Caenorhabditis elegans as a Model to Study Manganese-Induced Neurotoxicity

Abstract

Caenorhabditis elegans (C. elegans) is a nematode present worldwide. The worm shows homology to mammalian systems and expresses approximately 40% of human disease-related genes. Since Dr. Sydney Brenner first proposed C. elegans as an advantageous experimental worm-model system for genetic approaches, increasing numbers of studies using C. elegans as a tool to investigate topics in several fields of biochemistry, neuroscience, pharmacology, and toxicology have been performed. In this regard, C. elegans has been used to characterize the molecular mechanisms and affected pathways caused by metals that lead to neurotoxicity, as well as the pathophysiological interrelationship between metal exposure and ongoing neurodegenerative disorders. Several toxic metals, such as lead, cadmium, and mercury, are recognized as important environmental contaminants, and their exposure is associated with toxic effects on the human body. Essential elements that are required to maintain cellular homeostasis and normal physiological functions may also be toxic when accumulated at higher concentrations. For instance, manganese (Mn) is a trace essential element that participates in numerous biological processes, such as enzymatic activities, energy metabolism, and maintenance of cell functions. However, Mn overexposure is associated with behavioral changes in C. elegans, which are consistent with the dopaminergic system being the primary target of Mn neurotoxicity. Caenorhabditis elegans has been shown to be an important tool that allows for studies on neuron morphology using fluorescent transgenic worms. Moreover, behavioral tests may be conducted using worms, and neurotransmitter determination and related gene expression are likely to change after Mn exposure. Likewise, mutant worms may be used to study molecular mechanisms in Mn toxicity, as well as the expression of proteins responsible for the biosynthesis, transport, storage, and uptake of dopamine. Furthermore, this review highlights some advantages and limitations of using the experimental model of C. elegans and provides guidance for potential future applications of this model in studies directed toward assessing for Mn neurotoxicity and related mechanisms.

The Role of Oxidative Stress in Manganese Neurotoxicity: A Literature Review Focused on Contributions Made by Professor Michael Aschner

“…There is a growing interest in toxicology in the use of so-called New Alternative Models (NAMs) to reduce reliance on mammalian-based toxicity testing [ 93 ]. The Aschner laboratory has been at the forefront of using the nematode, C. elegans , to study the roles of oxidative stress, mitochondrial dysfunction, and dopaminergic neurodegeneration following manganese exposure [ 94 , 95 ]. The approximately 19,000 genes in the genome of this nematode have 60–80% homology with the mammalian genome [ 96 ] and C. elegans and mammals share many biological functions.…”

Mitochondria in the Spotlight: C. elegans as a Model Organism to Evaluate Xenobiotic-Induced Dysfunction

“…These mutants presented no alteration in the expression of divalent metal transporters, but a decrease in the efflux transporter ferroportin [71], resulting in increased Mn levels. High Mn levels are threatening as this metal accumulates in dopaminergic neurons and causes neuronal damage in humans and in C. elegans as well [7].…”

“…The increasing need to understand the intricate effects of contaminants and drugs of abuse on human health requires the use of effective scientific research tools. The nematode Caenorhabditis elegans (C. elegans) is a powerful model widely used to investigate several phenomena underlying toxic mechanisms since C. elegans displays remarkable homology (up to 80%) with the mammalian genome [7,8]. C. elegans has been extensively employed to address the mechanism of mitochondrial dysfunction in the pathophysiology of neurodegenerative disorders, and behavioral alterations, and to elucidate the impact of contaminants on mitochondrial functioning [4,9].…”

Simira cordifolia protects against metal induced-toxicity in Caenorhabditis elegans

“…Among these, the nematode Caenorhabditis elegans has significant advantages ( Xiong et al, 2017 ; Ha et al, 2022 ). Caenorhabditis elegans shares homology with mammalian systems and has approximately 40% of genes related to human diseases ( Martins et al, 2022 ). It possesses complete systems, muscles, basic physiological processes, and oxidative stress responses comparable to those of higher organisms ( Zhu et al, 2022 ), as well as high sensitivity to low concentrations of environmental toxic agents ( Stylianou et al, 2019 ).…”