Article
Cell & Tissue Engineering
Anna-Katharina Holzer, Christiaan Karreman, Ilinca Suciu, Lara-Seline Furmanowsky, Harald Wohlfarth, Dominik Loser, Wilhelm G. Dirks, Emilio Pardo Gonzalez, Marcel Leist
Summary: In this study, induced pluripotent stem cells were used to generate peripheral sensory neurons enriched in nociceptors, creating a culture system suitable for pharmacological and toxicological studies. Functional and immunocytochemical phenotyping, as well as transcriptome profiling, confirmed the feasibility of this cell culture system. Furthermore, the model was used to investigate the effects of a chemotherapeutic drug on neurons.
STEM CELLS TRANSLATIONAL MEDICINE
(2022)
Article
Environmental Sciences
Jonathan Blum, Stefan Masjosthusmann, Kristina Bartmann, Farina Bendt, Xenia Dolde, Arif Doenmez, Nils Foerster, Anna-Katharina Holzer, Ulrike Huebenthal, Hagen Eike Kessel, Sadiye Kilic, Joerdis Klose, Melanie Pahl, Lynn-Christin Stuerzl, Iris Mangas, Andrea Terron, Kevin M. Crofton, Martin Scholze, Axel Mosig, Marcel Leist, Ellen Fritsche
Summary: Developmental neurotoxicity is a major safety concern for chemicals, but animal studies provide limited data. Higher throughput test methods with improved human relevance are urgently needed. This study explores the feasibility of using new approach methods for developmental neurotoxicity hazard assessment.
Article
Cell Biology
Emanuele Panatta, Alessio Butera, Eleonora Mammarella, Consuelo Pitolli, Alessandro Mauriello, Marcel Leist, Richard A. Knight, Gerry Melino, Ivano Amelio
Summary: Gene-environment interactions can lead to perturbations in the epigenome that contribute to cancer development. In this study, we found that the tumor suppressor p53 plays a role in maintaining genomic integrity by regulating the levels of the universal methyl donor S-adenosylmethionine (SAM). Loss of p53 results in disruptions in DNA methylation, leading to chromosomal abnormalities and replication stress associated with R-loops. Insufficient levels of SAM contribute to the inability of p53-deficient cells to cope with these disruptions.
Article
Toxicology
Liliana Capinha, Yaran Zhang, Anna-Katharina Holzer, Anna-Katharina Uckert, Melinda Zana, Giada Carta, Cormac Murphy, Jenna Baldovini, Zahra Mazidi, Johannes Grillari, Andras Dinnyes, Bob van de Water, Marcel Leist, Jan N. M. Commandeur, Paul Jennings
Summary: This study used six human derived cell models to investigate the effects of trichloroethylene (TCE) S-conjugates. The results showed that TCE S-conjugates induced Nrf2 pathway and unfolded protein response, which may explain the nephrotoxicity and neurotoxicity of TCE. This study expands our knowledge on the tissue specificity of TCE S-conjugates and highlights the value of human cell models and transcriptomics in mechanistic studies.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Petra Kranaster, Jonathan Blum, Jeremias E. G. A. Dold, Valentin Wittmann, Marcel Leist
Summary: Metabolic glycoengineering (MGE) is a method for visualizing carbohydrates on live cells. It allows the fluorescent labeling of sialic acid (Sia) sugar residues on neuronal plasma membranes. By using human dopaminergic neurons as a model system, this study developed a method for differential labeling of sialylated membrane lipids or sialylated N-glycosylated proteins on live neurons.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Ilinca Suciu, Johannes Delp, Simon Gutbier, Anna-Katharina Ueckert, Anna-Sophie Spreng, Philipp Eberhard, Christiaan Karreman, Falk Schreiber, Katrin Madjar, Joerg Rahnenfuehrer, Ivana Celardo, Ivano Amelio, Marcel Leist
Summary: Proteasome inhibition is related to parkinsonian pathology and dopaminergic neuron degeneration. In this study, the metabolome and transcriptome regulations of human LUHMES neurons exposed to MG-132 were investigated, revealing compromised energy metabolism and activation of stress response pathways. These findings provide insights into the cellular responses to proteasome dysfunction and potential therapeutic interventions for Parkinson's disease.
Article
Cell Biology
Giada Carta, Wanda van der Stel, Emma W. J. Scuric, Liliana Capinha, Johannes Delp, Susanne Hougaard Bennekou, Anna Forsby, Paul Walker, Marcel Leist, Bob van de Water, Paul Jennings
Summary: Analysis of transcriptomic alterations upon chemical challenge reveals specific pathway activation and transcriptional modulations, providing mechanistic information on the toxic mode of action of chemical compounds. In this study, the transcriptional landscape of mitochondrial impairment caused by inhibition of the electron transport chain was assessed in human renal cells. The unfolded protein response pathway, particularly the PERK/ATF4 branch, was identified as a common cellular response to ETC inhibitions, which could help identify mitochondrial liabilities of chemicals in both legacy data and prospective studies.
CELL BIOLOGY AND TOXICOLOGY
(2023)
Review
Food Science & Technology
Sabine Guth, Matthias Baum, Alexander T. Cartus, Patrick Diel, Karl-Heinz Engel, Barbara Engeli, Bernd Epe, Tilman Grune, Dirk Haller, Volker Heinz, Michael Hellwig, Jan G. Hengstler, Thomas Henle, Hans-Ulrich Humpf, Henry Jaeger, Hans-Georg Joost, Sabine E. Kulling, Dirk W. Lachenmeier, Alfonso Lampen, Marcel Leist, Angela Mally, Doris Marko, Ute Noethlings, Elke Roehrdanz, Angelika Roth, Joachim Spranger, Richard Stadler, Pablo Steinberg, Stefan Vieths, Wim Waetjen, Gerhard Eisenbrand
Summary: This opinion from the SKLM presents arguments for an updated risk assessment of acrylamide (AA) exposure in diet, based on a critical review of relevant scientific evidence. The SKLM concludes that as long as exposure limits for AA are not exceeded, genotoxic effects leading to carcinogenicity are unlikely to occur. Considering the totality of evidence, the SKLM deems it scientifically justified to establish a tolerable daily intake (TDI) as a health-based guidance value.
FOOD AND CHEMICAL TOXICOLOGY
(2023)
Article
Toxicology
Philip Botham, Mark T. D. Cronin, Richard Currie, John Doe, Dorothee Funk-Weyer, Timothy W. Gant, Marcel Leist, Sue Marty, Bennard van Ravenzwaay, Carl Westmoreland
Summary: The REACH regulation determines the studies that must be conducted based on the annual tonnage of chemicals manufactured or imported into the EU. However, this criterion does not consider the physico-chemical properties and use patterns that determine exposure. An analysis of the REACH mandated study lists reveals that only 19% of registered substances have datasets covering all areas of health concern. Limited information is available for areas such as repeat and extended exposure and carcinogenicity. Using New Approach Methodologies (NAMs) at lower tonnage bands could provide additional information and enhance the use of NAMs by registrants and regulators. Projects in Europe are currently developing NAM-based assessment frameworks that could be used for low tonnage chemicals once confidence has been gained through evaluation with data-rich chemicals.
ARCHIVES OF TOXICOLOGY
(2023)
Editorial Material
Medicine, Research & Experimental
Alessio Butera, Lena Smirnova, Elisa Ferrando-May, Thomas Hartung, Thomas Brunner, Marcel Leist, Ivano Amelio
Summary: Human health is influenced by both genetics and environment. Different responses can be observed in groups of individuals exposed to the same environmental factors. The concept of gene-environment interactions is still not well defined, but examples of these interactions driving disease development are provided in this article. The cellular epigenome is suggested to hold the key to unravel these complex layers of regulation. Developing a method to decode epigenetic information could provide quantitative measures of disease risk, similar to the concept of an epigenetic clock for estimating biological age.
EMBO MOLECULAR MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Karin Grillberger, Eike Collen, Claudia Immacolata Trivisani, Jonathan Blum, Marcel Leist, Gerhard F. Ecker
Summary: Toxic effects of neonicotinoids and their metabolites on human neurons were investigated using a combination of in silico and in vitro methods. Calcium imaging on neurons confirmed a key event predicted by molecular simulations, providing a new approach for next-generation risk assessments.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cell Biology
Anna Cherianidou, Franziska Kappenberg, Florian Seidel, Aviseka Acharya, Panagiota Papazoglou, Sureshkumar Perumal Srinivasan, Juergen Hescheler, Luying Peng, Marcel Leist, Jan G. Hengstler, Joerg Rahnenfuehrer, Agapios Sachinidis
Summary: Animal studies for embryotoxicity evaluation are limited in their relevance to humans due to species differences. This study used human induced pluripotent stem cells (hiPSCs) to recapitulate cardiomyogenesis and identify key genes and processes affected by potential teratogens. We found that certain retinoids completely blocked cardiomyogenesis in hiPSCs and established a Developmental Cardiotoxicity Index that accurately differentiates teratogens from non-teratogens.
CELL DEATH DISCOVERY
(2023)
Article
Medicine, Research & Experimental
Giorgia Pallocca, Martijn J. Mone, Hennicke Kamp, Mirjam Luijten, Bob van de Water, Marcel Leist
Summary: In many industrial sectors, there is a need for reliable methods to evaluate the safety of chemicals based on human biology and pathology. To address this need, animal-free new approach methods (NAMs) have been developed and implemented in risk assessment. The RISK-HUNT3R project aims to combine computational toxicology, in vitro toxicology, and systems biology to create a comprehensive next-generation risk assessment strategy. This strategy is expected to result in faster and more accurate risk assessment procedures.
ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION
(2022)
Article
Medicine, Research & Experimental
Giorgia Pallocca, Marcel Leist
Summary: This article discusses the background information of laboratory animal studies and suggests criteria for judging their usefulness. It focuses on animals used as tools/test systems/models to provide information on humans and discusses the general features and performance characteristics of models. Examples are given for well-recognized criteria to judge the usefulness of predictive models. The main hypothesis is that a benefits evaluation is only possible within sharply circumscribed "use domains". The article also emphasizes the need to evaluate model advantages and disadvantages and compare them with alternatives.
ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION
(2022)
Article
Medicine, Research & Experimental
David Pamies, Marcel Leist, Sandra Coecke, Gerard Bowe, David G. Allen, Gerhard Gstraunthaler, Anna Bal-Price, Francesca Pistollato, Rob B. M. de Vries, Helena T. Hogberg, Thomas Hartung, Glyn Stacey
Summary: Good Cell and Tissue Culture Practice (GCCP) 2.0 is an updated guidance document that aims to ensure the reproducibility and high-quality scientific data of cell culture experiments. It describes six main principles to consider when performing cell culture and does not intend to impose detailed procedures, but rather describes potential quality issues.
ALTEX-ALTERNATIVES TO ANIMAL EXPERIMENTATION
(2022)
