Current Research in Toxicology最新文献

{"title":"The JPX/miR-495-3p/BRD4 axis mediates quercetin-induced toxicity via the X-inactivation center in NSCLC","authors":"Xiaofeng Lou,&nbsp;Jie Wu","doi":"10.1016/j.crtox.2025.100265","DOIUrl":"10.1016/j.crtox.2025.100265","url":null,"abstract":"<div><h3>Background</h3><div>Emerging evidence underscores the pivotal role of long non-coding RNAs (lncRNAs) as master regulators of oncogenic pathways, positioning them as compelling therapeutic targets in precision oncology. While the natural flavonoid quercetin has demonstrated potent anti-neoplastic activity against non-small cell lung cancer (NSCLC), its influence on lncRNA-mediated oncogenic pathways remains unknown. This study is designed to elucidate whether quercetin exerts its anti-NSCLC effects via modulation of lncRNA just proximal to XIST (JPX) and its downstream signaling axis.</div></div><div><h3>Methods</h3><div>NSCLC cell lines were treated with quercetin, and functional assays (CCK-8, BrdU incorporation, scratch assay, and Transwell migration) were conducted to assess proliferation and metastatic potential. Gain- and loss-of-function experiments, combined with qPCR and western blotting, were performed to validate the JPX-modulated regulatory network.</div></div><div><h3>Results</h3><div>Quercetin significantly suppressed NSCLC proliferation and migration by downregulating oncogenic JPX, which in turn upregulated tumor-suppressive miR-495-3p, leading to bromodomain-containing protein 4 (BRD4) suppression. JPX silencing mimicked quercetin’s effects, while rescue experiments confirmed the JPX/miR-495-3p/BRD4 axis as critical for quercetin’s activity.</div></div><div><h3>Conclusion</h3><div>Our findings identify quercetin as a natural compound targeting the JPX-miR-495-3p-BRD4 cascade, providing both mechanistic insights and a translational rationale for quercetin-based NSCLC therapy. These findings highlight the therapeutic potential of quercetin in NSCLC and support further exploration of lncRNA-targeted strategies.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"9 ","pages":"Article 100265"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525810","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":"Exploring transcriptomic databases to identify and experimentally validate tissue-specific consensus reference gene for gene expression normalization in BALB/c mice acutely exposed to 2,3,7,8-Tetrachlorodibenzo-p-dioxin","authors":"Nour Hammoudeh ,&nbsp;Reem Hasan ,&nbsp;Mohammad Deeb ,&nbsp;Zuher Radwan ,&nbsp;Omar Ayoubi ,&nbsp;Roaa Alendary ,&nbsp;Mouayad Youssef ,&nbsp;Abdulfattah Kazan ,&nbsp;Rasil Alsahli ,&nbsp;Walaa Faiad ,&nbsp;Nour Aldeli ,&nbsp;Abdulsamie Hanano","doi":"10.1016/j.crtox.2025.100234","DOIUrl":"10.1016/j.crtox.2025.100234","url":null,"abstract":"<div><div>2,3,7,8-Tetrachlorodibenzo-<em>p</em>-dioxin (TCDD) is a toxic compound affecting organs like the liver, kidney, lung, and reproductive systems in mammals. This study outlines a strategy for choosing appropriate HKGs for tissue-specific gene expression analysis in TCDD toxicity, including four steps: i) identifying candidate HKGs from literature and databases; ii) defining primers from literature or designing new ones; iii) validating primer efficiency and specificity; iv) experimentally assessing candidate HKGs’ stability in various tissues of TCDD-exposed mice.</div><div>Based on this strategy, a total of 40 potential HKGs was selected, further filtered based on their database sources and ranked according to their frequency of use or expression stability. Ultimately, we identified a final set of 15 HKGs (<em>Rps18</em>, <em>Calr</em>, <em>Polr2b</em>, <em>Brms1l</em>, <em>P4hb</em>, <em>Esd</em>, <em>Hdgf</em>, <em>Gapdh</em>, <em>Mlec</em>, <em>Tbp</em>, <em>Rn18s</em>, <em>Sdha</em>, <em>B2m</em>, <em>Actr3</em> and <em>Actb</em>) with typical efficiencies for further evaluation. Then, the stability of the selected HKGs was determined in the liver, kidney, lung, ovary and testis of TCDD-exposed mouse compared to the control group using the [log (2^ΔCt)] and statistically analyzed using Pearson correlation coefficient (<em>r</em>) by BestKeeper algorithm. Our data analysis revealed that <em>Actb</em>, <em>Rps18</em>, and <em>Polr2b</em> were the most stable HKGs for normalizing gene expression in the liver, while <em>Sdha</em>, <em>Actb</em>, and <em>Gapdh</em> were suitable for kidney tissue. In the lung, <em>Tbp</em>, <em>Sdha</em>, and <em>Rps18</em> showed stability, while <em>Tbp</em>, <em>B2m</em>, and <em>Actb</em> were most stable in ovary. Lastly, <em>Actb</em>, <em>B2m</em>, and <em>Tbp</em> were accurately stable in the testis of TCDD-exposed mice. Our study identifies stable HKGs, improving TCDD toxicity research accuracy and reliability.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100234"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885937","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":"The impact of in utero tobacco exposure on smoking behaviors, cardiovascular disease risk and all-cause mortality in adulthood: A UK Biobank study","authors":"Yanxu Zheng ,&nbsp;Xinyu Xiong ,&nbsp;Jing Bao ,&nbsp;Jingyu Liu ,&nbsp;Jin Wang ,&nbsp;Fang Zou ,&nbsp;Zixi Chen ,&nbsp;Yang Guo ,&nbsp;Qingyao Wang ,&nbsp;Yixuan Qiu ,&nbsp;Zhaowei Zhu","doi":"10.1016/j.crtox.2025.100226","DOIUrl":"10.1016/j.crtox.2025.100226","url":null,"abstract":"<div><div>The knowledge regarding the negative impacts of in utero tobacco exposure (IUTE) on cardiovascular disease (CVD) was incomplete. This study aims to assess the association between IUTE and the risks of CVD incidence and all-cause mortality, discuss the inter-group difference based on genetic susceptibility and smoking behaviors after birth, and explore the potential mediating factors. Utilizing a total of 375,024 participants from the UK Biobank, the outcomes include myocardial infarction, stroke, chronic ischemic heart disease, nonrheumatic aortic valve disorders, cardiomyopathy, heart failure, atherosclerosis, aortic aneurysm and dissection, and all-cause mortality. During a median follow-up period of 14.6 years, 50,434 cases of CVD were recorded. IUTE was significantly associated with increased CVD incidence (HR 1.10, 95 % CI 1.08–1.12) and all-cause mortality (HR 1.11, 95 % CI 1.09–1.14). Interaction effects between IUTE, smoking behaviors after birth, and genetic risk scores for CVD were observed significant (P for interaction &lt; 0.005). The results of the cross-sectional study revealed a significant positive association between IUTE and smoking behaviors after birth (OR 1.08, 95 % CI 1.06–1.09). Mediation analysis indicated that smoking behaviors (Proportion = 12.40 %, P &lt; 0.001) and HDL-c levels (Proportion = 14.20 %, P &lt; 0.001) partially mediated the IUTE-CVD relationship. This study demonstrated that individuals with IUTE have a higher risk of developing CVD, and smoking behaviors after birth have multifaceted influence on this correlation. These findings underscore the importance of mothers avoiding smoking during pregnancy to mitigate adverse effects on their offspring.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100226"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511086","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":"Comparative acute toxicity of intravenous paclitaxel and sirolimus in rats","authors":"Jing Xie ,&nbsp;Denise Schuett ,&nbsp;Ulrich Speck ,&nbsp;Tobias Haase","doi":"10.1016/j.crtox.2025.100248","DOIUrl":"10.1016/j.crtox.2025.100248","url":null,"abstract":"<div><h3>Aim</h3><div>In view of the exploration of sirolimus (rapamycin) as balloon coating for peripheral intravasal treatment and the reports on unfavorable tolerance of daily low-dose sirolimus, the aim of the study was to investigate potential toxicological effects of a single intravascular dose of sirolimus in comparison to paclitaxel and vehicle in the rat.</div></div><div><h3>Methods</h3><div>Rats were treated intravenously with a single dose of 20 mg/kg sirolimus or paclitaxel dissolved in identical vehicle and sacrificed 5- or 14-days post treatment. Vehicle (Cremophor<!--> <!-->EL/Ethanol diluted with saline) treated rats served as a control. Potential effects on survival, hematology, organ weights, organ histology were analyzed.</div></div><div><h3>Results</h3><div>Single dose i.v. injection of sirolimus, paclitaxel and vehicle induced temporary sedation after treatment. One animal treated with paclitaxel died, probably due to solvent toxicity. Sirolimus, paclitaxel and the vehicle control were tolerated. Animals treated with sirolimus or paclitaxel showed temporary hematological effects and thymic atrophy that subsided after 14 days. Sirolimus induced a temporary weight reduction of ovaries and uterus. Male rats showed histological changes of testes at 14 days after sirolimus treatment. Notably, sirolimus induced a prolonged body weight reduction compared to paclitaxel and vehicle treatment in male rats.</div></div><div><h3>Conclusion</h3><div>Both substances showed similar and acceptable tolerability after high single-dose intravenous treatment. The results of this study do not indicate safety concerns that would preclude the use of sirolimus as an active ingredient on balloon catheters as an alternative to paclitaxel.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"9 ","pages":"Article 100248"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534663","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":"A simple, reliable and easily generalizable cell-based assay for screening potential drugs that inhibit lipid accumulation","authors":"Weili Yang,&nbsp;Qiuyue Pan,&nbsp;Qi Li,&nbsp;Sirui Zhou,&nbsp;Xi Cao","doi":"10.1016/j.crtox.2024.100213","DOIUrl":"10.1016/j.crtox.2024.100213","url":null,"abstract":"<div><div>Ectopic lipid deposition in the hepatocyte plays an important role in the development of nonalcoholic fatty liver disease (NAFLD), which has become one of the most common causes of chronic liver disease worldwide yet no approved drugs are currently available. In this study, a cell-based method was developed to screen potential drugs with low toxicity that inhibit lipid accumulation. In the same 96-well plate, cytotoxicity was measured using CCK8 assay, followed by lipid content detection using BODIPY 493/503 via fluorometry assay, a lipid droplet-specific fluorescent dye commonly used in microscopy and flow cytometry, but not previously reported in fluorometry. Lipid content was normalized to DAPI staining to control for cell number. The results of this assay were highly consistent with the fluorescence microscopy, with significantly lower intra-group variability in detecting lipid accumulation induced by free fatty acids in Huh7 cells. Validation was conducted using 10 well documented steatotic compounds and 5 negative controls, all of which were correctly identified by the assay. In addition, the inhibitory effect of ML261, a well-known inhibitor of hepatic lipid droplets formation, was also confirmed by the assay both in AML12 cells and Hepa1-6 cells. To our knowledge, this study is the first to quantify lipid droplets using BODIPY 493/503 by fluorometry assay, and to demonstrate that CCK8 does not interfere with subsequent BODIPY 493/503 staining, both of which will reduce the cost and increase the efficiency. In conclusion, the method is simple, reliable, efficient and does not rely on expensive instruments, making it an easily generalizable approach to identify potential drug candidates for NAFLD treatment.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100213"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11743863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001848","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":"Developmental polychlorinated biphenyl (PCB) exposure impacts on voiding physiology persist into adulthood and influence sensitivity to bladder stimuli in mice","authors":"Monica Ridlon,&nbsp;Audrey Spiegelhoff,&nbsp;Conner L Kennedy,&nbsp;Thomas Lavery,&nbsp;Kathy Wang,&nbsp;Julia Tlapa,&nbsp;Tamryn Jordan,&nbsp;Lindsey Felth Tanaka,&nbsp;Kimberly Keil Stietz","doi":"10.1016/j.crtox.2025.100227","DOIUrl":"10.1016/j.crtox.2025.100227","url":null,"abstract":"<div><div>Polychlorinated biphenyls (PCBs) are toxicants present in the environment, foodstuff, animal and human tissues. PCBs are linked to numerous adverse health effects; however, impacts of developmental PCB exposure on lower urinary tract function are a comparatively newer area of interest. We have previously found developmental exposure (<em>in utero</em> and lactational) to a human-relevant PCB mixture in mice leads to sex- and dose- dependent changes to urinary voiding physiology at 6 weeks of age. This study expands upon previous findings to investigate if developmental PCB-induced urinary voiding phenotypes persist or shift as mice age to 12 weeks of age. Urinary voiding physiology testing through void spot assays, uroflowmetry, and cystometry demonstrated several sex- and dose- dependent effects of PCB exposure at 12 weeks of age. Further, patterns of dysfunction were either maintained, newly acquired, or reversed compared to those from younger adult mice in a previous study. Here, developmental PCB exposure decreased number of small urine spots in adult male and female mice in a dose dependent manner, and female mice had more frequent voiding events assessed by anesthetized cystometry. Mice also had PCB dose-dependent changes to urinary voiding physiology when challenged with intravesical capsaicin infusion to target transient receptor potential cation channel subfamily V member 1 (TRPV1)-mediated pathways. PCBs either blocked or exacerbated capsaicin induced responses depending on the endpoint examined, suggesting this pathway may play a role in PCB-dependent changes in voiding. PCBs also had subtle impacts on prostate wet weight, with high PCB doses reducing tissue mass compared to low PCB doses, while none differed from vehicle. This study demonstrates developmental exposure to PCBs continues to impact lower urinary tract function in adulthood to at least 12 weeks of age both during homeostatic conditions and upon challenge of capsaicin. Better understanding of how early life stressors like PCBs contribute to aging-associated voiding dysfunction are imperative as these findings may help mitigate risk or improve treatment strategies for patients suffering from lower urinary tract symptoms.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100227"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143628828","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":"Novel dose- and time-dependent toxicity biomarkers of fentanyl/carfentanyl: uncovered by urine-plasma metabolomics for forensics","authors":"Wanting Xie ,&nbsp;Shuo Yang ,&nbsp;Xin Wang ,&nbsp;Jinting Liu ,&nbsp;Wen Gao ,&nbsp;Yan Shi","doi":"10.1016/j.crtox.2025.100269","DOIUrl":"10.1016/j.crtox.2025.100269","url":null,"abstract":"<div><div>Fentanyl analogs present a significant global risk to public health and safety due to their high abuse potential and related mortality. However, the absence of a structured research framework focused on their clinical pharmacology and toxicology has led to a scarcity of studies on the mechanisms underlying the toxicity of and addiction to these substances, particularly regarding the rapidly emerging new fentanyl analogs. In this study, we employed a nontargeted metabolomics strategy. By conducting multivariate statistical analysis on ultrahigh performance liquid chromatography–high resolution mass spectrometry (UHPLC-HRMS) data from rat urine and plasma to elucidate the metabolic disruptions induced by fentanyl and carfentanyl. Adult male SD rats were randomly assigned to four groups: low-dose fentanyl group, high-dose fentanyl group, low-dose carfentanyl group, and high-dose carfentanyl group. All groups underwent continuous tail vein injection of toxicants for 5 consecutive days. Plasma and urine samples were collected from the rats before the first administration and at different time points after the last administration, followed by detection and analysis. Specifically, we aimed to elucidate the dose- and time-dependent metabolic toxicity of fentanyl and carfentanyl through a nontargeted metabolomics strategy. Oxidative stress, immunosuppression, and energy dysregulation were identified as core toxic effects of fentanyl and carfentanyl, tightly linked to perturbations in taurine and glutathione pathways, taurine regulating immune function and neuronal homeostasis, glutathione maintaining redox homeostasis. Succinic acid and taurine were confirmed as common biomarkers in urine and plasma. Succinic acid showed decreased plasma levels and increased urine levels, directly indicating fentanyl and carfentanyl-induced energy metabolism impairment. Taurine exhibited similar dysregulation, reflecting drug-induced immunosuppression and neuronal excitability abnormalities. These findings provide critical references and experimental support for studies on fentanyl-related hazards, toxicological mechanisms, and forensic detection.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"9 ","pages":"Article 100269"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145525288","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":"Assessing placental transfer and in utero reproductive effects in rats of a short-chained paraffin with in vitro endocrine disrupting properties","authors":"Mikala Melchiors ,&nbsp;Anna Kjerstine Rosenmai ,&nbsp;Ronan Cariou ,&nbsp;Mikael Pedersen ,&nbsp;Sofie Christiansen ,&nbsp;Terje Svingen","doi":"10.1016/j.crtox.2025.100237","DOIUrl":"10.1016/j.crtox.2025.100237","url":null,"abstract":"<div><div>Chlorinated paraffins (CPs) are industrial chemicals detected widely in the environment and human tissues, raising concerns due to their persistence, bioaccumulation, and potential health risks. CPs with lower chlorination or shorter carbon chain lengths can cross the placenta and have been detected in breast milk, indicating fetal and early postnatal exposure. Both <em>in vitro</em> and <em>in vivo</em> studies suggest that CPs exhibit endocrine-disrupting properties, particularly affecting reproductive development. This study investigates the developmental effects and placental transfer of 1,2,9,10-tetrachlorodecane (T₄C₁₀), a short-chained CP congener, by exposing pregnant rats from gestation days 7 to 21. T₄C₁₀ concentrations were measured in fetal and maternal blood, fetal steroid hormone levels were measured, and targeted gene expression was analyzed in the fetal genital tubercle. Despite prior <em>in vitro</em> evidence of endocrine-disrupting activity<em>, in vivo</em> exposure to T₄C₁₀ did not significantly affect reproductive parameters, including the anogenital distance (AGD), fetal steroid hormone profiles, or expression of androgen- and estrogen-regulated genes in the developing genital tubercle. The low systemic T₄C₁₀ levels in maternal and fetal blood suggest rapid metabolism or sequestration in adipose tissue, supported by increased liver weight in the exposed dams. These findings suggest that while T₄C₁₀ can cross the placenta, its bioavailability <em>in vivo</em> may be insufficient to elicit measurable endocrine-disrupting effects on reproductive development. This study underscores the importance of accounting for toxicokinetics when extrapolating <em>in vitro</em> findings to <em>in vivo</em> endpoints.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100237"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935673","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":"Evaluation of the endocrine disrupting potential of Di-isononyl phthalate","authors":"I.A. Lea ,&nbsp;A.N. Buerger ,&nbsp;D. Feifarek ,&nbsp;A. Mihalchik ,&nbsp;M.M. Heintz ,&nbsp;L.C. Haws ,&nbsp;H. Nyambego ,&nbsp;K. Goyak ,&nbsp;C. Palermo ,&nbsp;S.J. Borghoff","doi":"10.1016/j.crtox.2025.100220","DOIUrl":"10.1016/j.crtox.2025.100220","url":null,"abstract":"<div><div>Low molecular weight <em>ortho</em>-phthalate compounds have been implicated in disruption of androgen pathways when exposure occurs during the masculinization programming window. Di-isononyl phthalate (DINP) is a high molecular weight phthalate and a high production volume chemical. To understand the potential for DINP and its metabolites to disrupt endocrine pathways, a weight of evidence assessment was conducted according to the European Chemicals Agency (ECHA)/ European Food Safety Authority (EFSA) Endocrine Disruptor Guidance (2018). Toxicological data related to estrogen (E), androgen (A), thyroid (T), or steroidogenesis (S) pathways was assessed. Literature searches returned 110 articles from which data were extracted and assessed in conjunction with 105 high-throughput assays. An <em>in-silico</em> assessment of the EATS activity for DINP metabolites also was conducted. Based on the available evidence, DINP did not elicit thyroid- or estrogen-related apical outcomes <em>in vivo.</em> There were no studies evaluating thyroid hormone levels <em>in vivo</em> which, according to the ECHA/EFSA guidance, constitutes a data gap and prevents a conclusion being drawn on the T-pathway. The E, A, and S-pathways were sufficiently assessed to conclude on the endocrine disrupting potential of DINP. Based on the lack of apical outcomes, DINP did not disrupt the E-pathway. For the A and S-pathways, there was limited evidence to support adverse apical outcomes, so a mode of action assessment using a structured adverse outcome pathway (AOP) framework was performed. No biologically plausible link could be established between the key events in the hypothesized AOP that lead to adverse outcomes. Further, no dose or temporal concordance for A- and S-mediated findings were identified. Therefore, DINP does not meet the ECHA/EFSA criteria to be considered an endocrine disruptor.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100220"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143510178","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":"A computational dynamic systems model for in silico prediction of neural tube closure defects","authors":"Job H. Berkhout ,&nbsp;James A. Glazier ,&nbsp;Aldert H. Piersma ,&nbsp;Julio M. Belmonte ,&nbsp;Juliette Legler ,&nbsp;Richard M. Spencer ,&nbsp;Thomas B. Knudsen ,&nbsp;Harm J. Heusinkveld","doi":"10.1016/j.crtox.2024.100210","DOIUrl":"10.1016/j.crtox.2024.100210","url":null,"abstract":"<div><div>Neural tube closure is a critical morphogenetic event during early vertebrate development. This complex process is susceptible to perturbation by genetic errors and chemical disruption, which can induce severe neural tube defects (NTDs) such as spina bifida. We built a computational agent-based model (ABM) of neural tube development based on the known biology of morphogenetic signals and cellular biomechanics underlying neural fold elevation, bending and fusion. The computer model functionalizes cell signals and responses to render a dynamic representation of neural tube closure. Perturbations in the control network can then be introduced synthetically or from biological data to yield quantitative simulation and probabilistic prediction of NTDs by incidence and degree of defect. Translational applications of the model include mechanistic understanding of how singular or combinatorial alterations in gene-environmental interactions and animal-free assessment of developmental toxicity for an important human birth defect (spina bifida) and potentially other neurological problems linked to development of the brain and spinal cord.</div></div>","PeriodicalId":11236,"journal":{"name":"Current Research in Toxicology","volume":"8 ","pages":"Article 100210"},"PeriodicalIF":2.9,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403139","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}