Protein pathway analysis to study development-dependent effects of acute and repeated trimethyltin (TMT) treatments in 3D rat brain cell cultures

Schvartz, Domitille; González‐Ruiz, Víctor; Walter, Nadia; Antinori, Paola; Jeanneret, Fabienne; Tonoli, David; Bernard, Julien; Zurich, Marie-Gabrielle; Rudaz, Serge; Monnet‐Tschudi, Florianne; Sandström, Jenny; Sanchez, Jean‐Charles

doi:10.1016/j.tiv.2019.05.020

Cited by 8 publications

(6 citation statements)

References 59 publications

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“…However, pathway analysis did not suggest different mechanism of toxicity between immature and differentiated cultures. However, TMT-induced alterations of the maturation process were more prominent in immature cultures and the reverse was observed for TMT-induced glial reactivity [37]. This demonstrates the complementarity of the use of the present workflow and of an unbiased combination of the omics techniques, as summarized in Figure S1, for a more subtle and comprehensive analysis of the mechanism of toxicity.…”

Section: Resultsmentioning

confidence: 67%

“…The regulation of these two proteins, as well as two metallothioneins, upon TMT treatment suggested a cellular response to oxidative stress. These results from individual protein expression changes in immatures cultures confirm that the exposure is triggering protein changes reflecting the induction of TMT-related biological processes, such as the onset of inflammation, and oxidative stress [37]. Data for the whole ensemble of identified and quantified proteins was subsequently analyzed on the basis of their fold-change by comparison of the 1.0 vs. the 0.0 µM TMT concentrations.…”

Section: Resultsmentioning

confidence: 80%

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An Integrative Multi-Omics Workflow to Address Multifactorial Toxicology Experiments

et al. 2019

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Toxicology studies can take advantage of omics approaches to better understand the phenomena underlying the phenotypic alterations induced by different types of exposure to certain toxicants. Nevertheless, in order to analyse the data generated from multifactorial omics studies, dedicated data analysis tools are needed. In this work, we propose a new workflow comprising both factor deconvolution and data integration from multiple analytical platforms. As a case study, 3D neural cell cultures were exposed to trimethyltin (TMT) and the relevance of the culture maturation state, the exposure duration, as well as the TMT concentration were simultaneously studied using a metabolomic approach combining four complementary analytical techniques (reversed-phase LC and hydrophilic interaction LC, hyphenated to mass spectrometry in positive and negative ionization modes). The ANOVA multiblock OPLS (AMOPLS) method allowed us to decompose and quantify the contribution of the different experimental factors on the outcome of the TMT exposure. Results showed that the most important contribution to the overall metabolic variability came from the maturation state and treatment duration. Even though the contribution of TMT effects represented the smallest observed modulation among the three factors, it was highly statistically significant. The MetaCore™ pathway analysis tool revealed TMT-induced alterations in biosynthetic pathways and in neuronal differentiation and signaling processes, with a predominant deleterious effect on GABAergic and glutamatergic neurons. This was confirmed by combining proteomic data, increasing the confidence on the mechanistic understanding of such a toxicant exposure.

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Section: Resultsmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 80%

An Integrative Multi-Omics Workflow to Address Multifactorial Toxicology Experiments

et al. 2019

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“…The hMNR confirmed the two MoA of the test compounds: 1) the enhanced glutamatergic activity by TMT-induced glutamate release [89]; 2) the reduced GABAergic neurotransmission caused by the GABA A and GABA C agonist emamectin [88]. Long-term exposure studies showed that TMT also affects synaptic vesicle fusion and recycling [135,136]. This could be a possible explanation for the wMFR reduction at higher TMT concentrations.…”

Section: Discussionmentioning

confidence: 66%

Molecular and functional characterization of different BrainSphere models for use in neurotoxicity testing on microelectrode arrays

Hartmann

Henschel

Bartmann

et al. 2023

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The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low testing throughput hinder their application for large numbers of chemicals. To overcome these limitations, in vitro methods are currently developed which are based on human induced pluripotent stem cells (hiPSC) that allow higher testing throughput at lower costs. We applied six different protocols to generate 3D BrainSphere models for acute NT evaluation. These include three different media for 2D neural induction and two media for subsequent 3D differen-tiation resulting in self-organized, organotypic neuron/astrocyte microtissues. All induction pro-tocols yielded nearly 100 % nestin-positive hiPSC-derived neural progenitor cells (hiNPCs) yet with different gene expression profiles concerning regional patterning. Moreover, gene expression and immunocytochemistry analyses revealed that the choice of media determines neural differentiation patterns. On the functional level, BrainSpheres exhibited different levels of electrical activ-ity on microelectrode arrays (MEA). Spike sorting allowed BrainSphere functional characterization with the mixed cultures consisting of GABAergic, glutamatergic, dopaminergic, serotonergic, and cholinergic neurons. A test method for acute NT testing, the human multi-neurotransmitter receptor (hMNR) assay, was proposed applying such MEA-based spike sorting. These models are not only promising tools in toxicology but also for drug development and disease modeling.

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“…TMT-based protein quanti cation explained the relationship between long-term moderate exercise and key neurotrophic signaling pathways in rats 9 . In 3D rat brain cell cultures, a global view on protein pathways were unveiled using TMT-based protein quanti cation 10 . Accordingly, the screening of deregulated proteins might provide a deeper understanding of the molecular mechanisms regulating responses to speci c stimuli.…”

Section: Discussionmentioning

confidence: 99%

A global view on TMT-based quantitative proteomic analysis of rat livers during acute hypoxia

Zhan

Chen

et al. 2022

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Acute hypoxia consistently results in altitude sickness and can be fatal. Until present, no studies focusing on global proteomic changes induced by acute hypoxia have been reported. Here, we combined animal experiments and tandem mass tag (TMT)-based proteomic analysis to identify metabolic changes as a result of acute hypoxia. We first generated a rat model under acute hypoxia conditions. Then we used qPCR analyses to validate the key regulators, and present a schematic model of acute reactions occurring in the livers of rats subjected to acute hypoxia challenge. We identified a large number of acute hypoxic responsive proteins in diverse biological pathways, which helped unveil the different mechanisms involved in hypoxia responses in rats. According to data obtained from proteomic analysis, rats were able to maintain normal physical activity as a response to acute hypoxia by activating their catabolic capacity in order to get more energy, and decreasing biosynthesis to reduce energy consumption. We identified a large number of acute hypoxia-responsive proteins associated with diverse biological pathways, and showed rats quickly respond to acute hypoxia by activating lipid biosynthesis to increase lipid storage, and reducing lipolysis to reduce energy consumption.

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Protein pathway analysis to study development-dependent effects of acute and repeated trimethyltin (TMT) treatments in 3D rat brain cell cultures

Cited by 8 publications

References 59 publications

An Integrative Multi-Omics Workflow to Address Multifactorial Toxicology Experiments

An Integrative Multi-Omics Workflow to Address Multifactorial Toxicology Experiments

Molecular and functional characterization of different BrainSphere models for use in neurotoxicity testing on microelectrode arrays

A global view on TMT-based quantitative proteomic analysis of rat livers during acute hypoxia

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