Graciel Diamante , Sung Min Ha , Darren Wijaya , Xia Yang
{"title":"Single cell multiomics systems biology for molecular toxicity","authors":"Graciel Diamante , Sung Min Ha , Darren Wijaya , Xia Yang","doi":"10.1016/j.cotox.2024.100477","DOIUrl":"10.1016/j.cotox.2024.100477","url":null,"abstract":"<div><p>Exposure to environmental chemicals has been associated with increased risks for various diseases, but our understanding of their molecular targets and how they drive disease progression remains limited. Environmental toxicants can trigger a multitude of effects on the epigenome, transcriptome, proteome, and other molecular entities in individual cells and tissues. The recent advances in high throughput single cell multiomics technologies are enabling a deeper understanding of these complex molecular alterations and interactions underlying exposure mode of action at a single cell resolution. Accompanying the increased capacity to generate single cell multiomics data is the rapid advancement in computational tools for data analysis of individual omics layers, multimodal data integration and molecular network modeling. Recent applications of single cell omics technologies and analytical methods have enabled the elucidation of cell type specific genes and pathways affected by various environmental exposures. Further adoption of advanced single cell multiomics methodologies in the molecular toxicology field promises a more comprehensive understanding of the regulatory networks within and between cell types underlying the perturbations in physiological systems and disease risks posed by environmental toxicants.</p></div>","PeriodicalId":93968,"journal":{"name":"Current opinion in toxicology","volume":"39 ","pages":"Article 100477"},"PeriodicalIF":4.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2468202024000196/pdfft?md5=0b57f1b89e2ea33581a8cfdd65aac38f&pid=1-s2.0-S2468202024000196-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141131202","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":"Advances in genomic toxicology: In vitro developmental toxicity test based on signal network disruption dynamics","authors":"Yusuke Okubo , Yoko Hirabayashi , Junji Fukuda","doi":"10.1016/j.cotox.2024.100489","DOIUrl":"10.1016/j.cotox.2024.100489","url":null,"abstract":"<div><p>Developmental toxicity outcomes in humans and animals often exhibit variability; hence, the demand for predictive non-animal alternatives, particularly human cell-based models, are increasing. Despite advancements in genomic toxicology, which have facilitated the identification of toxicity mechanisms and potential biomarkers, existing transcriptome analysis-based methods have yet to yield highly predictive <em>in vitro</em> developmental toxicity assays. One possible reason is that assays at a single time point could not capture the entire dynamic signal network during developmental processes. This article addresses the challenges in comprehensive gene expression analysis and introduces novel <em>in vitro</em> developmental toxicity assays focused on the time-dependent dynamics of signaling pathway responses crucial to human development.</p></div>","PeriodicalId":93968,"journal":{"name":"Current opinion in toxicology","volume":"39 ","pages":"Article 100489"},"PeriodicalIF":4.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2468202024000317/pdfft?md5=24008ba91be5c75a73de9c26ba156ac6&pid=1-s2.0-S2468202024000317-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141705549","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":"NAMs: Beta testing needed","authors":"Denise Bloch, Philip Marx-Stoelting, Tewes Tralau","doi":"10.1016/j.cotox.2024.100490","DOIUrl":"10.1016/j.cotox.2024.100490","url":null,"abstract":"<div><p>A variety of new approach methodologies (NAMs) have already been developed for acute systemic and short-term toxicity, including <em>in vitro</em>, <em>in silico</em>, and omics methods. To advance their regulatory implementation, we suggest that beta testing of these methods in regulatory settings is urgently needed. There are several limitations to the use of NAMs for acute systemic and short-term toxicity, such as the lack of definitions for applicability domains, skewed reference data for validation, and the absence of representation of kinetic processes and multi-organ complexity. These limitations may lead to risks associated with the ordinary regulatory implementation, such as the application of methods to substances outside of their intended applicability domain or reduced predictivity due to a lack of mechanistic information or consideration of kinetics. We argue that this could be avoided by beta testing. Further benefits of beta testing would be the filling of <em>in vivo</em> data gaps and potentially improved validation with regard to human relevance of methods. In order to enhance the improvement, familiarisation, and acceptance of NAMs in the near future, it is essential for such concept of beta testing to rely on feedback loops between method testers and developers.</p></div>","PeriodicalId":93968,"journal":{"name":"Current opinion in toxicology","volume":"39 ","pages":"Article 100490"},"PeriodicalIF":4.6,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2468202024000329/pdfft?md5=43c34608e921555b7f5665fb5635a6ef&pid=1-s2.0-S2468202024000329-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141691074","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}
Dylan Hatai , Max T. Levenson , Virender K. Rehan , Patrick Allard
{"title":"Inter- and trans-generational impacts of environmental exposures on the germline resolved at the single-cell level","authors":"Dylan Hatai , Max T. Levenson , Virender K. Rehan , Patrick Allard","doi":"10.1016/j.cotox.2024.100465","DOIUrl":"10.1016/j.cotox.2024.100465","url":null,"abstract":"<div><p>Reproduction is a remarkably intricate process involving the interaction of multiple cell types and organ systems unfolding over long periods of time and that culminates with the production of gametes. The initiation of germ cell development takes place during embryogenesis but only completes decades later in humans. The complexity inherent to reproduction and its study has long hampered our ability to decipher how environmental agents disrupt this process. Single-cell approaches provide an opportunity for a deeper understanding of the action of toxicants on germline function and analyze how the response to their exposure is differentially distributed across tissues and cell types. In addition to single-cell RNA sequencing, other single-cell or nucleus level approaches such as ATAC-sequencing and multi-omics have expanded the strategies that can be implemented in reproductive toxicological studies to include epigenomic and the nuclear transcriptomic data. Here we will discuss the current state of single-cell technologies and how they can best be utilized to advance reproductive toxicological studies. We will then discuss case studies in two model organisms (<em>Caenorhabditis elegans</em> and rat) studying different environmental exposures (alcohol and e-cigarettes respectively) to highlight the value of single-cell and single-nucleus approaches for reproductive biology and reproductive toxicology.</p></div>","PeriodicalId":93968,"journal":{"name":"Current opinion in toxicology","volume":"38 ","pages":"Article 100465"},"PeriodicalIF":4.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139823857","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":"Editorial overview: Navigating complex chemical mixtures in risk assessment","authors":"Anne Marie Vinggaard, Andreas Kortenkamp","doi":"10.1016/j.cotox.2024.100474","DOIUrl":"10.1016/j.cotox.2024.100474","url":null,"abstract":"","PeriodicalId":93968,"journal":{"name":"Current opinion in toxicology","volume":"38 ","pages":"Article 100474"},"PeriodicalIF":4.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140405513","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":"Network medicine and artificial intelligence in cancer precision therapy: Path to prevent drug-induced toxic side effect","authors":"Asim Bikas Das","doi":"10.1016/j.cotox.2024.100476","DOIUrl":"10.1016/j.cotox.2024.100476","url":null,"abstract":"<div><p>The discovery of cancer-specific therapeutics and determining their sensitivity is a critical step in preventing drug-induced toxicity. Drug sensitivity varies among cancer patients due to intra-tumor heterogeneity. It demands rational drug design, target identification, and novel treatment modalities. This review discusses the use of network medicine in targeted therapy and AI-based drug response prediction for personalized cancer therapy. The network medicine is successfully implemented to integrate multiple omics data to identify the disease modules in cancer. The cancer-specific disease modules are utilized for drug screening and targeted therapy. Additionally, the model developed using AI, and genomic data shows superior performance and also reveals relationships between the genomic variability of cancer and their response to drugs. There is significant promise for network medicine and AI to handle large-scale omics data, leading to the identification of a novel cancer-specific treatment strategy and improved patient care.</p></div>","PeriodicalId":93968,"journal":{"name":"Current opinion in toxicology","volume":"38 ","pages":"Article 100476"},"PeriodicalIF":4.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140769633","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}
David Filipovic , Omar Kana , Daniel Marri , Sudin Bhattacharya
{"title":"Unique challenges and best practices for single cell transcriptomic analysis in toxicology","authors":"David Filipovic , Omar Kana , Daniel Marri , Sudin Bhattacharya","doi":"10.1016/j.cotox.2024.100475","DOIUrl":"10.1016/j.cotox.2024.100475","url":null,"abstract":"<div><p>The application and analysis of single-cell transcriptomics in toxicology presents unique challenges. These include identifying cell sub-populations sensitive to perturbation; interpreting dynamic shifts in cell type proportions in response to chemical exposures; and performing differential expression analysis in dose–response studies spanning multiple treatment conditions. This review examines these challenges while presenting best practices for critical single cell analysis tasks. This covers areas such as cell type identification; analysis of differential cell type abundance; differential gene expression; and cellular trajectories. Towards enhancing the use of single-cell transcriptomics in toxicology, this review aims to address key challenges in this field and offer practical analytical solutions. Overall, applying appropriate bioinformatic techniques to single-cell transcriptomic data can yield valuable insights into cellular responses to toxic exposures.</p></div>","PeriodicalId":93968,"journal":{"name":"Current opinion in toxicology","volume":"38 ","pages":"Article 100475"},"PeriodicalIF":4.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140405743","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}
Maureen M. Sampson , Rachel K. Morgan , Steven A. Sloan , Kelly M. Bakulski
{"title":"Single-cell investigation of lead toxicity from neurodevelopment to neurodegeneration: Current review and future opportunities","authors":"Maureen M. Sampson , Rachel K. Morgan , Steven A. Sloan , Kelly M. Bakulski","doi":"10.1016/j.cotox.2024.100464","DOIUrl":"10.1016/j.cotox.2024.100464","url":null,"abstract":"<div><p>Human exposure to the metal lead (Pb) is prevalent and associated with adverse neurodevelopmental and neurodegenerative outcomes. Pb disrupts normal brain function by inducing oxidative stress and neuroinflammation, altering cellular metabolism, and displacing essential metals. Prior studies on the molecular impacts of Pb have examined bulk tissues, which collapse information across all cell types, or in targeted cells, which are limited to cell autonomous effects. These approaches are unable to represent the complete biological implications of Pb exposure because the brain is a cooperative network of highly heterogeneous cells, with cellular diversity and proportions shifting throughout development, by brain region, and with disease. New technologies are necessary to investigate whether Pb and other environmental exposures alter cell composition in the brain and whether they cause molecular changes in a cell-type-specific manner. Cutting-edge, single-cell approaches now enable research resolving cell-type-specific effects from bulk tissues. This article reviews existing Pb neurotoxicology studies with genome-wide molecular signatures and provides a path forward for the field to implement single-cell approaches with practical recommendations.</p></div>","PeriodicalId":93968,"journal":{"name":"Current opinion in toxicology","volume":"38 ","pages":"Article 100464"},"PeriodicalIF":4.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139662174","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}
Mackenzie L. Connell, Danielle N. Meyer, Alex Haimbaugh, Tracie R. Baker
{"title":"Status of single-cell RNA sequencing for reproductive toxicology in zebrafish and the transcriptomic trade-off","authors":"Mackenzie L. Connell, Danielle N. Meyer, Alex Haimbaugh, Tracie R. Baker","doi":"10.1016/j.cotox.2024.100463","DOIUrl":"10.1016/j.cotox.2024.100463","url":null,"abstract":"<div><p>The utilization of transcriptomic studies identifying profiles of gene expression, especially in toxicogenomics, has catapulted next-generation sequencing to the forefront of reproductive toxicology. An innovative yet underutilized RNA sequencing technique emerging into this field is single-cell RNA sequencing (scRNA-seq), which provides sequencing at the individual cellular level of gonad tissue. ScRNA-seq provides a novel and unique perspective for identifying distinct cellular profiles, including identification of rare cell subtypes. The specificity of scRNA-seq is a powerful tool for reproductive toxicity research, especially for translational animal models including zebrafish. Studies to date not only have focused on ‘tissue atlassing’ or characterizing what cell types make up different tissues but have also begun to include toxicant exposure as a factor that this review aims to explore. Future scRNA-seq studies will contribute to understanding exposure-induced outcomes; however, the trade-offs with traditional methods need to be considered.</p></div>","PeriodicalId":93968,"journal":{"name":"Current opinion in toxicology","volume":"38 ","pages":"Article 100463"},"PeriodicalIF":4.6,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139585176","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":"Advanced technologies in genomic toxicology: Current trend and future directions","authors":"Pasquale Capone, Pieranna Chiarella, Renata Sisto","doi":"10.1016/j.cotox.2023.100444","DOIUrl":"10.1016/j.cotox.2023.100444","url":null,"abstract":"<div><p>Toxicogenomics is a subdiscipline of toxicology that assesses the toxicity using a combination of genomics, advanced computational technologies, and other high-throughput techniques. In the last few years, the rapid evolution of technologies such as transcriptomics, proteomics, metabolomics, and computational technologies allowed the application of a more flexible strategy for the risk assessment due to exposure to chemical and xenobiotic substances. The integration of bioinformatics approaches with novel genomic technologies permits extraordinary advancements in different fields of biology, toxicology, medicine, and, in particular, in occupational medicine, making accessible a “personalized” approach to this discipline. The scope of this paper is to investigate the recent trend of genomic toxicology in combination with bioinformatics approaches and its novel application in toxicological studies with reference to our experience and findings. In particular, it is shown how the dose biomarkers, the pollutants urine metabolites in our case, allow a precise exposure assessment whilst effect biomarkers can be individuated, significantly associated with the former. Among the effect biomarkers, our experience is mainly focused on oxidative stress biomarkers and miRNA profiles. Finally, it is shown how the early effect biomarkers are dysregulated when specific clinical outcomes are occurring. This early dysregulation can be used as individual susceptibility biomarker.</p></div>","PeriodicalId":93968,"journal":{"name":"Current opinion in toxicology","volume":"37 ","pages":"Article 100444"},"PeriodicalIF":4.6,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2468202023000591/pdfft?md5=9126629f8ba9407328b06c7c140847e8&pid=1-s2.0-S2468202023000591-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138529967","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}