Current Research in Toxicology最新文献

{"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":"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":"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}

{"title":"Tests for learning and memory in rodent regulatory studies","authors":"Charles V. Vorhees ,&nbsp;Michael T. Williams","doi":"10.1016/j.crtox.2024.100151","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100151","url":null,"abstract":"<div><p>For decades, regulatory guidelines for safety assessment in rodents for drugs, chemicals, pesticides, and food additives with developmental neurotoxic potential have recommended a single test of learning and memory (L&amp;M). In recent years some agencies have requested two such tests. Given the importance of higher cognitive function to health, and the fact that different types of L&amp;M are mediated by different brain regions assessing higher functions represents a step forward in providing better evidence-based protection against adverse brain effects. Given the myriad of tests available for assessing L&amp;M in rodents this leads to the question of which tests best fit regulatory guidelines. To address this question, we begin by describing the central role of two types of L&amp;M essential to all mammalian species and the regions/networks that mediate them. We suggest that the tests recommended possess characteristics that make them well suited to the needs in regulatory safety studies. By brain region, these are (1) the hippocampus and entorhinal cortex for spatial navigation, which assesses explicit L&amp;M for reference and episodic memory and (2) the striatum and related structures for egocentric navigation, which assesses implicit or procedural memory and path integration. Of the tests available, we suggest that in this context, the evidence supports the use of water mazes, specifically, the Morris water maze (MWM) for spatial L&amp;M and the Cincinnati water maze (CWM) for egocentric/procedural L&amp;M. We review the evidentiary basis for these tests, describe their use, and explain procedures that optimize their sensitivity.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100151"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000045/pdfft?md5=4cdf122e9c38230165b1676d856c4200&pid=1-s2.0-S2666027X24000045-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139549244","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":"Acceleration of benzo(a)pyrene-induced colon carcinogenesis by Western diet in a rat model of colon cancer","authors":"Kelly L. Harris ,&nbsp;Kenneth J. Harris ,&nbsp;Leah D. Banks ,&nbsp;Samuel E. Adunyah,&nbsp;Aramandla Ramesh","doi":"10.1016/j.crtox.2024.100162","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100162","url":null,"abstract":"<div><p>Colorectal cancer (CRC) is the third leading cause of cancer-related mortalities in the USA and around 52,550 people were expected to die from this disease by December 2023. The objective of this study was to investigate the effect of diet type on benzo(a)pyrene [B(a)P]-induced colon cancer in an adult male rat model, the Polyposis In the Rat Colon (PIRC) kindred type. Groups of PIRC rats (n = 10) were fed with AIN-76A regular diet (RD) or Western diet (WD) and received 25, 50 and 100 µg B(a)P/kg body wt. via oral gavage for 60 days. Rats fed diets alone, but no B(a)P, served as controls. After exposure, rats were euthanized; colon and liver samples were analyzed for activation of drug metabolizing enzymes (DMEs) CYP1A1, CYP1B1, SULT and GST. Plasma and tissue samples were analyzed by reverse phase-HPLC for B(a)P metabolites. In addition to these studies, DNA isolated from colon and liver tissues was analyzed for B(a)P-induced DNA adducts by the ³²P-postlabeling method using a thin-layer chromatography system. Western diet consumption resulted in a marked increase in DME expression and B(a)P metabolite concentrations in rats that were administered 100 µg/kg B(a)P + WD (p &lt; 0.05) compared to other treatment groups. Our findings demonstrate that WD accelerates the development of colon tumors induced by B(a)P through enhanced biotransformation, and the products of this process (metabolites) were found to bind with DNA and form B(a)P-DNA adducts, which may have given rise to colon polyps characterized by gain in tumor number, sizes, and dysplasia.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100162"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X2400015X/pdfft?md5=fa6e9e7a98636748599bec26e093a373&pid=1-s2.0-S2666027X2400015X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140096236","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":"Environmental cadmium-induced circRNA-miRNA-mRNA network regulatory mechanism in human normal liver cell model","authors":"Zhi Qu ,&nbsp;Lugang Deng ,&nbsp;Chunqian Feng ,&nbsp;Peisen Guo ,&nbsp;Peixi Wang ,&nbsp;Nan Liu","doi":"10.1016/j.crtox.2024.100192","DOIUrl":"10.1016/j.crtox.2024.100192","url":null,"abstract":"<div><p>At present, hundreds of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been confirmed to be related to the toxicity of cadmium (Cd). However, the role of circular RNAs (circRNAs) in the toxicity of Cd and the underlying regulatory mechanisms remain unclear. In this study, we chose human normal liver cells (L-02) as a model to investigate changes in transcriptome expression levels following exposure to Cd. Total RNA of each sample was extracted by Trizol method, and the expression profiles of circRNAs, miRNAs and mRNAs of each sample were determined by microarray hybridization and scanning. After standardizing the data, differential circRNAs, miRNAs, and mRNAs associated with the toxic effects of Cd were identified. By screening the predicted circRNAs, miRNAs, and mRNAs, we constructed a competing endogenous RNA (ceRNA) network, and predicted the main biological functions and metabolic pathways influenced by Cd toxicity. Our comprehensive screening strategy led to the identification of 266 different circRNAs, 223 different miRNAs and 519 different mRNAs exhibiting differential expression. Following further screening, even circRNAs, 10 miRNAs and 97 mRNAs were incorporated into the ceRNA network. After performing GO enrichment and KEGG pathway analyses on the 97 mRNAs within the ceRNA network, which indicated that the circRNAs in the ceRNA network are poised to modulate key cellular processes, including cell proliferation, apoptosis, oxidative stress and inflammatory responses under the toxic effects of Cd-induced damage in L-02 cells.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100192"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000458/pdfft?md5=ff0fa6c687127d74e562c5fe0095d0dd&pid=1-s2.0-S2666027X24000458-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142075899","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}