A transcriptomics data-driven gene space accurately predicts liver cytopathology and drug-induced liver injury

Kohonen, Pekka; Parkkinen, Juuso; Willighagen, Egon; Ceder, Rebecca; Wennerberg, Krister; Kaski, Samuel; Grafström, Roland C.

doi:10.1038/ncomms15932

Cited by 96 publications

(91 citation statements)

References 73 publications

(157 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The need to obtain data on mitochondrial toxicity has been realized in several large European research projects (Desprez et al 2018;Dragovic et al 2016;Jennings et al 2014;Kinsner-Ovaskainen et al 2013;Kohonen et al 2017;Wolters et al 2018) as well as by the Tox21 program (Attene-Ramos et al 2015;Xia et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants

et al. 2019

View full text Add to dashboard Cite

Many neurotoxicants affect energy metabolism in man, but currently available test methods may still fail to predict mito-and neurotoxicity. We addressed this issue using LUHMES cells, i.e., human neuronal precursors that easily differentiate into mature neurons. Within the NeuriTox assay, they have been used to screen for neurotoxicants. Our new approach is based on culturing the cells in either glucose or galactose (Glc-Gal-NeuriTox) as the main carbohydrate source during toxicity testing. Using this Glc-Gal-NeuriTox assay, 52 mitochondrial and non-mitochondrial toxicants were tested. The panel of chemicals comprised 11 inhibitors of mitochondrial respiratory chain complex I (cI), 4 inhibitors of cII, 8 of cIII, and 2 of cIV; 8 toxicants were included as they are assumed to be mitochondrial uncouplers. In galactose, cells became more dependent on mitochondrial function, which made them 2-3 orders of magnitude more sensitive to various mitotoxicants. Moreover, galactose enhanced the specific neurotoxicity (destruction of neurites) compared to a general cytotoxicity (plasma membrane lysis) of the toxicants. The Glc-Gal-NeuriTox assay worked particularly well for inhibitors of cI and cIII, while the toxicity of uncouplers and non-mitochondrial toxicants did not differ significantly upon glucose ↔ galactose exchange. As a secondary assay, we developed a method to quantify the inhibition of all mitochondrial respiratory chain functions/ complexes in LUHMES cells. The combination of the Glc-Gal-NeuriTox neurotoxicity screening assay with the mechanistic follow up of target site identification allowed both, a more sensitive detection of neurotoxicants and a sharper definition of the mode of action of mitochondrial toxicants. Keywords Neurotoxicity • Mitotoxicity • Metabolic reprogramming • High-throughput toxicity screening • High content imaging • Mechanistic safety assessment Abbreviations ADP Adenosine triphosphate AOP Adverse outcome pathway Asp l-Aspartate ATP Adenosine diphosphate cAMP N6,2′-O-Dibutyryladenosine 3′,5′-cyclic monophosphate cI-V MRC complex I-V CNS Central nervous system Cyt c Cytochrome c FAD(H 2) Flavin adenine dinucleotide (FAD: oxidized, FADH2: reduced) FCCP Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone G6P Glucose-6-phosphate Gal1P Galactose-1-phosphate GALK Galactokinase GALT Galactose-1-phosphate uridylyltransferase GDNF Glial derived neurotrophic factor Glc1P Glucose-1-phosphate Hex Hexose, in this study either glucose or galactose HK Hexokinase Lac Lactate Mal Malate MoA Mode of action MPP 1-Methyl-4-phenylpyridinium Electronic supplementary material The online version of this article (

show abstract

Section: Introductionmentioning

confidence: 99%

Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The functional content and polymorphism landscape of liver and brain cerebral cortex transcriptomes in brushtail possums are involved in a diverse array of biological processes. The functional content of these tissue types plays a critical part in the detoxification of xenobiotic substances [73,74] and modulation of complex behaviours [75,76] that potentially promote the development of physiological and behavioural tolerance against chemical compounds.…”

Section: Discussionmentioning

confidence: 99%

De Novo Transcriptome Assembly and Annotation of Liver and Brain Tissues of Common Brushtail Possums (Trichosurus vulpecula) in New Zealand: Transcriptome Diversity after Decades of Population Control

Emami‐Khoyi

Parbhu

Ross

et al. 2020

Genes

View full text Add to dashboard Cite

The common brushtail possum (Trichosurus vulpecula), introduced from Australia in the mid-nineteenth century, is an invasive species in New Zealand where it is widespread and forms the largest self-sustained reservoir of bovine tuberculosis (Mycobacterium bovis) among wild populations. Conservation and agricultural authorities regularly apply a series of population control measures to suppress brushtail possum populations. The evolutionary consequence of more than half a century of intensive population control operations on the species’ genomic diversity and population structure is hindered by a paucity of available genomic resources. This study is the first to characterise the functional content and diversity of brushtail possum liver and brain cerebral cortex transcriptomes. Raw sequences from hepatic cells and cerebral cortex were assembled into 58,001 and 64,735 transcripts respectively. Functional annotation and polymorphism assignment of the assembled transcripts demonstrated a considerable level of variation in the core metabolic pathways that represent potential targets for selection pressure exerted by chemical toxicants. This study suggests that the brushtail possum population in New Zealand harbours considerable variation in metabolic pathways that could potentially promote the development of tolerance against chemical toxicants.

show abstract

“…The common web services allow the genomics community to exchange reads, variants, and reference information, provided all data resources follow the API specification. The need for such protocols is essential as modeling data integration approaches to capture cytotoxicity effects are now emerging (Kohonen et al, 2017). …”

Section: Data Integration Approachesmentioning

confidence: 99%

Integration among databases and data sets to support productive nanotechnology: Challenges and recommendations

et al. 2018

Self Cite

View full text Add to dashboard Cite

Many groups within the broad field of nanoinformatics are already developing data repositories and analytical tools driven by their individual organizational goals. Integrating these data resources across disciplines and with non-nanotechnology resources can support multiple objectives by enabling the reuse of the same information. Integration can also serve as the impetus for novel scientific discoveries by providing the framework to support deeper data analyses. This article discusses current data integration practices in nanoinformatics and in comparable mature fields, and nanotechnology-specific challenges impacting data integration. Based on results from a nanoinformatics-community-wide survey, recommendations for achieving integration of existing operational nanotechnology resources are presented. Nanotechnology-specific data integration challenges, if effectively resolved, can foster the application and validation of nanotechnology within and across disciplines. This paper is one of a series of articles by the Nanomaterial Data Curation Initiative that address data issues such as data curation workflows, data completeness and quality, curator responsibilities, and metadata.

show abstract

A transcriptomics data-driven gene space accurately predicts liver cytopathology and drug-induced liver injury

Cited by 96 publications

References 73 publications

Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants

Development of a neurotoxicity assay that is tuned to detect mitochondrial toxicants

De Novo Transcriptome Assembly and Annotation of Liver and Brain Tissues of Common Brushtail Possums (Trichosurus vulpecula) in New Zealand: Transcriptome Diversity after Decades of Population Control

Integration among databases and data sets to support productive nanotechnology: Challenges and recommendations

Contact Info

Product

Resources

About