Current Research in Toxicology最新文献

{"title":"Evaluation of the endocrine disrupting potential of Di-isodecyl phthalate","authors":"I.A. Lea ,&nbsp;D. Feifarek ,&nbsp;A. Mihalchik ,&nbsp;M. Heintz ,&nbsp;L. Haws ,&nbsp;H. Nyambego ,&nbsp;K. Goyak ,&nbsp;C. Palermo ,&nbsp;S.J. Borghoff","doi":"10.1016/j.crtox.2025.100221","DOIUrl":"10.1016/j.crtox.2025.100221","url":null,"abstract":"<div><div>Low molecular weight <em>ortho</em>-phthalates have been implicated in perturbing androgen pathways when administered during the masculinization programming window. Di-isodecyl phthalate (DIDP) is a high molecular weight phthalate and as a high production volume chemical, its ability to disrupt endocrine pathways is important to understand its potential hazard. Both DIDP (and its metabolites) were evaluated to determine the potential to perturb endocrine pathways through a weight of evidence (WoE) assessment in accordance with the European Chemicals Agency (ECHA)/European Food Safety Authority (EFSA) Endocrine Disruptor Guidance (2018). A literature review was performed of toxicological data for DIDP related to estrogen, androgen, thyroid, or steroidogenesis pathways. Literature searches returned 41 relevant articles from which data were extracted and assessed in conjunction with data from 105 high-throughput assays. Because some of the <em>in vitro</em> assays lack metabolic capabilities, an <em>in silico</em> assessment of estrogen (E), androgen (A), thyroid (T) or steroidogenesis (S) activity was conducted. Based on the available evidence for the T pathway, DIDP did not elicit adverse thyroid outcomes <em>in vivo</em>. When considering the T mechanistic data, there was evidence that DIDP induced the liver pregnane X receptor (PXR) and some indication that DIDP increased iodide uptake in the thyroid. As there were no studies evaluating thyroid hormone levels <em>in vivo</em>, a data gap was identified because per the ECHA/EFSA guidance, the lack of this information prevents drawing a conclusion on the T pathway. However, the E, A and S pathways were sufficiently assessed to conclude a limited or lack of E, A or S related apical outcomes in <em>in vivo</em> studies; there was also a lack of endocrine activity in <em>in vitro</em> or <em>in vivo</em> mechanistic studies. These results suggest that DIDP does not meet the ECHA/EFSA criteria for an endocrine disruptor, therefore DIDP is unlikely to disrupt the androgen pathway during development.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100221"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143429111","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":"An automated platform for simultaneous, longitudinal analysis of engineered neuromuscular tissues for applications in neurotoxin potency testing","authors":"Jacob W. Fleming ,&nbsp;Molly C. McCloskey ,&nbsp;Kevin Gray ,&nbsp;David R. Nash ,&nbsp;Vincent Leung ,&nbsp;Christos Michas ,&nbsp;Shawn M. Luttrell ,&nbsp;Christopher Cavanaugh ,&nbsp;Julie Mathieu ,&nbsp;Shawn Mcquire ,&nbsp;Mark Bothwell ,&nbsp;David L. Mack ,&nbsp;Nicholas A. Geisse ,&nbsp;Alec S.T. Smith","doi":"10.1016/j.crtox.2025.100218","DOIUrl":"10.1016/j.crtox.2025.100218","url":null,"abstract":"<div><div>Animal models of the neuromuscular junction (NMJ) have been widely studied but exhibit critical differences from human biology limiting utility in drug and disease modelling. Challenges with scarcity, scalability, throughput, and ethical considerations further limit the suitability of animal models for preclinical screening. Engineered models have emerged as alternatives for studying NMJ functionality in response to genetic and/or pharmacological challenge. However, these models have faced challenges associated with their poorly scalable creation, sourcing suitable cells, and the extraction of reliable, quantifiable metrics. We present a turnkey iPSC-based model of the NMJ employing channelrhodopsin-2 expression within the motor neuron (MN) population driving muscle contraction in response to blue light. MNs co-cultured with engineered skeletal muscle tissues produced twitch forces of 34.7 ± 22.7 µN in response to blue light, with a response fidelity &gt; 92 %. Histological analysis revealed characteristic punctate acetylcholine receptor staining co-localized with the presynaptic marker synaptic vesicle protein-2. Dose-response studies using botulinum neurotoxin showed loss of function in a dose- and time-dependent manner (EC₅₀ − 0.11 ± 0.015 µg). Variability of the EC₅₀ values between 2 different iPSC differentiations of both cell types and 2 users was less than 2 %. Further testing with the acute neurotoxins acetylcholine mustard and d-tubocurarine validated the biological relevance of the postsynaptic machinery of the model. This model marks a meaningful progression of 3D engineered models of the NMJ, providing engineered tissues at a throughput relevant to potency and screening applications with an abundant iPSC cell source and standardized hardware-software ecosystem allowing technology transfer across laboratories.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100218"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143161444","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":"Systematic evaluation of the evidence base on methyl tert-butyl ether supporting a lack of concern for carcinogenic hazard in humans based on animal cancer studies and mechanistic data","authors":"S.J. Borghoff ,&nbsp;B.N. Rivera ,&nbsp;S. Fitch ,&nbsp;A.N. Buerger ,&nbsp;N.Y. Choksi ,&nbsp;A. Franzen ,&nbsp;M.J. Vincent ,&nbsp;T. Covington ,&nbsp;J. Bus ,&nbsp;E. Rushton ,&nbsp;I.A. Lea","doi":"10.1016/j.crtox.2025.100224","DOIUrl":"10.1016/j.crtox.2025.100224","url":null,"abstract":"<div><div>Methyl <em>tert</em>-butyl ether (MTBE) is a high-octane fuel component that helps gasoline burn cleaner and reduces automobile emissions. In 1999, the International Agency for Research on Cancer (IARC) categorized MTBE as “not classifiable” regarding human carcinogenicity. Since then, additional studies have been published that substantially added to the evidence base to examine the carcinogenic potential of MTBE in humans. A systematic literature search and review was conducted to identify mechanistic data, as well as studies investigating cancer in MTBE-exposed humans and experimental animals. Critical appraisal was performed for relevant studies with mechanistic data organized and evaluated within Key Characteristics of Carcinogens (KCCs). Three standard animal cancer bioassays showed a low incidence of hepatocellular adenomas in female mice (inhalation exposure), with renal adenomas/carcinoma (inhalation) and brain tumors (drinking water) in male rats exposed to high concentrations of MTBE. Evidence extracted from the literature demonstrate that the mechanism of male rat renal tumors does not operate in humans. Review of the strength of mechanistic data was based on activity, relevancy, and reliability, with information-dense KCC2—is genotoxic, and KCC10—alters cell proliferation, cell death, and nutrient supply, together supporting that MTBE is unlikely to be a carcinogenic hazard to humans.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100224"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143471517","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":"Microphysiological system to address the opioid crisis: A novel multi-organ model of acute opioid overdose and recovery","authors":"Aakash Patel ,&nbsp;Suruchi Poddar ,&nbsp;Daniel Nierenberg ,&nbsp;Stephanie Lang ,&nbsp;Hao Wang ,&nbsp;Camilly Pestana Pires DeMello ,&nbsp;Julio Gamarra ,&nbsp;Alisha Colon ,&nbsp;Paula Kennedy ,&nbsp;Jeffry Roles ,&nbsp;Jules Klion ,&nbsp;Will Bogen ,&nbsp;Christopher Long ,&nbsp;Xiufang Guo ,&nbsp;Patrick Tighe ,&nbsp;Stephan Schmidt ,&nbsp;Michael L. Shuler ,&nbsp;James J. Hickman","doi":"10.1016/j.crtox.2024.100209","DOIUrl":"10.1016/j.crtox.2024.100209","url":null,"abstract":"<div><div>Opioids have been the primary method used to manage pain for hundreds of years, however the increasing prescription rate of these drugs in the modern world has led to a public health crisis of overdose related deaths. Naloxone is the current standard treatment for opioid overdose rescue, but it has not been fully investigated for potential off-target toxicity effects. The current methods for pharmaceutical development do not correlate well with pre-clinical animal studies compared to clinical results, creating a need for improved methods for therapeutic evaluation. Microphysiological systems (MPS) are a rapidly growing field, and the FDA has accepted this area of research to address this concern, offering a promising alternative to traditional animal models. This study establishes a novel multi-organ MPS model of acute opioid overdose and rescue to investigate the efficacy and off-target toxicity of naloxone in combination with opioids. By integrating primary human and human induced pluripotent stem cell (hiPSC)-derived cells, including preBötzinger complex neurons, liver, cardiac, and skeletal muscle components, this study establishes a novel functional multi-organ MPS model of acute opioid overdose and rescue to investigate the efficacy and off-target toxicity of naloxone in combination with opioids, with clinically relevant functional readouts of organ function. The system was able to successfully exhibit opioid overdose using methadone, as well as rescue using naloxone evidenced by the neuronal component activity. In addition to efficacy, the multi-organ platform was able to characterize potential off-target toxicity effects of naloxone, specifically in the cardiac component.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100209"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11745978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001854","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":"Laying the groundwork: Exploring pesticide exposure and genetic factors in south-eastern Brazilian farmers","authors":"Débora Dummer Meira ,&nbsp;Victor Nogueira Da Gama Kohls ,&nbsp;Matheus Correia Casotti ,&nbsp;Luana Santos Louro ,&nbsp;Gabriel Mendonça Santana ,&nbsp;Thomas Erik Santos Louro ,&nbsp;Adriana Madeira Alvares da Silva ,&nbsp;Lorena Souza Castro Altoé ,&nbsp;Raquel Reis Trabach ,&nbsp;Sonia Groisman ,&nbsp;Elizeu Fagundes de Carvalho ,&nbsp;Jamila Alessandra Perini Machado ,&nbsp;Stephanie Seneff ,&nbsp;Iúri Drumond Louro","doi":"10.1016/j.crtox.2025.100215","DOIUrl":"10.1016/j.crtox.2025.100215","url":null,"abstract":"<div><div>Brazil is the world leader in pesticide consumption, and its indiscriminate use puts farmers’ health at risk. The <em>CYP2C9</em> gene encodes the CYP2C9 enzyme, which metabolizes several endogenous substrates and specific xenobiotics, especially pesticides. Our goal is to study the risk of pesticide use, especially the herbicide glyphosate, in the development of diseases and the association with two <em>CYP2C9</em> polymorphisms, in farmers living in the southern region of Espírito Santo state, Brazil. The allelic frequency of <em>CYP2C9</em>*1, <em>CYP2C9</em>*2 and <em>CYP2C9</em>*3 was determined in blood samples from individuals exposed or not to pesticides using real-time PCR. 304 blood samples were analyzed, dividing <em>CYP2C9</em> genotypes into three metabolization classes: normal, intermediate, and slow. Our results indicate that normal metabolizers may be more susceptible to conditions such as high blood pressure, cardiovascular disease, and kidney problems. Intermediate metabolizers show an association with attention deficit disorder and miscarriages, suggesting that farmers’ symptoms correlated with their <em>CYP2C9</em> genotype. Insufficient data prevented conclusions about slow metabolizers (*2 and/or *3). These findings suggest that the <em>CYP2C9</em> genotype may influence the way farmers exposed to pesticides respond, but more research is needed to clarify causality and investigate other possible health effects. As an introductory effort, this study provides insights into the complex relationship between genetic variations and pesticide exposure, laying the groundwork for future research. This pioneering work on associations between specific genetic variations and health risks with pesticide exposure, emphasizes the importance of personalized medicine and stricter regulation of pesticide use for public health and occupational safety.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100215"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11783379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078710","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":"Profiling assay performance in the DevTox germ layer reporter platform","authors":"John T. Gamble ,&nbsp;Chad Deisenroth","doi":"10.1016/j.crtox.2025.100223","DOIUrl":"10.1016/j.crtox.2025.100223","url":null,"abstract":"<div><div>The U.S. Environmental Protection Agency (U.S. EPA) is mandated to develop new approach methods (NAMs) to detect chemicals risks to susceptible populations, including effects on pregnant women and their offspring. With limited hazard information available for current and new chemicals, NAMs can provide greater relevance to human biology, mechanistic insight, and higher testing capacity than traditional animal models. The DevTox Germ Layer Reporter (GLR) model platform was recently established for high-throughput screening and prioritization of potential developmental hazards. The model platform utilizes the RUES2-GLR pluripotent stem cell reporter line that expresses fluorescent fusion protein biomarkers SOX17 (endoderm), Brachyury (mesoderm), and SOX2 (ectoderm and pluripotency); enabling a multi-lineage readout of gastrulation lineages. The DevTox GLR-Endo assay used the model platform to evaluate chemical effects on differentiating endoderm, yielding a balanced accuracy (BA) of 72% against a training set of 43 developmental toxicants and 23 non-developmental toxicants. To assess the predictivity of additional early embryonic lineages, assays for pluripotency (DevTox GLR-Pluri), ectoderm (DevTox GLR-Ecto), and mesoderm (DevTox GLR-Meso) were developed. Chemical reference set (12 developmental toxicants and 4 non-developmental toxicants) activity for each assay revealed BAs of 92% for DevTox GLR-Endo and DevTox GLR-Pluri, 71% for DevTox GLR-Ecto, and 58% for DevTox GLR-Meso. Expanded testing of the DevTox GLR-Endo and DevTox GLR-Pluri with 63 developmental and non-developmental toxicants yielded BAs of 75% and 68%, respectively. Amongst the four DevTox GLR platform assays, the DevTox GLR-Endo assay maintained the highest degree of efficacy and overall predictive accuracy for the compound set evaluated in this study.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100223"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143387663","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":"Investigating open access new approach methods (NAM) to assess biological points of departure: A case study with 4 neurotoxic pesticides","authors":"Marilyn H. Silva","doi":"10.1016/j.crtox.2024.100156","DOIUrl":"10.1016/j.crtox.2024.100156","url":null,"abstract":"<div><p>Open access new approach methods (NAM) in the US EPA ToxCast program and NTP Integrated Chemical Environment (ICE) were used to investigate activities of four neurotoxic pesticides: endosulfan, fipronil, propyzamide and carbaryl. Concordance of <em>in vivo</em> regulatory points of departure (POD) adjusted for interspecies extrapolation (AdjPOD) to modelled human Administered Equivalent Dose (AED_Human) was assessed using 3-compartment or Adult/Fetal PBTK <em>in vitro</em> to <em>in vivo</em> extrapolation. Model inputs were from Tier 1 (High throughput transcriptomics: HTTr, high throughput phenotypic profiling: HTPP) and Tier 2 (single target: ToxCast) assays. HTTr identified gene expression signatures associated with potential neurotoxicity for endosulfan, propyzamide and carbaryl in non-neuronal MCF-7 and HepaRG cells. The HTPP assay in U-2 OS cells detected potent effects on DNA endpoints for endosulfan and carbaryl, and mitochondria with fipronil (propyzamide was inactive). The most potent ToxCast assays were concordant with specific components of each chemical mode of action (MOA). Predictive adult IVIVE models produced fold differences (FD) &lt; 10 between the AED_Human and the measured <em>in vivo</em> AdjPOD. The 3-compartment model was concordant (i.e., smallest FD) for endosulfan, fipronil and carbaryl, and PBTK was concordant for propyzamide. The most potent AED_Human predictions for each chemical showed HTTr, HTPP and ToxCast were mainly concordant with <em>in vivo</em> AdjPODs but assays were less concordant with MOAs. This was likely due to the cell types used for testing and/or lack of metabolic capabilities and pathways available <em>in vivo</em>. The Fetal PBTK model had larger FDs than adult models and was less predictive overall.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100156"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000094/pdfft?md5=31c931d7a1bcb728b57343cdc6471724&pid=1-s2.0-S2666027X24000094-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139873916","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":"Alzheimer's disease: In silico study of rosemary diterpenes activities","authors":"Zakariae Abbaoui ,&nbsp;Mohammed Merzouki ,&nbsp;Imane Oualdi ,&nbsp;Abdelhamid Bitari ,&nbsp;Abdelouhed Oussaid ,&nbsp;Allal Challioui ,&nbsp;Rachid Touzani ,&nbsp;Belkheir Hammouti ,&nbsp;Wilson Agerico Diño","doi":"10.1016/j.crtox.2024.100159","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100159","url":null,"abstract":"<div><p>The global surge in Alzheimer's disease poses a significant public health concern. In response, we study the efficacy of carnosic acid and related abietane-type diterpenes extracted from rosemary as acetylcholinesterase (AChE) inhibitors. Our analyses, using in silico techniques, encompassed all the compounds within this extract. Through molecular docking, we explored how these compounds interact with the active site of the AChE protein. The docking scores, ranging from −5.560 Kcal/mol to −7.270 Kcal/mol, indicate robust binding affinities. Assessment of the ADME/T (Adsorption, Distribution, Metabolism, Excretion, and Toxicity) properties and pharmacokinetics of these compounds reveal favorable profiles for all the tested substances. These encouraging results suggest the potential of these compounds as candidates for further development to prevent and/or treat Alzheimer's disease. Among these compounds, we find rosmanol as the most likely candidate for further research and clinical trials to validate their efficacy.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100159"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000124/pdfft?md5=a81cfe8a39de5357800a7a007141150a&pid=1-s2.0-S2666027X24000124-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140030287","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":"Subcellular expression of CYP2E1 in HepG2 cells impacts response to free oleic and palmitic acid","authors":"Zaria K. Killingsworth ,&nbsp;Kelly R. Misare ,&nbsp;Abigail S. Ryan ,&nbsp;Elizabeth A. Ampolini ,&nbsp;Tsultrim T. Mendenhall ,&nbsp;Melinda A. Engevik ,&nbsp;Jessica H. Hartman","doi":"10.1016/j.crtox.2024.100195","DOIUrl":"10.1016/j.crtox.2024.100195","url":null,"abstract":"<div><h3>Aims</h3><div>Cytochrome P450 2E1 (CYP2E1) is a mammalian monooxygenase expressed at high levels in the liver that metabolizes low molecular weight pollutants and drugs, as well as endogenous fatty acids and ketones. Although CYP2E1 has been mainly studied in the endoplasmic reticulum (ER, microsomal fraction), it also localizes in significant amounts to the mitochondria, where it has been far less studied. We investigated the effects of CYP2E1 expression in mitochondria, endoplasmic reticulum, or both organelles in transgenic HepG2 cells exposed to free oleic and palmitic acid, including effects on cytotoxicity, lipid storage, respiration, and gene expression.</div></div><div><h3>Results</h3><div>We found that HepG2 cells expressing CYP2E1 in both the ER and mitochondria have exacerbated levels of palmitic acid cytotoxicity and inhibited respiration. CYP2E1 expression did not impact lipid accumulation from fatty acid exposures, but mitochondrial CYP2E1 expression promoted lipid droplet depletion during serum starvation. In contrast to HepG2 cells, differentiated HepaRG cells express abundant CYP2E1, but they are not sensitive to palmitic acid cytotoxicity. Oleic acid exposure prompted less cytotoxicity, and CYP2E1 expression in the ER prevented an oleic-acid-induced increase in respiration. HepG2 cells exposed to mixtures of palmitic and oleic acid are protected from palmitic acid cytotoxicity. Additionally, we identified that CYP2E1 was decreased at the gene and protein level in hepatocellular carcinoma. Moreover, patients with tumors that had higher CYP2E1 expression had a better prognosis compared to patients with lower CYP2E1 expression.</div></div><div><h3>Innovation</h3><div>This study has demonstrated that transgenic CYP2E1 subcellular localization plays an important role in sensitivity to cytotoxicity, lipid storage, and respiration in the hepatoma cell line HepG2 exposed to palmitic and oleic acid. HepaRG cells, in contrast, were insensitive to palmitic acid. This work demonstrates the clear importance of CYP2E1 in dictating lipotoxicity and differential roles for the mitochondrial and ER forms of the enzyme. Additionally, our data supports a potentially unique role for CYP2E1 in cancer cells.</div></div><div><h3>Conclusion</h3><div>There lies a role for CYP2E1 in altering lipotoxicity, and since CYP2E1 is known to be upregulated in both liver disease and hepatocellular carcinoma, it is important to better define how the role of CYP2E1 changes during disease progression.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100195"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142423220","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":"Protective effects of amphetamine and methylphenidate against dopaminergic neurotoxicants in SH-SY5Y cells","authors":"Patrícia Carneiro ,&nbsp;Mariana Ferreira ,&nbsp;Vera Marisa Costa ,&nbsp;Félix Carvalho ,&nbsp;João Paulo Capela","doi":"10.1016/j.crtox.2024.100165","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100165","url":null,"abstract":"<div><p>Full treatment of the second most common neurodegenerative disorder, Parkinson’s disease (PD), is still considered an unmet need. As the psychostimulants, amphetamine (AMPH) and methylphenidate (MPH), were shown to be neuroprotective against stroke and other neuronal injury diseases, this study aimed to evaluate their neuroprotective potential against two dopaminergic neurotoxicants, 6-hydroxydopamine (6-OHDA) and paraquat (PQ), in differentiated human dopaminergic SH-SY5Y cells.</p><p>Neither cytotoxicity nor mitochondrial membrane potential changes were seen following a 24-hour exposure to either therapeutic concentration of AMPH or MPH (0.001–10 μM). On the other hand, a 24-hour exposure to 6-OHDA (31.25–500 μM) or PQ (100–5000 μM) induced concentration-dependent mitochondrial dysfunction, assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and lysosomal damage, evaluated by the neutral red uptake assay. The lethal concentrations 25 and 50 retrieved from the concentration-toxicity curves in the MTT assay were 99.9 µM and 133.6 µM for 6-OHDA, or 422 µM and 585.8 µM for PQ. Both toxicants caused mitochondrial membrane potential depolarization, but only 6-OHDA increased reactive oxygen species (ROS). Most importantly, PQ-induced toxicity was partially prevented by 1 μM of AMPH or MPH. Nonetheless, neither AMPH nor MPH could prevent 6-OHDA toxicity in this experimental model.</p><p>According to these findings, AMPH and MPH may provide some neuroprotection against PQ-induced neurotoxicity, but further investigation is required to determine the exact mechanism underlying this protection.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100165"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000185/pdfft?md5=e8feb0868f6d3c35be317d1482d07e68&pid=1-s2.0-S2666027X24000185-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140209355","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}