C. elegans as a model in developmental neurotoxicology

Ruszkiewicz, Joanna A.; Pinkas, Adi; Miah, Mahfuzur R.; Weitz, Rebecca; Lawes, Michael; Akinyemi, Ayodele Jacob; Ijomone, Omamuyovwi M.; Aschner, Michael

doi:10.1016/j.taap.2018.03.016

Cited by 102 publications

(56 citation statements)

References 142 publications

(200 reference statements)

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“…These data suggest that the NeuroGlycoTest is able to detect specific effects on neurite glycosylation in the absence of general cytotoxicity and with higher sensitivity compared to neurite area measurements. This assay is therefore a useful novel addition to a battery of tests that are able to pick up alerts for potential neurotoxicants and modifiers of neural function (Bal-Price et al 2017;Gerhardt et al 2001;Hansson et al 2000;Hirt et al 2000;Ruszkiewicz et al 2018;Schultz et al 2015;Tiffany-Castiglioni et al 2006;Vassallo et al 2017;Zimmer et al 2011a, b). Based on the overall results of such a test battery, potential toxicants may be prioritized for further testing Li et al 2019;Schmidt et al 2017;Smirnova et al 2014;van Thriel et al 2012).…”

Section: Effect Of Mitochondrial Toxicants On the Neuroglycotest Readoutmentioning

confidence: 99%

Time and space-resolved quantification of plasma membrane sialylation for measurements of cell function and neurotoxicity

et al. 2019

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While there are many methods to quantify the synthesis, localization, and pool sizes of proteins and DNA during physiological responses and toxicological stress, only few approaches allow following the fate of carbohydrates. One of them is metabolic glycoengineering (MGE), which makes use of chemically modified sugars (CMS) that enter the cellular biosynthesis pathways leading to glycoproteins and glycolipids. The CMS can subsequently be coupled (via bio-orthogonal chemical reactions) to tags that are quantifiable by microscopic imaging. We asked here, whether MGE can be used in a quantitative and time-resolved way to study neuronal glycoprotein synthesis and its impairment. We focused on the detection of sialic acid (Sia), by feeding human neurons the biosynthetic precursor N-acetyl-mannosamine, modified by an azide tag. Using this system, we identified non-toxic conditions that allowed live cell labeling with high spatial and temporal resolution, as well as the quantification of cell surface Sia. Using combinations of immunostaining, chromatography, and western blotting, we quantified the percentage of cellular label incorporation and effects on glycoproteins such as polysialylated neural cell adhesion molecule. A specific imaging algorithm was used to quantify Sia incorporation into neuronal projections, as potential measure of complex cell function in toxicological studies. When various toxicants were studied, we identified a subgroup (mitochondrial respiration inhibitors) that affected neurite glycan levels several hours before any other viability parameter was affected. The MGE-based neurotoxicity assay, thus allowed the identification of subtle impairments of neurochemical function with very high sensitivity.

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Section: Effect Of Mitochondrial Toxicants On the Neuroglycotest Readoutmentioning

confidence: 99%

Time and space-resolved quantification of plasma membrane sialylation for measurements of cell function and neurotoxicity

et al. 2019

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“…Furthermore, Fe depletion, a key feature of RLS is associated with higher deposition of Mn in the brain. There is an established C. elegans model of Mn neurotoxicity (Chen et al, 2015; Ijomone et al, 2016; Peres et al, 2018; Ruszkiewicz et al, 2018). Given the association between Mn and Fe, this model can be harnessed to evaluate whether neuronal and/or systemic alteration in Mn may contribute to the pathophysiology of RLS.…”

Section: Elegans Methods For Rls Studymentioning

confidence: 99%

Caenorhabditis elegans and its applicability to studies on restless legs syndrome

Chen

Ijomone

Lee

et al. 2019

Pharmacology of Restless Legs Syndrome (RLS)

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Restless legs syndrome (RLS) is a common neurological disorder in the US. This disorder is characterized by an irresistible urge to move the legs, although the symptoms vary in a wide range. The pathobiology of RLS has been linked to iron (Fe) deficiency and dopaminergic (DAergic) dysfunction. Several genetic factors have been reported to increase the risk of RLS. Caenorhabditis elegans (C. elegans) is a well-established animal model with a fully sequenced genome, which is highly conserved with mammals. Given the detailed knowledge of its genomic architecture, ease of genetic manipulation and conserved biosynthetic and metabolic pathways, as well as its small size, ease of maintenance, speedy generation time and large brood size, C. elegans provides numerous advantages in studying RLS-associated gene-environment interactions. Here we will review current knowledge about RLS symptoms, pathology and treatments, and discuss the application of C. elegans in RLS study, including the worm homologous genes and methods that could be performed to advance the pathophysiology RLS.

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“…C. elegans has long been used as an effective in vivo model for neural development given the conservation of the neural pathways between C. elegans and mammals (Boyd, Smith, & Freedman, ; Ruszkiewicza et al, ). For example, C. elegans has neurotransmitters (e.g., dopamine, ACh, GABA, glutamate, and serotonin) and associated receptors present in higher eukaryotes (Kaletta & Hengartner, ; Rand & Nonet, ).…”

Section: Neurodevelopmental and Neurobehavioral Effects Of Cpf In Rodmentioning

confidence: 99%

Effects of low‐dose chlorpyrifos on neurobehavior and potential mechanisms: A review of studies in rodents, zebrafish, and Caenorhabditis elegans

Silva

2020

Birth Defects Research

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Objectives Exposure to chlorpyrifos (CPF), a neurotoxic insecticide, is implicated with adverse neurodevelopmental effects in children through noncholinergic mechanisms. Methods This review presents qualitative and quantitative evidence in three animal models (rodent, zebrafish, and Caenorhabditis elegans), for neurodevelopmental and behavioral effects occurring at CPF doses lower than those inhibiting acetylcholinesterase (AChE). Results CPF treatment in rodents at low noncholinergic doses during neurodevelopment showed behavioral effects, including locomotor activity, neuromotor function (NMF), cognition, anxiety, social behavior, and maternal care. Zebrafish and C. elegans, which are transparent during development, allow for detailed analysis of specific systems; further, they exhibit neurotoxic effects closely emulating those observed in mammalian pathways. Qualitative results showed concordance among rodents, zebrafish and C. elegans for adverse effects on locomotor activity, NMF, and AChE inhibition. Male rodents had greater sensitivity for effects on locomotor activity than females and exposure during the gestation day 10–14 window showed consistent increases in locomotor activity at low CPF doses (≤1.0 mg kg−1 day−1). Zebrafish had cognitive and anxiety deficits after CPF treatment at low doses and young adult C. elegans had reproductive dysfunction associated NMF and disruption of the serotonergic pathway. Quantitative data for all three species showed neurobehavioral effects after exposure to CPF doses approximately 2–10‐fold below the threshold for AChE inhibition. Conclusions Taken together, these findings provided a weight‐of‐evidence for low‐dose CPF neurotoxicity and noncholinergic mechanisms. Variability in laboratories, exposure methods, tests, sex, and animal species/strain might have contributed to the inconsistent results. The detrimental CPF effects during early development are relevant to human populations.

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C. elegans as a model in developmental neurotoxicology

Cited by 102 publications

References 142 publications

Time and space-resolved quantification of plasma membrane sialylation for measurements of cell function and neurotoxicity

Time and space-resolved quantification of plasma membrane sialylation for measurements of cell function and neurotoxicity

Caenorhabditis elegans and its applicability to studies on restless legs syndrome

Effects of low‐dose chlorpyrifos on neurobehavior and potential mechanisms: A review of studies in rodents, zebrafish, and Caenorhabditis elegans

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