Current Research in Toxicology最新文献

{"title":"Assessing the sensitivity and specificity of phosphatidylethanol (PEth) cutoffs to identify alcohol exposed pregnancies","authors":"Julie M. Hasken ,&nbsp;Anna-Susan Marais ,&nbsp;Marlene M. de Vries ,&nbsp;Wendy O. Kalberg ,&nbsp;David Buckley ,&nbsp;Charles D.H. Parry ,&nbsp;Soraya Seedat ,&nbsp;Philip A. May","doi":"10.1016/j.crtox.2023.100105","DOIUrl":"10.1016/j.crtox.2023.100105","url":null,"abstract":"<div><p>In the literature on alcohol use biomarkers, there has been debate as to what a valid and/or utilitarian cut off level should be for various research applications. In this manuscript, we assessed the sensitivity and specificity of multiple cutoff values for phosphatidylethanol (PEth) from bloodspots relative to self-report, the Alcohol Use Disorder Identification Test (AUDIT) scores, and another alcohol use biomarker ethyl glucuronide (EtG) from fingernails in a sample of 222 pregnant women in the Western Cape Province of South Africa. Receiver operating characteristic (ROC) curves were used to assess the area under the curve (AUC) and assess PEth cutoff values of ≥2, ≥4, ≥8, ≥14, and ≥20 nanograms per milliliter (ng/ml). The highest AUC value was attained when PEth was compared to an AUDIT score of 1 or more. Depending on the cutoff used to determine alcohol consumption, PEth identified 47%–70% of the individuals as alcohol-consuming while 62.6%–75.2% were identified by self-reported measures, and 35.6% were identified by EtG. In this sample, sensitivity and accuracy were highest at less stringent PEth cutoffs when compared to self-report, AUDIT score of 1 or more, 5 or more, 8 or more, and EtG ≥ 8 picograms per milligram (pg/mg). For research purposes, less stringent cutoffs, such as PEth ≥ 8 ng/ml, may be considered a valid, positive cutoff for identifying women who consume alcohol during pregnancy in this population. A cutoff of PEth ≥ 20 ng/ml may miss individuals who reported consuming alcohol (false negatives).</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"4 ","pages":"Article 100105"},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10123138/pdf/main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9414263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of wheatgrass (Triticum aestivum Linn) toxicity against breast cancer cell lines by simulated microgravity","authors":"Wajdy Al-Awaida ,&nbsp;Hamzeh J. Al-Ameer ,&nbsp;Ahmad Sharab ,&nbsp;Rand T. Akasheh","doi":"10.1016/j.crtox.2023.100127","DOIUrl":"https://doi.org/10.1016/j.crtox.2023.100127","url":null,"abstract":"<div><p>This study scrutinizes the effects of simulated microgravity on the antioxidant and cytotoxic potential, along with the phytochemical content of wheatgrass (<em>Triticum aestivum Linn</em>). To imitate microgravity, wheatgrass seeds were germinated in a 3D-clinostat at different rotations per minute (5, 10, 15, and 20 rpm), together with terrestrial gravity control, over 10 days. After germination, the methanolic extracts were analyzed using UPLC-Triple Quad LCMS for their phytochemical composition and tested for their hydrogen peroxide, nitric oxide, and DPPH scavenging activities. The cytotoxic effects of these extracts were evaluated against normal skin fibroblasts, normal breast cells (MCF-10), and breast cancer cells (MCF-7 and MDA-231). The findings showed an extended root growth in wheatgrass germinated under microgravity (WGM) compared to under gravity (WGG). Additionally, WGM extracts demonstrated increased H2O2–, NO–, and DPPH-scavenging activities and a higher content of polyphenols and flavonoids than WGG extracts. These effects were amplified with an increase in clinostat rotations. Moreover, WGM extracts were found to contain a unique set of bioactive compounds (compounds that were detected in the microgravity-germinated wheatgrass but were either absent or present in lower concentrations in wheatgrass germinated under standard gravity conditions.), including pyridoxine, apigenin, and tocopherol, among others, which were absent in WGG. The UPLC-Triple Quad LCMS analysis revealed these unique bioactive compounds in WGM. Notably, WGM extracts showed enhanced cytotoxic effects against normal skin fibroblasts, normal MCF-10, MCF-7, and breast cancer MDA-231 cell lines, with increased cytotoxicity correlating with the number of clinostat rotations. Particularly, WGM extract (at 20 rpm) demonstrated significantly stronger cytotoxicity against MCF-7 breast cancer cells. Further in-depth gene expression analysis of MCF-7 cells exposed to WGM revealed a significant downregulation of genes integral to breast cancer pathways, tyrosine kinase signaling, and DNA repair, complemented by upregulation of certain cell survival and cytotoxic genes. These alterations in genetic pathways associated with cell survival, hormone responses, and cancer progression may elucidate the enhanced cytotoxicity observed in WGM extracts. Our findings underscore the potential of microgravity as a tool to enhance the cytotoxic capabilities of wheatgrass against cancer cell lines, presenting a promising direction for future research in the field of space biology and its implications for terrestrial health.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"5 ","pages":"Article 100127"},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49772587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fluorene-9-bisphenol affects the terminal differentiation of mouse embryonic bodies","authors":"Aidan J. McLaughlin ,&nbsp;Anthony I. Kaniski ,&nbsp;Darena I. Matti ,&nbsp;Nicodemus C. Monear ,&nbsp;Jessica L. Tischler ,&nbsp;Besa Xhabija","doi":"10.1016/j.crtox.2023.100133","DOIUrl":"https://doi.org/10.1016/j.crtox.2023.100133","url":null,"abstract":"<div><p>Fluorene-9-bisphenol (BHPF) has recently attracted interest as it is increasingly used in industrial settings as a substitute for Bisphenol A (BPA). However, the effects of BHPF exposure on embryonic stem cell (ESC) self-renewal, pluripotency, and differentiation remain poorly understood. This study investigates the impacts of BHPF on mouse embryonic stem cells (mESCs) and embryonic bodies (EBs). Our results reveal that BHPF exposure leads to a morphological shift in mESCs, reducing the percentage of dome-shaped colonies and indicating loss of self-renewal and pluripotency. BHPF exposure also appeared to affect the early stages of EB formation and their growth dynamics, with a reduction in EB numbers and an increase in their size. Subsequent gene expression analysis revealed that BHPF exposure led to increased expression of the inflammatory gene Il6, indicating a potential stress response.</p><p>Furthermore, BHPF affected the terminal differentiation pathway, modulating the expression of 16 genes associated with distinct cell types, including lymphatic endothelium, keratinocyte epithelium, pancreatic beta cells, macrophages, monocytes, T-cells, neurons, retinal ganglion cells, nephrons proximal tubule cells, and cardiomyocytes. These findings offer insights into the impact of BHPF on ESC biology and suggest potential implications for developmental and neurodegenerative disorders. Future work should focus on elucidating the underlying mechanisms of BHPF-mediated effects on stem cell function. This may offer new perspectives for understanding the health impacts of environmental exposure to BHPF.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"5 ","pages":"Article 100133"},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X23000312/pdfft?md5=b38e261825fe611e9869dd083e87cd6f&pid=1-s2.0-S2666027X23000312-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92099019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between metal mixture exposure and abnormal glucose metabolism in multiple mixture exposure models: Evidence from NHANES 2015–2016","authors":"Jiamin Zhu ,&nbsp;Shiman Hu ,&nbsp;Shanshan Wang ,&nbsp;Yuting Zhang ,&nbsp;Qingyi Zhu ,&nbsp;Mingzhi Zhang ,&nbsp;Zhonghua Shi","doi":"10.1016/j.crtox.2023.100141","DOIUrl":"https://doi.org/10.1016/j.crtox.2023.100141","url":null,"abstract":"<div><p>Previous studies primarily focused on the single metal exposure and one-sided glucose metabolism disordered states, leading to conflicting results. Herein, we combined diabetes and prediabetes as abnormal glucose metabolism (AGM) to describe the effect of metal mixture exposure on it. Eligible data were obtained from the National Health and Nutrition Examination Survey (NHANES) 2015–2016. In the generalized linear model (GLM), Cd (OR: 1.060, 95 %CI: 1.032–1.089, <em>P value</em> &lt; 0.001) and Tl (OR: 1.039, 95 %CI: 1.004–1.075, <em>P value</em> = 0.031) exposure were positively associated with AGM. In the weighted quantile sum (WQS) regression model, the positive index was obviously associated with AGM (OR: 1.358, 95 %CI: 1.007–1.832, <em>P value</em> = 0.045). In the least absolute shrinkage and selection operator (LASSO) regression model, Cd and Tl were selected as the most contributors. In the Bayesian kernel machine regression (BKMR) model, the effect of co-exposure to metal mixture was associated with AGM, and Cd exposure showed a significantly positive trend. In conclusion, Cd and Tl exposure exhibited independent positive effects on AGM among metal mixture exposure, consistent with their effects on prediabetes.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"5 ","pages":"Article 100141"},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X23000397/pdfft?md5=ed3ccca9642b3f06a6786111625165f2&pid=1-s2.0-S2666027X23000397-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138484124","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methylmercury (MeHg) transcriptionally regulates NAD(P)H:quinone oxidoreductase 1 (NQO1) in Hepa-1c1c7 cells","authors":"Mohammed A. Alqahtani,&nbsp;Mahmoud A. El-Ghiaty,&nbsp;Sara R. El-Mahrouk,&nbsp;Ayman O.S. El-Kadi","doi":"10.1016/j.crtox.2023.100126","DOIUrl":"10.1016/j.crtox.2023.100126","url":null,"abstract":"<div><p>The detoxification of quinones through NAD(P)H:quinone oxidoreductase (NQO1) is a crucial mechanism to maintain cellular homeostasis. The exposure to heavy metals, specifically methylmercury (MeHg), induces several antioxidant enzymes, including NQO1. The nuclear factor erythroid 2-related factor-2 (NRF2) is known to regulate the expression of <em>Nqo1</em> gene and also the aryl hydrocarbon receptor (AHR) is another <em>Nqo1</em> gene regulator. This co-regulation prompted us to investigate which transcription factor (NRF2 or AHR) orchestrates the regulation of NQO1 expression upon MeHg exposure. Therefore, we investigated how MeHg can modulate the level of NQO1 expression by exposing Hepa-1c1c7 cells to several concentrations of MeHg with and without the addition of NQO1 inducers, DL-sulforaphane (SUL) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We found that the mRNA expression <em>of Nqo1</em> is up-regulated by MeHg in time- as well as dose-dependent fashions. Additionally, MeHg increased the NQO1 at all expression levels with and without the presence of its inducers, SUL or TCDD. Furthermore, the MeHg-mediated increase of NQO1 expression was in parallel with a concurrent increase in the nuclear localization of NRF2 protein, but not that of AHR. Mechanistically, the antioxidant response element-driven reporter gene activity was induced by 215% upon MeHg exposure. Also, transfecting Hepa-1c1c7 with <em>Nrf2</em> siRNA reduced the MeHg-induced NQO1 protein expression by 60%. In conclusion, our findings provide evidence supporting the hypothesis that MeHg upregulates the <em>Nqo1</em> gene through a transcriptional mechanism at least in part via a NRF2-dependent mechanism.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"5 ","pages":"Article 100126"},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10556580/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41113470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of short-chain per- and polyfluoroalkyl substances (PFAS) on human cytochrome P450 (CYP450) enzymes and human hepatocytes: An in vitro study","authors":"Megan E. Solan,&nbsp;Ramon Lavado","doi":"10.1016/j.crtox.2023.100116","DOIUrl":"https://doi.org/10.1016/j.crtox.2023.100116","url":null,"abstract":"<div><p>Short-chain per- and polyfluoroalkyl substances (PFAS) have been developed as alternatives to legacy long-chain PFAS, but they may still pose risks due to their potential to interact with biomolecules. Cytochrome P450 (CYP450) enzymes are essential for xenobiotic metabolism, and disruptions of these enzymes by PFAS can have significant human health implications. The inhibitory potential of two legacy long-chain (PFOA and PFOS) and five short-chain alternative PFAS (PFBS, PFHxA, HFPO-DA, PFHxS, and 6:2 FTOH) were assessed in recombinant CYP1A2, − 2B6, −2C19, −2E1, and −3A4 enzymes. Most of the short-chain PFAS, except for PFHxS, tested did not result in significant inhibition up to 100 μM. PFOS inhibited recombinant CYP1A2, −2B6, −2C19, and −3A4 enzymes. However, concentrations where inhibition occurred, were all higher than the averages reported in population biomonitoring studies, with IC₅₀ values higher than 10 µM. We also evaluated the activities of CYP1A2 and CYP3A4 in HepaRG monolayers following 48 h exposures of the short-chain PFAS at two concentrations (1 nM or 1 µM) and with or without an inducer (benzo[a]pyrene, BaP, for CYP1A2 and rifampicin for CYP3A4). Our findings suggest that both 1 nM and 1 µM exposures to short-chain PFAS can modulate the CYP1A2 activity induced by BaP. Except for PFHxS, the short-chain PFAS appear to have little effect on CYP3A4 activity. Understanding the effects of PFAS exposure on biotransformation can shed light on the mechanisms of PFAS toxicity and aid in developing effective strategies for managing chemical risks, enabling regulators to make more informed decisions.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"5 ","pages":"Article 100116"},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49772588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lung surfactant as a biophysical assay for inhalation toxicology","authors":"James Y. Liu,&nbsp;Christie M. Sayes","doi":"10.1016/j.crtox.2022.100101","DOIUrl":"10.1016/j.crtox.2022.100101","url":null,"abstract":"<div><p>Lung surfactant (LS) is a mixture of lipids and proteins that forms a thin film at the gas-exchange surfaces of the alveoli. The components and ultrastructure of LS contribute to its biophysical and biochemical functions in the respiratory system, most notably the lowering of surface tension to facilitate breathing mechanics. LS inhibition can be caused by metabolic deficiencies or the intrusion of endogenous or exogenous substances. While LS has been sourced from animals or synthesized for clinical therapeutics, the biofluid mixture has also gained recent interest as a biophysical model for inhalation toxicity. Various methods can be used to evaluate LS function quantitatively or qualitatively after exposure to potential toxicants. A narrative review of the recent literature was conducted. Studies focused whether LS was inhibited by various environmental contaminants, nanoparticles, or manufactured products. A review is also conducted on synthetic lung surfactants (SLS), which have emerged as a promising alternative to conventional animal-sourced LS. The intrinsic advantages and recent advances of SLS make a strong case for more widespread usage in LS-based toxicological assays.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"4 ","pages":"Article 100101"},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b2/2b/main.PMC9849875.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10587907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"hERG-toxicity prediction using traditional machine learning and advanced deep learning techniques","authors":"Erik Ylipää ,&nbsp;Swapnil Chavan ,&nbsp;Maria Bånkestad ,&nbsp;Johan Broberg ,&nbsp;Björn Glinghammar ,&nbsp;Ulf Norinder ,&nbsp;Ian Cotgreave","doi":"10.1016/j.crtox.2023.100121","DOIUrl":"10.1016/j.crtox.2023.100121","url":null,"abstract":"<div><p>The rise of artificial intelligence (AI) based algorithms has gained a lot of interest in the pharmaceutical development field. Our study demonstrates utilization of traditional machine learning techniques such as random forest (RF), support-vector machine (SVM), extreme gradient boosting (XGBoost), deep neural network (DNN) as well as advanced deep learning techniques like gated recurrent unit-based DNN (GRU-DNN) and graph neural network (GNN), towards predicting human ether-á-go-go related gene (hERG) derived toxicity. Using the largest hERG dataset derived to date, we have utilized 203,853 and 87,366 compounds for training and testing the models, respectively. The results show that GNN, SVM, XGBoost, DNN, RF, and GRU-DNN all performed well, with validation set AUC ROC scores equals 0.96, 0.95, 0.95, 0.94, 0.94 and 0.94, respectively. The GNN was found to be the top performing model based on predictive power and generalizability. The GNN technique is free of any feature engineering steps while having a minimal human intervention. The GNN approach may serve as a basis for comprehensive automation in predictive toxicology. We believe that the models presented here may serve as a promising tool, both for academic institutes as well as pharmaceutical industries, in predicting hERG-liability in new molecular structures.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"5 ","pages":"Article 100121"},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10493507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10242434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early diagnostic biomarkers for acute kidney injury using cisplatin-induced nephrotoxicity in rat model","authors":"Sahadeb Jana ,&nbsp;Palash Mitra ,&nbsp;Ananya Dutta ,&nbsp;Amina Khatun ,&nbsp;Tridip Kumar Das ,&nbsp;Shrabani Pradhan ,&nbsp;Dilip Kumar Nandi ,&nbsp;Suchismita Roy","doi":"10.1016/j.crtox.2023.100135","DOIUrl":"https://doi.org/10.1016/j.crtox.2023.100135","url":null,"abstract":"<div><p>Chronic kidney diseases (CKD) caused by acute kidney injury (AKI) results rapid and reversible loss in renal function. A real-time, highly accurate, and sensitive acute kidney injury biomarker is urgently required in order to keep these patients alive and prevent end stage renal disease and related complications that include hypertension, fluid and electrolyte retention, metabolic acidosis, anemia, stroke etc. This study was designed to develop a specific and sensitive model for the early identification of renal damage in male albino rats. Using a single intraperitoneal dose of cisplatin (10 mg/kg body weight) to the rats, the various duration-dependent nephrotoxic activities were compared using multiple physiological, biochemical, genomic, and histopathological markers. We looked into when renal dysfunction would start occurring after receiving a single high dose of cisplatin while blood urea nitrogen (BUN) and serum creatinine (sCr) remained normal. Following a single cisplatin injection, various measurements were taken in plasma, urine, and/or kidney tissues of rats euthanized on days 1, 2, 3, 5, and 7. When the urine kidney injury molecule (KIM-1), interleukine 18 (IL-18), nephrin, neutrophil gelatinase-associated lipocalin (NGAL) and serum cystatin C (Cys C) levels are greatly raised on day 3 after cisplatin treatment, BUN and sCr levels remain normal. Nephrotoxicity of cisplatin is also indicated by the upregulated mRNA expression of KIM-1, IL-18, Cys C, and NGAL and downregulated expression of nephrin in kidney tissue at very initial stage. Protein expression of KIM-1, IL-18 and NGAL level of kidney tissues was upregulated indicated confirmatory results done by western blot. Utilising an array of kidney impairment indicators has emerged as an earlier, more effective, and more reliable technique to diagnose AKI when compared to the most sophisticated signs now available.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"5 ","pages":"Article 100135"},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X23000336/pdfft?md5=c86c33325e5fb7db8b1197e14343b9b9&pid=1-s2.0-S2666027X23000336-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91989546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating the effect of acute diesel exhaust particle exposure on P-glycoprotein efflux transporter in the blood–brain barrier co-cultured with microglia","authors":"Grace V. Aquino ,&nbsp;Amjad Dabi ,&nbsp;Gabriel J. Odom ,&nbsp;Ramon Lavado ,&nbsp;Kaitlin Nunn ,&nbsp;Kathryn Thomas ,&nbsp;Bennett Schackmuth ,&nbsp;Nazeel Shariff ,&nbsp;Manogna Jarajapu ,&nbsp;Morgan Pluto ,&nbsp;Sara R. Miller ,&nbsp;Leah Eller ,&nbsp;Justin Pressley ,&nbsp;Rishi R. Patel ,&nbsp;Jeffrey Black ,&nbsp;Erica D. Bruce","doi":"10.1016/j.crtox.2023.100107","DOIUrl":"10.1016/j.crtox.2023.100107","url":null,"abstract":"<div><p>A growing public health concern, chronic Diesel Exhaust Particle (DEP) exposure is a heavy risk factor for the development of neurodegenerative diseases like Alzheimer’s (AD). Considered the brain’s first line of defense, the Blood–Brain Barrier (BBB) and perivascular microglia work in tandem to protect the brain from circulating neurotoxic molecules like DEP. Importantly, there is a strong association between AD and BBB dysfunction, particularly in the Aβ transporter and multidrug resistant pump, P-glycoprotein (P-gp). However, the response of this efflux transporter is not well understood in the context of environmental exposures, such as to DEP. Moreover, microglia are seldom included in <em>in vitro</em> BBB models, despite their significance in neurovascular health and disease. Therefore, the goal of this study was to evaluate the effect of acute (24 hr.) DEP exposure (2000 μg/ml) on P-gp expression and function, paracellular permeability, and inflammation profiles of the human <em>in vitro</em> BBB model (hCMEC/D3) with and without microglia (hMC3). Our results suggested that DEP exposure can decrease both the expression and function of P-gp in the BBB, and corroborated that DEP exposure impairs BBB integrity (i.e. increased permeability), a response that was significantly worsened by the influence of microglia in co-culture. Interestingly, DEP exposure seemed to produce atypical inflammation profiles and an unexpected general downregulation in inflammatory markers in both the monoculture and co-culture, which differentially expressed IL-1β and GM-CSF. Interestingly, the microglia in co-culture did not appear to influence the response of the BBB, save in the permeability assay, where it worsened the BBB’s response. Overall, our study is important because it is the first (to our knowledge) to investigate the effect of acute DEP exposure on P-gp in the <em>in vitro</em> human BBB, while also investigating the influence of microglia on the BBB’s responses to this environmental chemical.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"4 ","pages":"Article 100107"},"PeriodicalIF":3.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ef/3e/main.PMC10276163.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9716277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}