Archives of Toxicology最新文献

Fullerene and fullerene whisker are not carcinogenic to the lungs and pleura in rat long-term study after 2-week intra-tracheal intrapulmonary administration 大鼠气管内肺部给药 2 周后的长期研究表明，富勒烯和富勒烯晶须不会对肺部和胸膜产生致癌作用

IF 6.1 2区医学

Archives of Toxicology Pub Date : 2024-09-13 DOI: 10.1007/s00204-024-03863-7

Asraful Nahar Sheema, Aya Naiki-Ito, Anna Kakehashi, Omnia Hosny Mohamed Ahmed, David B. Alexander, William T. Alexander, Takamasa Numano, Hiroyuki Kato, Yuko Goto, Hiroshi Takase, Akihiko Hirose, Takatsugu Wakahara, Kun’ichi Miyazawa, Satoru Takahashi, Hiroyuki Tsuda

{"title":"Fullerene and fullerene whisker are not carcinogenic to the lungs and pleura in rat long-term study after 2-week intra-tracheal intrapulmonary administration","authors":"Asraful Nahar Sheema, Aya Naiki-Ito, Anna Kakehashi, Omnia Hosny Mohamed Ahmed, David B. Alexander, William T. Alexander, Takamasa Numano, Hiroyuki Kato, Yuko Goto, Hiroshi Takase, Akihiko Hirose, Takatsugu Wakahara, Kun’ichi Miyazawa, Satoru Takahashi, Hiroyuki Tsuda","doi":"10.1007/s00204-024-03863-7","DOIUrl":"https://doi.org/10.1007/s00204-024-03863-7","url":null,"abstract":"Fullerene whiskers (FLW)s are thin rod-like structures composed of C60 and C70 fullerene (FL). The shape of FLWs suggests potential toxic effects including carcinogenicity to the lung and pleura, similar to effects elicited by asbestos and multi-walled carbon nanotubes (MWCNT)s. However, no long-term carcinogenic studies of FL or FLW have been conducted. In the present study we investigated the pulmonary and pleural carcinogenicity of FL and FLW. Twelve-week-old male F344 rats were administered 0.25 or 0.5 mg FL, FLW, MWCNT-7, and MWCNT-N by intra-tracheal intra-pulmonary spraying (TIPS). Acute lung lesions and carcinogenicity were analyzed at 1 and 104 weeks after 8 doses/15 days TIPS administration. At week 1, FLW, MWCNT-7, and MWCNT-N significantly increased alveolar macrophage infiltration. Expression of Ccl2 and Ccl3, reactive oxygen species production, and cell proliferation were significantly increased by administration of MWCNT-7 and MWCNT-N but not FL or FLW. At week 104, the incidence of bronchiolo-alveolar adenoma plus adenocarcinoma was significantly increased in the MWCNT-7 and MWCNT-N groups, and the incidence of mesothelioma was significantly increased in the MWCNT-7 group. No significant induction of pulmonary or pleural tumorigenesis was observed in the FL or FLW groups. The number of 8-OHdG-positive cells in the alveolar epithelium was significantly increased in the MWCNT-7 and MWCNT-N groups but not in the FL or FLW groups. FL and FLW did not exert pulmonary or pleural carcinogenicity in our study. In addition, oxidative DNA damage was implicated in MWCNT-induced lung carcinogenesis, suggesting that it may be a useful initial marker of carcinogenicity.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MicroRNAs in fluorosis pathogenesis: impact on dental, skeletal, and soft tissues 氟中毒发病机制中的微小核糖核酸：对牙齿、骨骼和软组织的影响

IF 6.1 2区医学

Archives of Toxicology Pub Date : 2024-09-13 DOI: 10.1007/s00204-024-03853-9

Suryaa Manoharan, Syed Saadullah Ashfaq, Ekambaram Perumal

{"title":"MicroRNAs in fluorosis pathogenesis: impact on dental, skeletal, and soft tissues","authors":"Suryaa Manoharan, Syed Saadullah Ashfaq, Ekambaram Perumal","doi":"10.1007/s00204-024-03853-9","DOIUrl":"https://doi.org/10.1007/s00204-024-03853-9","url":null,"abstract":"Fluoride-induced toxicity (fluorosis) poses a significant health concern globally, affecting millions of individuals. Understanding the molecular mechanisms underlying fluorosis, particularly the role of microRNAs (miRNAs), is crucial for developing effective preventive and therapeutic strategies. This review explores the pivotal role of miRNAs in the pathogenesis of fluorosis, particularly examining its impact on both hard (skeletal and dental) and soft (brain, liver, kidney, heart, and reproductive organs) tissues. Skeletal fluorosis manifests as abnormal bone mineralization and structure, while dental fluorosis affects enamel formation. In vitro and in vivo studies suggest a significant involvement of miRNAs in the progression of these conditions. For skeletal fluorosis, miR-124, miR-155, and miR-200c-3p have been identified as key regulators, while miR-296-5p and miR-214-3p are implicated in dental fluorosis. Moreover, soft tissue fluorosis encompasses a spectrum of adverse effects on various organs, including the brain, liver, kidneys, heart, and reproductive system. In soft tissues, miRNAs, such as miR-124, miR-200c-3p, miR-132, and miR-34b-5p, have been linked to cellular damage and dysfunction. Notably, miRNAs exert their effects through the modulation of critical pathways involved in fluorosis pathology, including Wnt signaling, apoptosis, cell cycle, and autophagy. Understanding the regulatory roles of miRNAs in fluorosis pathogenesis holds promise for identifying biomarkers and therapeutic targets. However, further research is needed to elucidate the molecular mechanisms underlying miRNA-mediated responses to fluoride exposure. Integration of miRNA research into fluorosis studies could facilitate the development of diagnostic tools and therapeutic interventions, thus mitigating the detrimental effects of fluorosis on both hard and soft tissues.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Towards characterization of cell culture conditions for reliable proteomic analysis: in vitro studies on A549, differentiated THP-1, and NR8383 cell lines 为可靠的蛋白质组分析确定细胞培养条件的特征：A549、分化的 THP-1 和 NR8383 细胞系的体外研究

IF 6.1 2区医学

Archives of Toxicology Pub Date : 2024-09-12 DOI: 10.1007/s00204-024-03858-4

Rico Ledwith, Tobias Stobernack, Antje Bergert, Aileen Bahl, Mario Pink, Andrea Haase, Verónica I. Dumit

{"title":"Towards characterization of cell culture conditions for reliable proteomic analysis: in vitro studies on A549, differentiated THP-1, and NR8383 cell lines","authors":"Rico Ledwith, Tobias Stobernack, Antje Bergert, Aileen Bahl, Mario Pink, Andrea Haase, Verónica I. Dumit","doi":"10.1007/s00204-024-03858-4","DOIUrl":"https://doi.org/10.1007/s00204-024-03858-4","url":null,"abstract":"Proteomic investigations result in high dimensional datasets, but integration or comparison of different studies is hampered by high variances due to different experimental setups. In addition, cell culture conditions can have a huge impact on the outcome. This study systematically investigates the impact of experimental parameters on the proteomic profiles of commonly used cell lines—A549, differentiated THP-1 macrophage-like cells, and NR8383—for toxicity studies. The work focuses on analyzing the influence at the proteome level of cell culture setup involving different vessels, cell passage numbers, and post-differentiation harvesting time, aiming to improve the reliability of proteomic analyses for hazard assessment. Mass-spectrometry-based proteomics was utilized for accurate protein quantification by means of a label-free approach. Our results showed that significant proteome variations occur when cells are cultivated under different setups. Further analysis of these variations revealed their association to specific cellular pathways related to protein misfolding, oxidative stress, and proteasome activity. Conversely, the influence of cell passage numbers on the proteome is minor, suggesting a reliable range for conducting reproducible biological replicates. Notable, substantial proteome alterations occur over-time post-differentiation of dTHP-1 cells, particularly impacting pathways crucial for macrophage function. This finding is key for the interpretation of experimental results. These results highlight the need for standardized culture conditions in proteomic-based evaluations of treatment effects to ensure reliable results, a prerequisite for achieving regulatory acceptance of proteomics data.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Methodological steps forward in toxicological in vitro screening of mineral wools in primary rat alveolar macrophages and normal rat mesothelial NRM2 cells 在原代大鼠肺泡巨噬细胞和正常大鼠间皮细胞 NRM2 中体外筛选矿棉毒理学的方法步骤

IF 6.1 2区医学

Archives of Toxicology Pub Date : 2024-09-11 DOI: 10.1007/s00204-024-03855-7

Christina Ziemann, Florian Schulz, Christoph Koch, Mette Solvang, Annette Bitsch

{"title":"Methodological steps forward in toxicological in vitro screening of mineral wools in primary rat alveolar macrophages and normal rat mesothelial NRM2 cells","authors":"Christina Ziemann, Florian Schulz, Christoph Koch, Mette Solvang, Annette Bitsch","doi":"10.1007/s00204-024-03855-7","DOIUrl":"https://doi.org/10.1007/s00204-024-03855-7","url":null,"abstract":"Man-made vitreous fibers (MMVF) comprise diverse materials for thermal and acoustic insulation, including stone wool. Depending on dimension, durability, and dose, MMVF might induce adverse health effects. Therefore, early predictive in vitro (geno)toxicity screening of new MMVF is highly desired to ensure safety for exposed workers and consumers. Here, we investigated, as a starting point, critical in vitro screening determinants and pitfalls using primary rat alveolar macrophages (AM) and normal rat mesothelial cells (NRM2). A stone wool fiber (RIF56008) served as an exemplary MMVF (fibrous vs. ground to estimate impact of fiber shape) and long amosite (asbestos) as insoluble fiber reference. Materials were comprehensively characterized, and in vivo-relevant in vitro concentrations defined, based on different approaches (low to supposed overload: 0.5, 5 and 50 µg/cm2). After 4–48 h of incubation, certain readouts were analyzed and material uptake was investigated by light and fluorescence-coupled darkfield microscopy. DNA-strand break induction was not morphology-dependent and nearly absent in both cell types. However, NRM2 demonstrated material-, morphology- and concentration-dependent membrane damage, CINC-1 release, reduction in cell count, and induction of binucleated cells (asbestos > RIF56008 > RIF56008 ground). In contrast to NRM2, asbestos was nearly inactive in AM, with CINC-1 release solely induced by RIF56008. In conclusion, to define an MMVF-adapted, predictive in vitro (geno)toxicity screening tool, references, endpoints, and concentrations should be carefully chosen, based on in vivo relevance, and sensitivity and specificity of the chosen cell model. Next, further endpoints should be evaluated, ideally with validation by in vivo data regarding their predictivity.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Interleukin-9 promotes EMT-mediated PM2.5-induced pulmonary fibrosis by activating the STAT3 pathway 白细胞介素-9通过激活STAT3通路促进EMT介导的PM2.5诱导的肺纤维化

IF 6.1 2区医学

Archives of Toxicology Pub Date : 2024-09-11 DOI: 10.1007/s00204-024-03864-6

Yuxuan Li, Yi Zhong, Chenwen Li, Zhixia Han, Yan Cui, Renjiang He, Yingyi Liu, Qinlin Cui, Daping He, Zhengquan Hu, Qingbi Zhang, Jun Bai

{"title":"Interleukin-9 promotes EMT-mediated PM2.5-induced pulmonary fibrosis by activating the STAT3 pathway","authors":"Yuxuan Li, Yi Zhong, Chenwen Li, Zhixia Han, Yan Cui, Renjiang He, Yingyi Liu, Qinlin Cui, Daping He, Zhengquan Hu, Qingbi Zhang, Jun Bai","doi":"10.1007/s00204-024-03864-6","DOIUrl":"https://doi.org/10.1007/s00204-024-03864-6","url":null,"abstract":"This study investigated the impact of PM2.5 on promoting EMT in PM2.5-induced pulmonary fibrosis (PF) development and explored molecular mechanisms of the IL-9/STAT3/Snail/TWIST1 signaling pathway in PF owing to PM2.5. Four groups of male SD rats were formed: control (0 mg/kg.bw), low (1 mg/kg.bw), medium (5 mg/kg.bw), and high-dose (25 mg/kg.bw) PM2.5 groups. Experimental rats were subjected to PM2.5 exposure via intratracheal instillation, given once weekly for 16 weeks. 24 h after the final exposure, blood, BALF, and lung tissues were collected. Pulmonary epithelial cells underwent cultivation and exposure to varying PM2.5 concentrations with/without inhibitors for 24 h, after which total protein was extracted for relevant protein assays. The findings demonstrated that PM2.5 damaged lung tissue to different degrees and led to PF in rats. Rats subjected to PM2.5 exposure exhibited elevated concentrations of IL-9 protein in both serum and BALF, and elevated levels of IL-9 and its receptor, IL-9R, in lung tissues, compared to control counterparts. Furthermore, PM2.5-exposed groups demonstrated significantly augmented protein levels of p-STAT3, Snail, TWIST1, Vimentin, COL-I, and α-SMA, while displaying notably diminished levels of E-Cadherin compared to control group. The same findings were observed in PM2.5-treated cells. In BEAS-2B cells co-treated with Stattic (STAT3 inhibitor) and PM2.5, the opposite results occurred. Similar results were obtained for cells co-treated with IL-9-neutralizing antibody and PM2.5. Our findings suggest PM2.5 mediates PF development by promoting IL-9 expression, leading to STAT3 phosphorylation and upregulation of Snail and TWIST1 expression, triggering EMT occurrence and progression in lung epithelial cells.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142227582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Escaping the cohort of concern: in vitro experimental evidence supports non-mutagenicity of N-nitroso-hydrochlorothiazide 逃离关注人群：体外实验证据支持 N-亚硝基-氢氯噻嗪的非突变性

IF 6.1 2区医学

Archives of Toxicology Pub Date : 2024-09-11 DOI: 10.1007/s00204-024-03859-3

R. D. Gandhi, S. Hickert, Y. Hoevelmann, C. D. Mee, J. Schlingemann, A. Adams, A. Blanazs, S. Simon, J. Elloway, L. Rigger, A. Teasdale, C. V. Beaumont, L. Wright, A. Doherty

{"title":"Escaping the cohort of concern: in vitro experimental evidence supports non-mutagenicity of N-nitroso-hydrochlorothiazide","authors":"R. D. Gandhi, S. Hickert, Y. Hoevelmann, C. D. Mee, J. Schlingemann, A. Adams, A. Blanazs, S. Simon, J. Elloway, L. Rigger, A. Teasdale, C. V. Beaumont, L. Wright, A. Doherty","doi":"10.1007/s00204-024-03859-3","DOIUrl":"https://doi.org/10.1007/s00204-024-03859-3","url":null,"abstract":"In recent years, nitrosamine impurities in pharmaceuticals have been subject to intense regulatory scrutiny, with nitrosamine drug substance-related impurities (NDSRIs) treated as cohort of concern impurities, regardless of predicted mutagenic potential. Here, we describe a case study of the NDSRI N-nitroso-hydrochlorothiazide (NO-HCTZ), which was positive in the bacterial reverse mutation (Ames) test but is unstable under the test conditions, generating formaldehyde among other products. The mutagenic profile of NO-HCTZ was inconsistent with that expected of a mutagenic nitrosamine, exhibiting mutagenicity in the absence of metabolic activation, and instead aligned well with that of formaldehyde. To assess further, a modified Ames system including glutathione (3.3 mg/plate) to remove formaldehyde was developed. Strains used were S. typhimurium TA98, TA100, TA1535, and TA1537, and E. coli WP2 uvrA/pKM101. In this system, formaldehyde levels were considerably lower, with a concomitant increase in levels of S-(hydroxymethyl)glutathione (the adduct formed between glutathione and formaldehyde). Upon retesting NO-HCTZ in the modified system (1.6–5000 µg/plate), a clear decrease in the mutagenic response was observed in the strains in which NO-HCTZ was mutagenic in the original system (TA98, TA100, and WP2 uvrA/pKM101), indicating that formaldehyde drives the response, not NO-HCTZ. In strain TA1535, an increase in revertant colonies was observed in the modified system, likely due to a thiatriazine degradation product formed from NO-HCTZ under Ames test conditions. Overall, these data support a non-mutagenic designation for NO-HCTZ and demonstrate the value of further investigation when a positive Ames result does not align with the expected profile.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The food-borne carcinogenic 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) disrupts circadian rhythms and ameliorated by pterostilbene (PSB) in Caenorhabditis elegans 食源性致癌物 2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）会扰乱草履虫的昼夜节律，而紫檀芪（PSB）可改善其昼夜节律

IF 6.1 2区医学

Archives of Toxicology Pub Date : 2024-09-10 DOI: 10.1007/s00204-024-03857-5

Chun-Han Chang, Pei-Ling Yen, Min-Hsiung Pan, Vivian Hsiu-Chuan Liao

{"title":"The food-borne carcinogenic 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) disrupts circadian rhythms and ameliorated by pterostilbene (PSB) in Caenorhabditis elegans","authors":"Chun-Han Chang, Pei-Ling Yen, Min-Hsiung Pan, Vivian Hsiu-Chuan Liao","doi":"10.1007/s00204-024-03857-5","DOIUrl":"https://doi.org/10.1007/s00204-024-03857-5","url":null,"abstract":"The food-borne 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potential human carcinogen abundant in cooked meat. While circadian rhythms are crucial biological oscillations, the negative impact of PhIP on circadian systems and the potential of mitigation remain underexplored. We investigated the effects of PhIP on circadian rhythms and the mitigating effects of the phytochemical antioxidant pterostilbene (PSB) in Caenorhabditis elegans. We show that exposure to 10 μM PhIP disrupts the 24-h circadian rhythms of C. elegans, an effect mitigated by co-exposure to 100 μM PSB. In addition, PhIP-induced circadian disruption can be linked to defective oxidative stress resistance, which is associated with the DAF-16/FOXO pathway and is modulated by PSB. Molecular docking suggested that PhIP and PSB bind similarly to DAF-16. Moreover, 10 μM PhIP abolished the rhythmic expression of the core clock gene prdx-2, which is restored by 100 μM PSB. Findings from this study provide novel insight of how food-borne contaminant like PhIP may contribute to the disruption of circadian rhythms and suggest potential for PSB to mitigate these effects in higher organisms.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":6.1,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142181768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Elevated risk of adverse effects from foodborne contaminants and drugs in inflammatory bowel disease: a review. 炎症性肠病患者受到食源性污染物和药物不良影响的风险升高：综述。

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2024-09-09 DOI: 10.1007/s00204-024-03844-w

Tom Walraven, Mathias Busch, Jingxuan Wang, Joanne M Donkers, Marjolijn Duijvestein, Evita van de Steeg, Nynke I Kramer, Hans Bouwmeester

{"title":"Elevated risk of adverse effects from foodborne contaminants and drugs in inflammatory bowel disease: a review.","authors":"Tom Walraven, Mathias Busch, Jingxuan Wang, Joanne M Donkers, Marjolijn Duijvestein, Evita van de Steeg, Nynke I Kramer, Hans Bouwmeester","doi":"10.1007/s00204-024-03844-w","DOIUrl":"https://doi.org/10.1007/s00204-024-03844-w","url":null,"abstract":"The global burden of Inflammatory bowel disease (IBD) has been rising over the last decades. IBD is an intestinal disorder with a complex and largely unknown etiology. The disease is characterized by a chronically inflamed gastrointestinal tract, with intermittent phases of exacerbation and remission. This compromised intestinal barrier can contribute to, enhance, or even enable the toxicity of drugs, food-borne chemicals and particulate matter. This review discusses whether the rising prevalence of IBD in our society warrants the consideration of IBD patients as a specific population group in toxicological safety assessment. Various in vivo, ex vivo and in vitro models are discussed that can simulate hallmarks of IBD and may be used to study the effects of prevalent intestinal inflammation on the hazards of these various toxicants. In conclusion, risk assessments based on healthy individuals may not sufficiently cover IBD patient safety and it is suggested to consider this susceptible subgroup of the population in future toxicological assessments.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Predictive biomarkers for embryotoxicity: a machine learning approach to mitigating multicollinearity in RNA-Seq. 胚胎毒性的预测性生物标志物：减轻 RNA-Seq 中多重共线性的机器学习方法。

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2024-09-06 DOI: 10.1007/s00204-024-03852-w

Yixian Quah, Soontag Jung, Jireh Yi-Le Chan, Onju Ham, Ji-Seong Jeong, Sangyun Kim, Woojin Kim, Seung-Chun Park, Seung-Jin Lee, Wook-Joon Yu

{"title":"Predictive biomarkers for embryotoxicity: a machine learning approach to mitigating multicollinearity in RNA-Seq.","authors":"Yixian Quah, Soontag Jung, Jireh Yi-Le Chan, Onju Ham, Ji-Seong Jeong, Sangyun Kim, Woojin Kim, Seung-Chun Park, Seung-Jin Lee, Wook-Joon Yu","doi":"10.1007/s00204-024-03852-w","DOIUrl":"https://doi.org/10.1007/s00204-024-03852-w","url":null,"abstract":"Multicollinearity, characterized by significant co-expression patterns among genes, often occurs in high-throughput expression data, potentially impacting the predictive model's reliability. This study examined multicollinearity among closely related genes, particularly in RNA-Seq data obtained from embryoid bodies (EB) exposed to 5-fluorouracil perturbation to identify genes associated with embryotoxicity. Six genes-Dppa5a, Gdf3, Zfp42, Meis1, Hoxa2, and Hoxb1-emerged as candidates based on domain knowledge and were validated using qPCR in EBs perturbed by 39 test substances. We conducted correlation studies and utilized the variance inflation factor (VIF) to examine the existence of multicollinearity among the genes. Recursive feature elimination with cross-validation (RFECV) ranked Zfp42 and Hoxb1 as the top two among the seven features considered, identifying them as potential early embryotoxicity assessment biomarkers. As a result, a t test assessing the statistical significance of this two-feature prediction model yielded a p value of 0.0044, confirming the successful reduction of redundancies and multicollinearity through RFECV. Our study presents a systematic methodology for using machine learning techniques in transcriptomics data analysis, enhancing the discovery of potential reporter gene candidates for embryotoxicity screening research, and improving the predictive model's predictive accuracy and feasibility while reducing financial and time constraints.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142144927","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rapid quantitative high-throughput mouse embryoid body model for embryotoxicity assessment. 用于胚胎毒性评估的快速定量高通量小鼠胚状体模型。

IF 4.8 2区医学

Archives of Toxicology Pub Date : 2024-09-05 DOI: 10.1007/s00204-024-03845-9

Yixian Quah, Soontag Jung, Onju Ham, Ji-Seong Jeong, Sangyun Kim, Woojin Kim, Jireh Yi-Le Chan, Seung-Chun Park, Seung-Jin Lee, Wook-Joon Yu

{"title":"Rapid quantitative high-throughput mouse embryoid body model for embryotoxicity assessment.","authors":"Yixian Quah, Soontag Jung, Onju Ham, Ji-Seong Jeong, Sangyun Kim, Woojin Kim, Jireh Yi-Le Chan, Seung-Chun Park, Seung-Jin Lee, Wook-Joon Yu","doi":"10.1007/s00204-024-03845-9","DOIUrl":"https://doi.org/10.1007/s00204-024-03845-9","url":null,"abstract":"Individuals are exposed to a wide arrays of hazardous chemicals on a daily basis through various routes, many of which have not undergone comprehensive toxicity assessments. While traditional developmental toxicity tests involving pregnant animals are known for their reliability, they are also associated with high costs and time requirements. Consequently, there is an urgent demand for alternative, cost-efficient, and rapid in vitro testing methods. This study aims to address the challenges related to automating and streamlining the screening of early developmental toxicity of chemicals by introducing a mouse embryoid body test (EBT) model in a 384-ultra low attachment well format. Embryoid bodies (EBs) generated in this format were characterized by a spontaneous differentiation trajectory into cardiac mesoderm by as analyzed by RNA-seq. Assessing prediction accuracy using reference compounds suggested in the ICH S5(R3) guideline and prior studies resulted in the establishment of the acceptance criteria and applicability domain of the EBT model. The results indicated an 84.38% accuracy in predicting the developmental toxicity of 23 positive and 9 negative reference compounds, with an optimized cutoff threshold of 750 µM. Overall, the developed EBT model presents a promising approach for more rapid, high-throughput chemical screening, thereby facilitating well-informed decision-making in environmental management and safety assessments.","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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