Current Research in Toxicology最新文献

{"title":"Prenatal test cohort of a modified rat comparative thyroid assay adding brain thyroid hormone measurements and histology but lowering group size appears able to detect disruption by sodium phenobarbital","authors":"Kenta Minami ,&nbsp;Akira Sato ,&nbsp;Naruto Tomiyama ,&nbsp;Keiko Ogata ,&nbsp;Tadashi Kosaka ,&nbsp;Hitoshi Hojo ,&nbsp;Naofumi Takahashi ,&nbsp;Hidenori Suto ,&nbsp;Hiroaki Aoyama ,&nbsp;Tomoya Yamada","doi":"10.1016/j.crtox.2024.100168","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100168","url":null,"abstract":"<div><p>The Comparative Thyroid Assay (CTA, USEPA) is a screening test for thyroid hormone (TH) disruption in peripheral blood of dams and offspring. Recently, we began investigating feasible improvements to the CTA by adding examination of offspring brain TH concentrations and brain histopathology. In addition, we hypothesize that the number of animals required could be reduced by 50 % while still maintaining sensitivity to characterize treatment related changes in THs. Previously, we showed that the prenatal test cohort of the modified CTA could detect 1000 ppm sodium phenobarbital (NaPB)-induced suppression of brain T3 (by 9 %) and T4 (by 33 %) with no significant changes in serum T3 and T4 (less than 8 %). In the current study we expanded the dose response in a prenatal test cohort. Pregnant SD rats (N = 10/group) were exposed to 0, 1000 or 1500 ppm NaPB in the diet from gestational days (GD) 6 to GD20. Serum THs concentrations in GD20 dams together with serum/brain THs concentrations and brain histopathology in the GD20 fetuses were examined. NaPB dose-dependently suppressed serum T3 (up to −26 %) and T4 (up to −44 %) in dams, with suppression of T3 in serum (up to −26 %) and brain (up to −18 %) and T4 in serum (up to −26 %) and brain (up to −29 %) of fetuses but without clear dose dependency. There were no remarkable findings that deviated significantly from controls in GD20 fetal brain by qualitative histopathology. Overall, the present study suggests that the prenatal test cohort of this modified CTA is able to detect the expected fetal TH disruptions by prenatal exposure to NaPB, while also reducing the number of animals used by 50 %, consistent with the results of our previous study. These findings add to the suggestion that lowering group sizes and adding endpoints may be a useful alternative to the original CTA design.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100168"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000215/pdfft?md5=7499a0ae4c5a9041672a636569a69cfb&pid=1-s2.0-S2666027X24000215-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140633208","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":"The role of TFEB-mediated autophagy-lysosome dysfunction in manganese neurotoxicity","authors":"Jiaqiao Lu ,&nbsp;Peng Su ,&nbsp;Fang Zhao ,&nbsp;Kailun Yu ,&nbsp;Xunbo Yang ,&nbsp;Hui Lv ,&nbsp;Diya Wang ,&nbsp;Jianbin Zhang","doi":"10.1016/j.crtox.2024.100193","DOIUrl":"10.1016/j.crtox.2024.100193","url":null,"abstract":"<div><p>Excessive long-term manganese intake can inflict irreversible damage to the nervous system, with a predominant effect on the substantia nigra-striatum pathway. Through a mouse model simulating manganese exposure, we delved into its implications on the central nervous motor system, uncovering autophagy-lysosome dysfunction as a pivotal factor in manganese-induced neurotoxicity. Our research illuminated the molecular mechanisms behind TFEB’s role in manganese-triggered neuronal autophagy dysfunction, offering insights into the cellular and molecular mechanisms of manganese-induced abnormal protein accumulation. This study lays a significant theoretical foundation for future endeavors aimed at safeguarding against manganese neurotoxicity. Furthermore, TFEB emerges as a potential early molecular biomarker for manganese exposure, providing a solid basis for preemptive protection and clinical treatment for populations exposed to manganese.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100193"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X2400046X/pdfft?md5=1d04db65e11909aa79e1d3dea58023c3&pid=1-s2.0-S2666027X2400046X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142272229","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":"RNA sequencing analysis of early-stage atherosclerosis in vascular-on-a-chip and its application for comparing combustible cigarettes with heated tobacco products","authors":"Kazuhiro Ohashi ,&nbsp;Ayaka Hayashida ,&nbsp;Atsuko Nozawa,&nbsp;Shigeaki Ito","doi":"10.1016/j.crtox.2024.100163","DOIUrl":"10.1016/j.crtox.2024.100163","url":null,"abstract":"<div><p>Our previous study showed promising results in replicating early-stage atherosclerosis when vascular endothelial cells (VECs) were exposed to cigarette smoke (CS) extract via M0 macrophages. We used an organ-on-a-chip system as an alternative to animal testing to model atherosclerosis, which is a complex disease involving endothelial and immune cell communications. By incorporating macrophages into the vascular-on-a-chip system, we aimed to mimic the indirect effects of inhalable substances, such as CS, on VECs. In the current study, we further examined the suitability of our <em>in vitro</em> system for mimicking early-stage atherosclerosis by transcriptomic analyses of VECs exposed to CS directly or indirectly via macrophages. We also incorporated M1 macrophages to replicate a preexisting inflammatory state. We found a greater number of differentially expressed genes (DEGs) in direct exposure methods than indirect exposure methods. However, a pathway analysis showed that the direct exposure of CS to VECs primarily caused cell death-related pathway alterations, and the “Atherosclerosis Signaling” pathway was predicted to be negatively regulated. Indirect exposure via M0 macrophages similarly showed that the identified DEGs were related to cell death, while the “Atherosclerosis Signaling” pathway was predicted to be activated. In contrast, cell death-related pathway alterations were not observed by indirect exposure of CS to VECs via M1 macrophages, but the pathway perturbations were similar to a pro-inflammatory positive control. In addition, the “Atherosclerosis Signaling” pathway was predicted to be activated in VECs that were indirectly exposed to CS via M1 macrophages. These results suggest that M0 or M1 macrophages contribute to atherogenic transcriptomic changes in VECs, although they affect cell death-related pathways differently. We also used indirect exposure methods to compare the effects of CS and heated tobacco product (HTP) aerosol. Notably, gene expression changes related to atherosclerosis were less pronounced in HTP aerosol-exposed VECs than CS. Our study highlights the utility of the vascular-on-a-chip system with indirect exposure of CS extract via macrophages for replicating atherogenesis and suggests a reduced risk potential of the HTP. This research contributes to advancing alternatives to animal testing for toxicological and disease modeling studies.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100163"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000161/pdfft?md5=d9dbee79c936851f77c5e3c234823928&pid=1-s2.0-S2666027X24000161-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140272549","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":"Ethylene dimethanesulfonate effects on gene promoter activities related to the endocrine function of immortalized Leydig cell lines R2C and MA-10","authors":"Jorge W.F. de Barros ,&nbsp;Kenley Joule Pierre ,&nbsp;Wilma De G. Kempinas ,&nbsp;Jacques J. Tremblay","doi":"10.1016/j.crtox.2023.100147","DOIUrl":"https://doi.org/10.1016/j.crtox.2023.100147","url":null,"abstract":"<div><p>Ethylene dimethanesulfonate (EDS) is a molecule with known selective cytotoxicity on adult Leydig cells. A single intraperitoneal injection in rats but not mice, leads to male androgen deprivation and infertility. <em>In vitro</em> studies using rat and mouse immortalized Leydig cell lines, showed similar effects of cell death promoted by EDS in rat cells as seen <em>in vivo</em>, and suggest that EDS affects gene transcription, which could firstly compromise steroidogenesis before the apoptosis process. Using gene reporter assay, this study aimed to investigate EDS effects on the promoter activity of genes important for endocrine function (<em>Star</em>, <em>Insl3</em>) and response to toxic agents (<em>Gsta3</em>) in immortalized Leydig cell lines (rat R2C and mouse MA-10 cells), as well as identify possible EDS-responsive elements in the <em>Star</em> gene promoter. EDS exposure of R2C and MA-10 Leydig cells increased <em>Gsta3</em> promoter activity after 4 h of treatment and decreased <em>Insl3</em> promoter activity only in R2C cells after 24 h of treatment. EDS also decreased <em>Star</em> promoter activity in both Leydig cell lines. Using R2C cells, the EDS-responsive region in the <em>Star</em> promoter was located between −400 and −195 bp. This suggests that this region and the associated transcription factors, which include MEF2, might be targeted by EDS. Additional somatic gonadal cell lines expressing <em>Star</em> were used and EDS did not affect <em>Star</em> promoter activity in DC3 granulosa cells while <em>Star</em> promoter activity was increased in MSC-1 Sertoli cells after 24 h of treatment. This study contributes to the knowledge regarding the mechanism of EDS action in Leydig cells, and in other gonadal cell lineages, and brings new light regarding the rats and mice differential susceptibility to EDS effects, in addition to providing new avenues for experimental approaches to better understand Leydig cell function and dynamics in different rodent species.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100147"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X23000452/pdfft?md5=7638e3700b61387d77ad30d1e6ae81c8&pid=1-s2.0-S2666027X23000452-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139108115","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":"Assessing developmental toxicity and non-CYP mediated biotransformation of two anti-epileptics and their human metabolites in zebrafish embryos and larvae","authors":"Jente Hoyberghs ,&nbsp;Axelle Coppens ,&nbsp;Chloé Bars ,&nbsp;Chris Van Ginneken ,&nbsp;Kenn Foubert ,&nbsp;Steven Van Cruchten","doi":"10.1016/j.crtox.2024.100186","DOIUrl":"10.1016/j.crtox.2024.100186","url":null,"abstract":"<div><p>Zebrafish embryo-based assays are a promising alternative for animal testing to screen new compounds for developmental toxicity. However, recent studies in zebrafish embryos showed an immature intrinsic cytochrome P450 (CYP)-mediated biotransformation capacity, as most CYPs were only active at the end of the organogenesis period. Data on other phase I enzymes involved in the biotransformation of xenobiotics in zebrafish embryos is limited. This information is pivotal for proteratogens needing bioactivation to exert their teratogenic potential. Therefore, this study aimed to investigate whether carbamazepine (CBZ) and levetiracetam (LTC), two anti-epileptic drugs that require bioactivation to exert their teratogenic potential, are biotransformed into non-CYP mediated metabolites in the zebrafish embryo and whether one or more of these metabolites cause developmental toxicity in this species. In the first step, zebrafish embryos were exposed to LTC and CBZ and their non-CYP mediated human metabolites, etiracetam carboxylic acid (ECA) and 9-acridine carboxaldehyde (9ACA), acridine (AI), and acridone (AO), respectively, from 5.25 to 120 hpf and morphologically evaluated. Next, the uptake of all compounds and the formation of the metabolites were assessed using LC-MS methods. As LTC and ECA were, respectively, poorly or not taken up by zebrafish larvae during the exposure experiments, we could not determine if LTC and ECA are teratogenic. However, biotransformation of LTC into ECA was observed at 24 hpf and 120 hpf, which indicates that the special type of B-esterase is already active at 24 hpf. CBZ and its three metabolites were teratogenic, as a significant increase in malformed embryos was observed for all of them. All three metabolites were more potent teratogens than CBZ, with AI being the most potent, followed by 9ACA and AO. The myeloperoxidase (MPO) homologue is already active at 24 hpf, as CBZ was biotransformed into 9ACA and AO in 24 hpf zebrafish embryos, and into 9ACA in 120 hpf larvae. Moreover, 9ACA was also found to be biotransformed into AI and AO, and AI into AO. As such, one or more of these metabolites probably contribute to the teratogenic effects observed in zebrafish larvae after exposure to CBZ.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100186"},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000392/pdfft?md5=14a59dc81d0aa75c48d98d92747ceecd&pid=1-s2.0-S2666027X24000392-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141703758","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":"Acute toxicity of binary mixtures for quorum sensing inhibitors and sulfonamides against Aliivibrio fischeri: QSAR investigations and joint toxic actions","authors":"Zhenheng Long ,&nbsp;Jingyi Yao ,&nbsp;Minghong Wu ,&nbsp;Shu-shen Liu ,&nbsp;Liang Tang ,&nbsp;Bo Lei ,&nbsp;Jiajun Wang ,&nbsp;Haoyu Sun","doi":"10.1016/j.crtox.2024.100172","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100172","url":null,"abstract":"<div><p>Quorum sensing inhibitors (QSIs), as a kind of ideal antibiotic substitutes, have been recommended to be used in combination with traditional antibiotics in medical and aquaculture fields. Due to the co-existence of QSIs and antibiotics in environmental media, it is necessary to evaluate their joint risk. However, there is little information about the acute toxicity of mixtures for QSIs and antibiotics. In this study, 10 QSIs and 3 sulfonamides (SAs, as the representatives for traditional antibiotics) were selected as the test chemicals, and their acute toxic effects were determined using the bioluminescence of <em>Aliivibrio fischeri</em> (<em>A. fischeri</em>) as the endpoint. The results indicated that SAs and QSIs all induced S-shaped dose-responses in <em>A. fischeri</em> bioluminescence. Furthermore, SAs possessed greater acute toxicity than QSIs, and luciferase (Luc) might be the target protein of test chemicals. Based on the median effective concentration (EC₅₀) for each test chemical, QSI-SA mixtures were designed according to equitoxic (EC_50(QSI):EC_50(SA) = 1:1) and non-equitoxic ratios (EC_50(QSI):EC_50(SA) = 1:10, 1:5, 1:0.2, and 1:0.1). It could be observed that with the increase of QSI proportion, the acute toxicity of QSI-SA mixtures enhanced while the corresponding TU values decreased. Furthermore, QSIs contributed more to the acute toxicity of test binary mixtures. The joint toxic actions of QSIs and SAs were synergism for 23 mixtures, antagonism for 12 mixtures, and addition for 1 mixture. Quantitative structure–activity relationship (QSAR) models for the acute toxicity QSIs, SAs, and their binary mixtures were then constructed based on the lowest CDOCKER interaction energy (<em>E</em>_bind-Luc) between Luc and each chemical and the component proportion in the mixture. These models exhibited good robustness and predictive ability in evaluating the toxicity data and joint toxic actions of QSIs and SAs. This study provides reference data and applicable QSAR models for the environmental risk assessment of QSIs, and gives a new perspective for exploring the joint effects of QSI-antibiotic mixtures.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100172"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000252/pdfft?md5=4d273a8b47eb940adc329daf679fba1f&pid=1-s2.0-S2666027X24000252-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140951175","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":"Visible particles in parenteral drug products: A review of current safety assessment practice","authors":"Frank Liu ,&nbsp;Richard Hutchinson","doi":"10.1016/j.crtox.2024.100175","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100175","url":null,"abstract":"<div><p>Parenteral drug products (PDPs) are administered extensively to treat various diseases. Product quality plays a critical role in ensuring patient safety and product efficacy. One important quality challenge is the contamination of particles in PDPs. Particle presence in PDPs represents potential safety risk to patients. Differential guidance and practice have been in place for visible (VPs) and subvisible particles (SVPs) in PDPs. For SVPs, the amount limits have been harmonized in multiple Pharmacopeias. The pharmaceutical industry follows the guided limits for regulatory and quality compliance. However, for VPs, no such acceptable limit has been set. This results in not only quality but also safety challenges for manufacturers and drug developers in managing and evaluating VPs. It is important to understand the potential safety risk of VPs so these can be weighed against the benefit of the PDPs. To evaluate their potential risk(s), it is necessary to understand their nature, origin, frequency of their occurrence, safety risk, the risk mitigation measures, and the method to evaluate their safety. The current paper reviews the critical literature on these aspects and provides insight into considerations when performing safety assessment and managing the risk(s) for VPs in PDPs.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"7 ","pages":"Article 100175"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000288/pdfft?md5=efc636ba939c818d5db77f3189465eb5&pid=1-s2.0-S2666027X24000288-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141308253","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 in vitro toxicological assessment of two electronic cigarettes: E-liquid to aerosolisation","authors":"E. Bishop,&nbsp;F. Miazzi,&nbsp;S. Bozhilova,&nbsp;N. East,&nbsp;R. Evans,&nbsp;D. Smart,&nbsp;M. Gaca,&nbsp;D. Breheny,&nbsp;D. Thorne","doi":"10.1016/j.crtox.2024.100150","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100150","url":null,"abstract":"<div><p>Interest in the toxicological assessment of iterations of e-cigarette devices, e-liquid formulations and flavour use is increasing. Here, we describe a multiple test matrix and <em>in<!--> <!-->vitro</em> approach to assess the biological impact of differing e-cigarette activation mechanism (button vs. puff-activated) and heating technology (cotton vs. ceramic wick). The e-liquids selected for each device contained the same nicotine concentration and flavourings. We tested both e-liquid and aqueous extract of e-liquid aerosol using a high throughput cytotoxicity and genotoxicity screen. We also conducted whole aerosol assessment both in a reconstituted human airway lung tissue (MucilAir) with associated endpoint assessment (cytotoxicity, TEER, cilia beat frequency and active area) and an Ames whole aerosol assay with up to 900 consecutive undiluted puffs. Following this testing it is shown that the biological impact of these devices is similar, taking into consideration the limitations and capturing efficiencies of the different testing matrices. We have contextualised these responses against previous published reference cigarette data to establish the comparative reduction in response consistent with reduced risk potential of the e-cigarette products tested in this study as compared to conventional cigarettes.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100150"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000033/pdfft?md5=4e092ed55a75181fa32f780895b7e5fe&pid=1-s2.0-S2666027X24000033-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139480197","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":"Identification of estrogen receptor agonists among hydroxylated polychlorinated biphenyls using classification-based quantitative structure–activity relationship models","authors":"Lukman K. Akinola ,&nbsp;Adamu Uzairu ,&nbsp;Gideon A. Shallangwa ,&nbsp;Stephen E. Abechi ,&nbsp;Abdullahi B. Umar","doi":"10.1016/j.crtox.2024.100158","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100158","url":null,"abstract":"<div><p>Identification of estrogen receptor (ER) agonists among environmental toxicants is essential for assessing the potential impact of toxicants on human health. Using 2D autocorrelation descriptors as predictor variables, two binary logistic regression models were developed to identify active ER agonists among hydroxylated polychlorinated biphenyls (OH-PCBs). The classifications made by the two models on the training set compounds resulted in accuracy, sensitivity and specificity of 95.9 %, 93.9 % and 97.6 % for ERα dataset and 91.9 %, 90.9 % and 92.7 % for ERβ dataset. The areas under the ROC curves, constructed with the training set data, were found to be 0.985 and 0.987 for the two models. Predictions made by models I and II correctly classified 84.0 % and 88.0 % of the test set compounds and 89.8 % and 85.8% of the cross-validation set compounds respectively. The two classification-based QSAR models proposed in this paper are considered robust and reliable for rapid identification of ERα and ERβ agonists among OH-PCB congeners.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100158"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000112/pdfft?md5=aaea4139aa15cb5789aef7803b3c55c3&pid=1-s2.0-S2666027X24000112-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139985348","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":"Cigarette smoking inhibits myoblast regeneration by promoting proteasomal degradation of NPAT protein and hindering cell cycle progression","authors":"Jianfeng Wang ,&nbsp;Jinling Liu ,&nbsp;Jingjing Shao ,&nbsp;Hongyu Chen ,&nbsp;Luyun Cui ,&nbsp;Pei Zhang ,&nbsp;Yinan Yao ,&nbsp;Jianying Zhou ,&nbsp;Zhang Bao","doi":"10.1016/j.crtox.2024.100161","DOIUrl":"https://doi.org/10.1016/j.crtox.2024.100161","url":null,"abstract":"<div><p>Cigarette smoking (CS) causes skeletal muscle dysfunction, leading to sarcopenia and worse prognosis of patients with diverse systemic diseases. Here, we found that CS exposure prevented C2C12 myoblasts proliferation in a dose-dependent manner. Immunoblotting assays verified that CS exposure promoted the expression of cell cycle suppressor protein p21. Furthermore, CS exposure significantly inhibited replication-dependent (RD) histone transcription and caused S phase arrest in the cell cycle during C2C12 proliferation. Mechanistically, CS deregulated the expression levels of Nuclear Protein Ataxia-Telangiectasia Locus (NPAT/p220). Notably, the proteasome inhibitor MG132 was able to reverse the expression of NPAT in myoblasts, implying that the degradation of CS-mediated NPAT is proteasome-dependent. Overexpression of NPAT also rescued the defective proliferation phenotype induced by CS in C2C12 myoblasts. Taken together, we suggest that CS exposure induces NPAT degradation in C2C12 myoblasts and impairs myogenic proliferation through NPAT associated proteasomal-dependent mechanisms. As an application of the proteasome inhibitor MG132 or overexpression of NPAT could reverse the impaired proliferation of myoblasts induced by CS, the recovery of myoblast proliferation may be potential strategies to treat CS-related skeletal muscle dysfunction.</p></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"6 ","pages":"Article 100161"},"PeriodicalIF":3.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2666027X24000148/pdfft?md5=62b76c5eac046a7203d59ddece106329&pid=1-s2.0-S2666027X24000148-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140062871","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}