Manganese-Induced Toxicity in C. elegans : What Can We Learn from the Transcriptome?

Manganese (Mn) is an essential ubiquitous transition metal and, when occupationally or environmentally overexposed, a well-known risk factor for several neurological pathologies. However, the molecular mechanisms underlying Mn-induced neurotoxicity are largely unknown. In this study, addressing RNA-Seq analysis, bioavailability and survival assays, key pathways of transcriptional responses to Mn overexposure were investigated in the model organism Caenorhabditis elegans (C. elegans), providing insights into the Mn-induced cellular stress and damage response. Comparative transcriptome analyses identified a large number of differentially expressed genes (DEGs) in nematodes exposed to MnCl2 , and functional annotation suggested oxidative nucleotide damage, unfolded protein response and innate immunity as major damage response pathways. Additionally, a time-dependent increase in the transcriptional response after MnCl2 exposure was identified by means of increased numbers of DEGs, indicating a time-dependent response and activation of the stress responses in Mn neurotoxicity. The data provided here represent a powerful transcriptomic resource in the field of Mn toxicity, and therefore, this study provides a useful basis for further planning of targeted mechanistic studies of Mn-induced neurotoxicity that are urgently needed in the face of increasing industrially caused environmental pollution with Mn

Toxicity of three types of arsenolipids : species-specific effects in Caenorhabditis elegans

This work was supported by the German Research Foundation (DFG), grant number SCHW 903/10-1 and the Austrian Science Fund (FWF), project number I2412-B21. MA was supported in part by grants from the NIEHS, R01ES10563 and R0107331.Peer reviewedPostprin

Scientific opinion on the tolerable upper intake level for manganese

Funding Information: The Panel wishes to thank for their contribution to this output: the WG on Upper Levels: Peter Aggett, Brandy Beverly, Torsten Bohn, Julia Bornhorst, Marta Crous-Bou, Francesco Cubadda, Aymeric Dopter, Susan Fairweather-Tait, Rex FitzGerald, Susan Lanham New, Georg Lietz, Harry J McArdle, Anne Molloy, Giovanni Passeri, Kristina Pentieva, Marco Vinceti and Misha Vrolijk; hearing expert: Peter Willatts, individual scientific advisor (ISA) expert: Keyvin Darney and EFSA staff members: Constanza De Matteu Monteiro, Jean-Lou Dorne, Alessandra Giarola, Irene Muñoz Guajardo, Nena Karavasiloglou, Laura Ciccolallo, Roanne Marie Saad, Angeliki Sofroniou and Silvia Valtueña Martínez. The Panel also wishes to thank Carmen Peláez for her contribution as member of the NDA Panel until June 2023. The Panel acknowledges Thorhallur I Halldorsson, Bryndis Eva Birgisdottir, Anete Dudele, Jacob Juel Christensen and Birna Thorisdottir for the preparatory work as part of a procurement procedure. The Panel also wishes to acknowledge the contribution of all national institutions in European countries that provided consumption data for this scientific output. Publisher Copyright: © 2023 European Food Safety Authority. EFSA Journal published by Wiley-VCH GmbH on behalf of European Food Safety Authority.Peer reviewe

Mass Surveilance of <i>C. elegans</i>—Smartphone-Based DIY Microscope and Machine-Learning-Based Approach for Worm Detection

The nematode Caenorhabditis elegans (C. elegans) is often used as an alternative animal model due to several advantages such as morphological changes that can be seen directly under a microscope. Limitations of the model include the usage of expensive and cumbersome microscopes, and restrictions of the comprehensive use of C. elegans for toxicological trials. With the general applicability of the detection of C. elegans from microscope images via machine learning, as well as of smartphone-based microscopes, this article investigates the suitability of smartphone-based microscopy to detect C. elegans in a complete Petri dish. Thereby, the article introduces a smartphone-based microscope (including optics, lighting, and housing) for monitoring C. elegans and the corresponding classification via a trained Histogram of Oriented Gradients (HOG) feature-based Support Vector Machine for the automatic detection of C. elegans. Evaluation showed classification sensitivity of 0.90 and specificity of 0.85, and thereby confirms the general practicability of the chosen approach

Oxidative Stress Mechanisms Underlying Parkinson’s Disease-Associated Neurodegeneration in C. elegans

Oxidative stress is thought to play a significant role in the development and progression of neurodegenerative diseases. Although it is currently considered a hallmark of such processes, the interweaving of a multitude of signaling cascades hinders complete understanding of the direct role of oxidative stress in neurodegeneration. In addition to its extensive use as an aging model, some researchers have turned to the invertebrate model Caenorhabditis elegans (C. elegans) in order to further investigate molecular mediators that either exacerbate or protect against reactive oxygen species (ROS)-mediated neurodegeneration. Due to their fully characterized genome and short life cycle, rapid generation of C. elegans genetic models can be useful to study upstream markers of oxidative stress within interconnected signaling pathways. This report will focus on the roles of C. elegans homologs for the oxidative stress-associated transcription factor Nrf2, as well as the autosomal recessive, early-onset Parkinson’s disease (PD)-associated proteins Parkin, DJ-1, and PINK1, in neurodegenerative processes

Involvement of heat shock proteins on Mn-induced toxicity in Caenorhabditis elegans

BACKGROUND: All living cells display a rapid molecular response to adverse environmental conditions, and the heat shock protein family reflects one such example. Hence, failing to activate heat shock proteins can impair the cellular response. In the present study, we evaluated whether the loss of different isoforms of heat shock protein (hsp) genes in Caenorhabditis elegans would affect their vulnerability to Manganese (Mn) toxicity. METHODS: We exposed wild type and selected hsp mutant worms to Mn (30 min) and next evaluated further the most susceptible strains. We analyzed survival, protein carbonylation (as a marker of oxidative stress) and Parkinson's disease related gene expression immediately after Mn exposure. Lastly, we observed dopaminergic neurons in wild type worms and in hsp-70 mutants following Mn treatment. Analysis of the data was performed by one-way or two way ANOVA, depending on the case, followed by post-hoc Bonferroni test if the overall p value was less than 0.05. RESULTS: We verified that the loss of hsp-70, hsp-3 and chn-1 increased the vulnerability to Mn, as exposed mutant worms showed lower survival rate and increased protein oxidation. The importance of hsp-70 against Mn toxicity was then corroborated in dopaminergic neurons, where Mn neurotoxicity was aggravated. The lack of hsp-70 also blocked the transcriptional upregulation of pink1, a gene that has been linked to Parkinson's disease. CONCLUSIONS: Taken together, our data suggest that Mn exposure modulates heat shock protein expression, particularly HSP-70, in C. elegans. Furthermore, loss of hsp-70 increases protein oxidation and dopaminergic neuronal degeneration following manganese exposure, which is associated with the inhibition of pink1 increased expression, thus potentially exacerbating the vulnerability to this metal

Manganese-Induced Toxicity in C. elegans: What Can We Learn from the Transcriptome?

Manganese (Mn) is an essential ubiquitous transition metal and, when occupationally or environmentally overexposed, a well-known risk factor for several neurological pathologies. However, the molecular mechanisms underlying Mn-induced neurotoxicity are largely unknown. In this study, addressing RNA-Seq analysis, bioavailability and survival assays, key pathways of transcriptional responses to Mn overexposure were investigated in the model organism Caenorhabditis elegans (C. elegans), providing insights into the Mn-induced cellular stress and damage response. Comparative transcriptome analyses identified a large number of differentially expressed genes (DEGs) in nematodes exposed to MnCl2, and functional annotation suggested oxidative nucleotide damage, unfolded protein response and innate immunity as major damage response pathways. Additionally, a time-dependent increase in the transcriptional response after MnCl2 exposure was identified by means of increased numbers of DEGs, indicating a time-dependent response and activation of the stress responses in Mn neurotoxicity. The data provided here represent a powerful transcriptomic resource in the field of Mn toxicity, and therefore, this study provides a useful basis for further planning of targeted mechanistic studies of Mn-induced neurotoxicity that are urgently needed in the face of increasing industrially caused environmental pollution with Mn

Exposure to the environmentally relevant fungicide Maneb: Studying toxicity in the soil nematode Caenorhabditis elegans

Maneb is a manganese-containing ethylene bisdithiocarbamate fungicide and is still commonly used as no cases of resistance have been documented. However, studies have shown that Maneb exposure has neurodegenerative potential in mammals, resulting in symptoms affecting the motor system. Despite its extensive use, structural elucidation of Maneb has only recently been accomplished by our group. This study aimed to examine the bioavailability of Maneb, the quantification of oxidative stress-related endpoints and neurotransmitters employing pure Maneb, its metabolites and structural analogues, in the model organism Caenorhabditis elegans. Exposure to Maneb did not increase the bioavailability of Mn compared to manganese chloride, although Maneb was about 8 times more toxic with regard to lethality. Maneb generated not significantly reactive oxygen and nitrogen species (RONS) but decreased the ATP level while increasing the amount of glutathione and its oxidized form in a dose-dependent manner. Nevertheless, an alteration in the neurotransmitter homeostasis of dopamine, acetylcholine, and gamma-butyric acid (GABA) was observed as well as morphological changes in the dopaminergic neurons upon Maneb exposure, which underlines the assumption of the neurotoxic potential of Maneb. This study showed that Maneb exhibits effects based on a combined interaction of the ligand and manganese