects of GBH on P. canaliculata and may sheds light on its potential implications for other molluscs.
Topics: Animals; Glyphosate; Glycine; Herbicides; Gastrointestinal Microbiome; Water Pollutants, Chemical; Hepatopancreas; Snails; RNA, Ribosomal, 16S; Metabolomics
PubMed: 38852467
DOI: 10.1016/j.ecoenv.2024.116549 -
Laboratory Animal Research Jun 2024The aim of the study was to develop a technique for quantitative determination of rat urine metabolites by HPLC-MS/MS, which can be used to search for biomarkers of...
BACKGROUND
The aim of the study was to develop a technique for quantitative determination of rat urine metabolites by HPLC-MS/MS, which can be used to search for biomarkers of acute intoxication with organophosphates (OPs).
RESULTS
The content of metabolites in the urine of rats exposed to a single dose of paraoxon (POX1x); interval, twice daily administration of paraoxon (POX2x); exposure to 2-(o-cresyl)-4H-1, 3, 2-benzodioxaphosphorin-2-oxide and paraoxon (CBPOX) was investigated. New data were obtained on the content in the urine of intact rats as well as rats in 3 models of OP poisoning: 3-methylhistidine, threonine, creatine, creatinine, lactic acid, acetylcarnitine, inosine, hypoxanthine, adenine, 3-hydroxymethyl-butyrate and 2-hydroxymethyl-butyrate.
CONCLUSIONS
The proposed assay procedure is a simple and reliable tool for urine metabolomic studies. Within 1-3 days after OP exposure in all three models of acute intoxication, the concentration of metabolites in rat urine, with the exception of adenine, changes similarly and symmetrically, regardless of the method of poisoning modeling, in all three models of acute intoxication. Further studies are needed to determine the specificity and reliability of using urinary metabolite concentration changes as potential biomarkers of acute organophosphate intoxication.
PubMed: 38845041
DOI: 10.1186/s42826-024-00209-3 -
Nature Communications Jun 2024Farmers from South Asian countries spray insecticides without protective gear, which leads to insecticide exposure through dermal and nasal routes. Acetylcholinesterase...
Oxime-functionalized anti-insecticide fabric reduces insecticide exposure through dermal and nasal routes, and prevents insecticide-induced neuromuscular-dysfunction and mortality.
Farmers from South Asian countries spray insecticides without protective gear, which leads to insecticide exposure through dermal and nasal routes. Acetylcholinesterase plays a crucial role in controlling neuromuscular function. Organophosphate and carbamate insecticides inhibit acetylcholinesterase, which leads to severe neuronal/cognitive dysfunction, breathing disorders, loss of endurance, and death. To address this issue, an Oxime-fabric is developed by covalently attaching silyl-pralidoxime to the cellulose of the fabric. The Oxime-fabric, when stitched as a bodysuit and facemask, efficiently deactivates insecticides (organophosphates and carbamates) upon contact, preventing exposure. The Oxime-fabric prevents insecticide-induced neuronal damage, neuro-muscular dysfunction, and loss of endurance. Furthermore, we observe a 100% survival rate in rats when repeatedly exposed to organophosphate-insecticide through the Oxime-fabric, while no survival is seen when organophosphate-insecticide applied directly or through normal fabric. The Oxime-fabric is washable and reusable for at least 50 cycles, providing an affordable solution to prevent insecticide-induced toxicity and lethality among farmers.
Topics: Animals; Insecticides; Rats; Oximes; Male; Pralidoxime Compounds; Textiles; Cholinesterase Inhibitors; Acetylcholinesterase; Occupational Exposure; Carbamates; Organophosphates; Administration, Intranasal
PubMed: 38844466
DOI: 10.1038/s41467-024-49167-3 -
Chemical Research in Toxicology Jun 2024Benchmark dose (BMD) modeling estimates the dose of a chemical that causes a perturbation from baseline. Transcriptional BMDs have been shown to be relatively consistent...
Benchmark dose (BMD) modeling estimates the dose of a chemical that causes a perturbation from baseline. Transcriptional BMDs have been shown to be relatively consistent with apical end point BMDs, opening the door to using molecular BMDs to derive human health-based guidance values for chemical exposure. Metabolomics measures the responses of small-molecule endogenous metabolites to chemical exposure, complementing transcriptomics by characterizing downstream molecular phenotypes that are more closely associated with apical end points. The aim of this study was to apply BMD modeling to in vivo metabolomics data, to compare metabolic BMDs to both transcriptional and apical end point BMDs. This builds upon our previous application of transcriptomics and BMD modeling to a 5-day rat study of triphenyl phosphate (TPhP), applying metabolomics to the same archived tissues. Specifically, liver from rats exposed to five doses of TPhP was investigated using liquid chromatography-mass spectrometry and H nuclear magnetic resonance spectroscopy-based metabolomics. Following the application of BMDExpress2 software, 2903 endogenous metabolic features yielded viable dose-response models, confirming a perturbation to the liver metabolome. Metabolic BMD estimates were similarly sensitive to transcriptional BMDs, and more sensitive than both clinical chemistry and apical end point BMDs. Pathway analysis of the multiomics data sets revealed a major effect of TPhP exposure on cholesterol (and downstream) pathways, consistent with clinical chemistry measurements. Additionally, the transcriptomics data indicated that TPhP activated xenobiotic metabolism pathways, which was confirmed by using the underexploited capability of metabolomics to detect xenobiotic-related compounds. Eleven biotransformation products of TPhP were discovered, and their levels were highly correlated with multiple xenobiotic metabolism genes. This work provides a case study showing how metabolomics and transcriptomics can estimate mechanistically anchored points-of-departure. Furthermore, the study demonstrates how metabolomics can also discover biotransformation products, which could be of value within a regulatory setting, for example, as an enhancement of OECD Test Guideline 417 (toxicokinetics).
Topics: Animals; Metabolomics; Rats; Biotransformation; Liver; Male; Dose-Response Relationship, Drug; Benchmarking; Organophosphates; Rats, Sprague-Dawley
PubMed: 38842447
DOI: 10.1021/acs.chemrestox.4c00002 -
Ecotoxicology and Environmental Safety Jul 2024Organophosphate esters (OPEs) and Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants with common exposure sources, leading to their...
Association of co-exposure to organophosphate esters and per- and polyfluoroalkyl substances and mixture with cardiovascular-kidney-liver-metabolic biomarkers among Chinese adults.
BACKGROUND
Organophosphate esters (OPEs) and Per- and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants with common exposure sources, leading to their widespread presence in human body. However, evidence on co-exposure to OPEs and PFAS and its impact on cardiovascular-kidney-liver-metabolic biomarkers remains limited.
METHODS
In this cross-sectional study, 467 adults were enrolled from January to May 2022 during physical visits in Shijiazhuang, Hebei province. Eleven types of OPEs and twelves types of PFAS were detected, among which eight OPEs and six PFAS contaminants were detected in more than 60% of plasma samples. Seventeen biomarkers were assessed to comprehensively evaluate the cardiovascular-kidney-liver-metabolic function. Multiple linear regression, multipollutant models with sparse partial least squares, and Bayesian kernel machine regression (BKMR) models were applied to examine the associations of individual OPEs and PFAS and their mixtures with organ function and metabolism, respectively.
RESULTS
Of the over 400 exposure-outcome associations tested when modelling, we observed robust results across three models that perfluorohexanoic acid (PFHxS) was significantly positively associated with alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and indirect bilirubin (IBIL). Perfluorononanoic acid was significantly associated with decreased AST/ALT and increased very-low-density lipoprotein cholesterol levels. Besides, perfluorodecanoic acid was correlated with increased high lipoprotein cholesterol and perfluoroundecanoic acid was consistently associated with lower glucose level. BKMR analysis showed that OPEs and PFAS mixtures were positively associated with IBIL and TBIL, among which PFHxS was the main toxic chemicals.
CONCLUSIONS
Our findings suggest that exposure to OPEs and PFAS, especially PFHxS and PFNA, may disrupt organ function and metabolism in the general population, providing insight into the potential pathophysiological mechanisms of OPEs and PFAS co-exposure and chronic diseases.
Topics: Humans; Biomarkers; Female; Male; Cross-Sectional Studies; Adult; Fluorocarbons; China; Middle Aged; Environmental Pollutants; Liver; Kidney; Esters; Organophosphates; Environmental Exposure; Caproates; Young Adult; Aged; East Asian People
PubMed: 38838464
DOI: 10.1016/j.ecoenv.2024.116524 -
The Science of the Total Environment Sep 2024Pesticide mixtures are frequently utilized in agriculture, yet their cumulative effects on aquatic organisms remain poorly understood. Aquatic animals can be effective...
Pesticide mixtures are frequently utilized in agriculture, yet their cumulative effects on aquatic organisms remain poorly understood. Aquatic animals can be effective bioindicators and invasive bivalves, owing to their widespread distribution, provide an opportunity to assess these impacts. Glyphosate and imidacloprid, among the most prevalent pesticides globally, are frequently detected in freshwater systems in South America. This study aims to understand the cumulative effects of pesticide mixtures on aquatic organisms, using invasive Corbicula largillierti clams from a natural stream in northwestern Argentina. We conducted 48-hour exposure experiments using two concentrations of imidacloprid (20 and 200 μg L a.i), two concentrations of glyphosate (0.3 and 3 mg L a.i), and two combinations of these pesticides (both at low and high concentrations, respectively), simulating the direct contamination of both pesticides based on their agronomic recipe and observed values in Argentine aquatic environments. Clam metabolism was assessed through the examination of multiple oxidative stress parameters and measuring oxygen consumption rate as a proxy for standard metabolic rate (SMR). Our findings revealed that imidacloprid has a more pronounced effect compared to glyphosate. Imidacloprid significantly decreased clam SMR and cellular levels of reduced glutathione (GSH). However, when both pesticides were present, also cellular glycogen and thiobarbituric acid-reactive substances (TBARS) were affected. Proteins and glutathione S-Transferase (GST) activity were unaffected by either pesticide or their mixture at the assayed concentrations, highlighting the need to test several stress parameters to detect toxicological impacts. Our results indicated additive effects of imidacloprid and glyphosate across all measured parameters. The combination of multiple physiological and cytological biomarkers in invasive bivalves offers significant potential to enhance biomonitoring sensitivity and obtain insights into the origins and cellular mechanisms of chemical impacts. These studies can improve pollution regulatory policies and pesticide management.
Topics: Neonicotinoids; Glyphosate; Animals; Nitro Compounds; Water Pollutants, Chemical; Glycine; Biomarkers; Argentina; Corbicula; Herbicides; Environmental Monitoring; Oxidative Stress; Insecticides
PubMed: 38825192
DOI: 10.1016/j.scitotenv.2024.173685 -
Molecular Metabolism Jul 2024Cancer cells must maintain lipid supplies for their proliferation and do so by upregulating lipogenic gene programs. The sterol regulatory element-binding proteins...
OBJECTIVE
Cancer cells must maintain lipid supplies for their proliferation and do so by upregulating lipogenic gene programs. The sterol regulatory element-binding proteins (SREBPs) act as modulators of lipid homeostasis by acting as transcriptional activators of genes required for fatty acid and cholesterol synthesis and uptake. SREBPs have been recognized as chemotherapeutic targets in multiple cancers, however it is not well understood which SREBP target genes are essential for tumorigenesis. In this study, we examined the requirement of SREBP target genes for pancreatic ductal adenocarcinoma (PDAC) tumor growth.
METHODS
Here we constructed a custom CRISPR knockout library containing known SREBP target genes and performed in vitro 2D culture and in vivo orthotopic xenograft CRISPR screens using a patient-derived PDAC cell line. In vitro, we grew cells in medium supplemented with 10% fetal bovine serum (FBS) or 10% lipoprotein-deficient serum (LPDS) to examine differences in gene essentiality in different lipid environments. In vivo, we injected cells into the pancreata of nude mice and collected tumors after 4 weeks.
RESULTS
We identified terpenoid backbone biosynthesis genes as essential for PDAC tumor development. Specifically, we identified the non-sterol isoprenoid product of the mevalonate pathway, geranylgeranyl diphosphate (GGPP), as an essential lipid for tumor growth. Mechanistically, we observed that restricting mevalonate pathway activity using statins and SREBP inhibitors synergistically induced apoptosis and caused disruptions in small G protein prenylation that have pleiotropic effects on cellular signaling pathways. Finally, we demonstrated that geranylgeranyl diphosphate synthase 1 (GGPS1) knockdown significantly reduces tumor burden in an orthotopic xenograft mouse model.
CONCLUSIONS
These findings indicate that PDAC tumors selectively require GGPP over other lipids such as cholesterol and fatty acids and that this is a targetable vulnerability of pancreatic cancer cells.
Topics: Humans; Animals; Pancreatic Neoplasms; Mice; Mice, Nude; Cell Line, Tumor; Cell Proliferation; Polyisoprenyl Phosphates; Carcinoma, Pancreatic Ductal; Sterol Regulatory Element Binding Proteins; Clustered Regularly Interspaced Short Palindromic Repeats
PubMed: 38823776
DOI: 10.1016/j.molmet.2024.101964