Toxicological Sciences最新文献_第8页

Comment on: "microplastic presence in dog and human testis and its potential association with sperm count and weights of testis and epididymis". 评论："狗和人类睾丸中的微塑料及其与精子数量、睾丸和附睾重量的潜在联系"。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-30 DOI: 10.1093/toxsci/kfae136

Rao M Uppu, Ir Willie Peijnenburg, Sean M Hays

引用次数: 0

Response to Comment on: "Microplastic presence in dog and human testis and its potential association with sperm count and weights of testis and epididymis". 对有关评论的回应："狗和人类睾丸中的微塑料及其与精子数量、睾丸和附睾重量的潜在联系"。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-21 DOI: 10.1093/toxsci/kfae137

Chelin Jamie Hu, Marcus A Garcia, Alexander Nihart, Rui Liu, Lei Yin, Natalie Adolphi, Daniel F Gallego, Huining Kang, Matthew J Campen, Xiaozhong Yu

引用次数: 0

ToxPoint: Waste incineration management of plastic materials-an issue of increasing global public health importance. ToxPoint：塑料材料的废物焚化管理--一个对全球公众健康日益重要的问题。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-04 DOI: 10.1093/toxsci/kfae111

Keith Rogers, Ilona Jaspers

引用次数: 0

Deconvoluting and derisking QRS complex widening to improve cardiac safety profile of novel plasmepsin X antimalarials. 去卷积和去风险 QRS 波群增宽以改善新型血浆蛋白酶 X 抗疟疾药物的心脏安全性。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-01 DOI: 10.1093/toxsci/kfae087

Annie Delaunois, Alvaro Cardenas, Teresa de Haro, Helga H J Gerets, Vitalina Gryshkova, Simon Hebeisen, Chloé Korlowski, Benoit Laleu, Martin A Lowe, Jean-Pierre Valentin

{"title":"Deconvoluting and derisking QRS complex widening to improve cardiac safety profile of novel plasmepsin X antimalarials.","authors":"Annie Delaunois, Alvaro Cardenas, Teresa de Haro, Helga H J Gerets, Vitalina Gryshkova, Simon Hebeisen, Chloé Korlowski, Benoit Laleu, Martin A Lowe, Jean-Pierre Valentin","doi":"10.1093/toxsci/kfae087","DOIUrl":"10.1093/toxsci/kfae087","url":null,"abstract":"Quinoline-related antimalarial drugs have been associated with cardiotoxicity risk, in particular QT prolongation and QRS complex widening. In collaboration with Medicines for Malaria Venture, we discovered novel plasmepsin X (PMX) inhibitors for malaria treatment. The first lead compounds tested in anesthetized guinea pigs (GPs) induced profound QRS widening, although exhibiting weak inhibition of NaV1.5-mediated currents in standard patch clamp assays. To understand the mechanism(s) underlying QRS widening to identify further compounds devoid of such liability, we established a set of in vitro models including CaV1.2, NaV1.5 rate-dependence, and NaV1.8 patch clamp assays, human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), and Langendorff-perfused isolated GP hearts. Six compounds were tested in all models including anesthetized GP, and 8 additional compounds were tested in vitro only. All compounds tested in anesthetized GP and isolated hearts showed a similar cardiovascular profile, consisting of QRS widening, bradycardia, negative inotropy, hypotension, and for some, QT prolongation. However, a left shift of the concentration-response curves was noted from in vitro to in vivo GP data. When comparing in vitro models, there was a good consistency between decrease in sodium spike amplitude in hiPSC-CM and QRS widening in isolated hearts. Patch clamp assay results showed that the QRS widening observed with PMX inhibitors is likely multifactorial, primarily due to NaV1.8 and NaV1.5 rate-dependent sodium blockade and/or calcium channel-mediated mechanisms. In conclusion, early de-risking of QRS widening using a set of different in vitro assays allowed to identify novel PMX inhibitors with improved cardiac safety profile.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"321-330"},"PeriodicalIF":3.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

A transcriptomic biomarker predictive of cell proliferation for use in adverse outcome pathway-informed testing and assessment. 预测细胞增殖的转录组生物标志物，可用于不良后果路径知情测试和评估。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-01 DOI: 10.1093/toxsci/kfae102

J Christopher Corton, Victoria Ledbetter, Samuel M Cohen, Ella Atlas, Carole L Yauk, Jie Liu

{"title":"A transcriptomic biomarker predictive of cell proliferation for use in adverse outcome pathway-informed testing and assessment.","authors":"J Christopher Corton, Victoria Ledbetter, Samuel M Cohen, Ella Atlas, Carole L Yauk, Jie Liu","doi":"10.1093/toxsci/kfae102","DOIUrl":"10.1093/toxsci/kfae102","url":null,"abstract":"High-throughput transcriptomics (HTTr) is increasingly being used to identify molecular targets of chemicals that can be linked to adverse outcomes. Cell proliferation (CP) is an important key event in chemical carcinogenesis. Here, we describe the construction and characterization of a gene expression biomarker that is predictive of the CP status in human and rodent tissues. The biomarker was constructed from 30 genes known to be increased in expression in prostate cancers relative to surrounding tissues and in cycling human MCF-7 cells after estrogen receptor (ER) agonist exposure. Using a large compendium of gene expression profiles to test utility, the biomarker could identify increases in CP in (i) 308 out of 367 tumor vs. normal surrounding tissue comparisons from 6 human organs, (ii) MCF-7 cells after activation of ER, (iii) after partial hepatectomy in mice and rats, and (iv) the livers of mice and rats after exposure to nongenotoxic hepatocarcinogens. The biomarker identified suppression of CP (i) under conditions of p53 activation by DNA damaging agents in human cells, (ii) in human A549 lung cells exposed to therapeutic anticancer kinase inhibitors (dasatinib, nilotnib), and (iii) in the mouse liver when comparing high levels of CP at birth to the low background levels in the adult. The responses using the biomarker were similar to those observed using conventional markers of CP including PCNA, Ki67, and BrdU labeling. The CP biomarker will be a useful tool for interpretation of HTTr data streams to identify CP status after exposure to chemicals in human cells or in rodent tissues.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"174-189"},"PeriodicalIF":3.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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

Quantitative label-free proteomic analysis of mouse ovarian antral follicles following oral exposure to a human-relevant mixture of three phthalates. 口服三种邻苯二甲酸盐人类相关混合物后小鼠卵巢前叶滤泡的无标签定量蛋白质组分析。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-01 DOI: 10.1093/toxsci/kfae089

Kara L Miller, Xiaosong Liu, Maile G McSwain, Estela J Jauregui, Paul R Langlais, Zelieann R Craig

{"title":"Quantitative label-free proteomic analysis of mouse ovarian antral follicles following oral exposure to a human-relevant mixture of three phthalates.","authors":"Kara L Miller, Xiaosong Liu, Maile G McSwain, Estela J Jauregui, Paul R Langlais, Zelieann R Craig","doi":"10.1093/toxsci/kfae089","DOIUrl":"10.1093/toxsci/kfae089","url":null,"abstract":"Dibutyl phthalate (DBP), di-2-ethylhexyl phthalate (DEHP), and benzyl butyl phthalate (BBP) are used in personal and medical care products. In the ovary, antral follicles are essential for steroidogenesis and ovulation. DBP, BBP, and DEHP are known to inhibit mouse antral follicle growth and ovulation in vitro, and associate with decreased antral follicle counts in women. Given that the in vivo effects of a three-phthalate mixture on antral follicles are unknown, we evaluated the effects of a human-relevant mixture of DBP, BBP, and DEHP on ovarian follicles through proteome profiling analysis. Adult CD-1 female mice were fed corn oil (vehicle), or two dose levels of a phthalate mixture based on estimated exposures in general (32 µg/kg/d; PHT 32) and occupationally exposed (500 µg/kg/d; PHT 500) populations for 10 d. Antral follicles (>250 µm) were isolated and subjected to proteome profiling via label-free tandem mass spectrometry. A total of 5,417 antral follicle proteins were detected, of which 194 were differentially abundant between vehicle and PHT 32, and 136 between vehicle and PHT 500. Bioinformatic analysis revealed significantly different responses between the two phthalate doses. Protein abundance differences in the PHT 32 exposure mapped to cytoplasm, mitochondria, and lipid metabolism; whereas those in the PHT 500 exposure mapped to cytoplasm, nucleus, and phosphorylation. When both doses altered proteins mapped to common processes, the associated predicted transcription factors were different. These findings provide novel mechanistic insight into phthalate-associated, ovary-driven reproductive outcomes in women.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"226-239"},"PeriodicalIF":3.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11424887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141601806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Robust differential gene expression patterns in the prefrontal cortex of male mice exposed to an occupationally relevant dose of laboratory-generated wildfire smoke. 雄性小鼠暴露于与职业相关剂量的实验室产生的野火烟雾后，其前额叶皮层出现了强大的差异基因表达模式。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-01 DOI: 10.1093/toxsci/kfae097

Adam Schuller, Jessica Oakes, Tom LaRocca, Jacqueline Matz, Matthew Eden, Chiara Bellini, Luke Montrose

{"title":"Robust differential gene expression patterns in the prefrontal cortex of male mice exposed to an occupationally relevant dose of laboratory-generated wildfire smoke.","authors":"Adam Schuller, Jessica Oakes, Tom LaRocca, Jacqueline Matz, Matthew Eden, Chiara Bellini, Luke Montrose","doi":"10.1093/toxsci/kfae097","DOIUrl":"10.1093/toxsci/kfae097","url":null,"abstract":"Wildfires have become common global phenomena concurrent with warmer and drier climates and are now major contributors to ambient air pollution worldwide. Exposure to wildfire smoke has been classically associated with adverse cardiopulmonary health outcomes, especially in vulnerable populations. Recent work has expanded our understanding of wildfire smoke toxicology to include effects on the central nervous system and reproductive function; however, the neurotoxic profile of this toxicant remains ill-explored in an occupational context. Here, we sought to address this by using RNA sequencing to examine transcriptomic signatures in the prefrontal cortex of male mice modeling career wildland firefighter smoke exposure. We report robust changes in gene expression profiles between smoke-exposed samples and filtered air controls, evidenced by 2,862 differentially expressed genes (51.2% increased). We further characterized the functional relevance of these genes highlighting enriched pathways related to synaptic transmission, neuroplasticity, blood-brain barrier integrity, and neurotransmitter metabolism. Additionally, we identified possible contributors to these alterations through protein-protein interaction network mapping, which revealed a central node at ß-catenin and secondary hubs centered around mitochondrial oxidases, the Wnt signaling pathway, and gene expression machinery. The data reported here will serve as the foundation for future experiments aiming to characterize the phenotypic effects and mechanistic underpinnings of occupational wildfire smoke neurotoxicology.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"300-310"},"PeriodicalIF":3.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11424885/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identifying assessment criteria for in vitro studies: a method and item bank. 确定体外研究的评估标准：方法和项目库。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-01 DOI: 10.1093/toxsci/kfae083

Paul Whaley, Robyn B Blain, Derek Draper, Andrew A Rooney, Vickie R Walker, Stephen Wattam, Rob Wright, Carlijn R Hooijmans

{"title":"Identifying assessment criteria for in vitro studies: a method and item bank.","authors":"Paul Whaley, Robyn B Blain, Derek Draper, Andrew A Rooney, Vickie R Walker, Stephen Wattam, Rob Wright, Carlijn R Hooijmans","doi":"10.1093/toxsci/kfae083","DOIUrl":"10.1093/toxsci/kfae083","url":null,"abstract":"To support the development of appraisal tools for assessing the quality of in vitro studies, we developed a method for literature-based discovery of study assessment criteria, used the method to create an item bank of assessment criteria of potential relevance to in vitro studies, and analyzed the item bank to discern and critique current approaches for appraisal of in vitro studies. We searched four research indexes and included any document that identified itself as an appraisal tool for in vitro studies, was a systematic review that included a critical appraisal step, or was a reporting checklist for in vitro studies. We abstracted, normalized, and categorized all criteria applied by the included appraisal tools to create an \"item bank\" database of issues relevant to the assessment of in vitro studies. The resulting item bank consists of 676 unique appraisal concepts from 67 appraisal tools. We believe this item bank is the single most comprehensive resource of its type to date, should be of high utility for future tool development exercises, and provides a robust methodology for grounding tool development in the existing literature. Although we set out to develop an item bank specifically targeting in vitro studies, we found that many of the assessment concepts we discovered are readily applicable to other study designs. Item banks can be of significant value as a resource; however, there are important challenges in developing, maintaining, and extending them of which researchers should be aware.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"240-253"},"PeriodicalIF":3.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11424884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141535351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Toxicity of waterpipe tobacco smoking: the role of flavors, sweeteners, humectants, and charcoal. 吸食水烟的毒性：香料、甜味剂、保湿剂和木炭的作用。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-01 DOI: 10.1093/toxsci/kfae095

Nada O F Kassem, Robert M Strongin, Andrea M Stroup, Marielle C Brinkman, Ahmad El-Hellani, Hanno C Erythropel, Arash Etemadi, Maciej L Goniewicz, Eleanore G Hansen, Noura O Kassem, Dongmei Li, Sandy Liles, Alexandra Noël, Mary Rezk-Hanna, Qixin Wang, Irfan Rahman

{"title":"Toxicity of waterpipe tobacco smoking: the role of flavors, sweeteners, humectants, and charcoal.","authors":"Nada O F Kassem, Robert M Strongin, Andrea M Stroup, Marielle C Brinkman, Ahmad El-Hellani, Hanno C Erythropel, Arash Etemadi, Maciej L Goniewicz, Eleanore G Hansen, Noura O Kassem, Dongmei Li, Sandy Liles, Alexandra Noël, Mary Rezk-Hanna, Qixin Wang, Irfan Rahman","doi":"10.1093/toxsci/kfae095","DOIUrl":"10.1093/toxsci/kfae095","url":null,"abstract":"Waterpipe tobacco (WPT) smoking is a public health concern, particularly among youth and young adults. The global spread of WPT use has surged because the introduction of pre-packaged flavored and sweetened WPT, which is widely marketed as a safer tobacco alternative. Besides flavorants and sugars, WPT additives include humectants, which enhance the moisture and sweetness of WPT, act as solvents for flavors, and impart smoothness to the smoke, thus increasing appeal to users. In the United States, unlike cigarette tobacco flavoring (with the exception of menthol), there is no FDA product standard or policy in place prohibiting sales of flavored WPT. Research has shown that the numerous fruit, candy, and alcohol flavors added to WPT entice individuals to experience those flavors, putting them at an increased risk of exposure to WPT smoke-related toxicants. Additionally, burning charcoal briquettes-used as a heating source for WPT-contributes to the harmful health effects of WPT smoking. This review presents existing evidence on the potential toxicity resulting from humectants, sugars, and flavorants in WPT, and from the charcoal used to heat WPT. The review discusses relevant studies of inhalation toxicity in animal models and of biomarkers of exposure in humans. Current evidence suggests that more data are needed on toxicant emissions in WPT smoke to inform effective tobacco regulation to mitigate the adverse impact of WPT use on human health.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"159-173"},"PeriodicalIF":3.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11424890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141749088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Assessing the interplay between off-target promiscuity, cytotoxicity, and tolerability in rodents to improve the safety profile of novel anti-malarial plasmepsin X inhibitors. 评估啮齿类动物的脱靶杂交性、细胞毒性和耐受性之间的相互作用，以改善新型抗疟疾胰蛋白酶 X 抑制剂的安全性。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2024-10-01 DOI: 10.1093/toxsci/kfae086

Helga H J Gerets, Annie Delaunois, Alvaro Cardenas, Reiner Class, Renaud Fleurance, Teresa de Haro, Benoît Laleu, Martin A Lowe, Marie-Luce Rosseels, Jean-Pierre Valentin

{"title":"Assessing the interplay between off-target promiscuity, cytotoxicity, and tolerability in rodents to improve the safety profile of novel anti-malarial plasmepsin X inhibitors.","authors":"Helga H J Gerets, Annie Delaunois, Alvaro Cardenas, Reiner Class, Renaud Fleurance, Teresa de Haro, Benoît Laleu, Martin A Lowe, Marie-Luce Rosseels, Jean-Pierre Valentin","doi":"10.1093/toxsci/kfae086","DOIUrl":"10.1093/toxsci/kfae086","url":null,"abstract":"Within drug development, high off-target promiscuity as well as potent cytotoxicity, are associated with a high attrition rate. We investigated the safety profile of novel plasmepsin X (PMX) inhibitors for the treatment of malaria. In our screening cascade, a total of 249 PMX compounds were profiled in a panel of in vitro secondary pharmacology assays containing 44 targets (SafetyScreen44 panel) and in a cytotoxicity assay in HepG2 cells using ATP as an endpoint. Six of the lead compounds were subsequently tested in a 7-d rat toxicology study, and/or in a cardiovascular study in guinea pigs. Overall, compounds with high cytotoxicity in HepG2 cells correlated with high promiscuity (off-target hit rate >20%) in the SafetyScreen44 panel and were associated with poor tolerability in vivo (decedents, morbidity, adverse clinical signs, or severe cardiovascular effects). Some side effects observed in rats or guinea pigs could putatively be linked with hits in the secondary pharmacological profiling, such as the M1 or M2 muscarinic acetylcholine receptor, opioid µ and/or κ receptors or hERG/CaV1.2/Na+ channels, which were common to >50% the compounds tested in vivo. In summary, compounds showing high cytotoxicity and high promiscuity are likely to be poorly tolerated in vivo. However, such associations do not necessarily imply a causal relationship. Identifying the targets that cause these undesirable effects is key for early safety risk assessment. A tiered approach, based on a set of in vitro assays, helps selecting the compounds with highest likelihood of success to proceed to in vivo toxicology studies.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"311-320"},"PeriodicalIF":3.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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