Genome-Wide Analyses of Metal Responsive Genes in Caenorhabditis elegans

Abstract

Metals are major contaminants that influence human health. Many metals have physiologic roles, but excessive levels can be harmful. Advances in technology have made toxicogenomic analyses possible to characterize the effects of metal exposure on the entire genome. Much of what is known about cellular responses to metals has come from mammalian systems; however the use of non-mammalian species is gaining wider attention. Caenorhabditis elegans is a small round worm whose genome has been fully sequenced and its development from egg to adult is well characterized. It is an attractive model for high throughput screens due to its short lifespan, ease of genetic mutability, low cost, and high homology with humans. Research performed in C. elegans has led to insights in apoptosis, gene expression, and neurodegeneration, all of which can be altered by metal exposure. Additionally, by using worms one can potentially study mechanisms that underline differential responses to metals in nematodes and humans, allowing for identification of novel pathways and therapeutic targets. In this review, toxicogenomic studies performed in C. elegans exposed to various metals will be discussed, highlighting how this non-mammalian system can be utilized to study cellular processes and pathways induced by metals. Recent work focusing on neurodegeneration in Parkinson’s disease will be discussed as an example of the usefulness of genetic screens in C. elegans and the novel findings that can be produced.

Comprehensive phenotyping and transcriptome profiling to study nanotoxicity inC. elegans

“…Comparison of the transcriptomics changes during Ag and SiO 2 exposures with the findings in previous studies on metal toxicities indicated that metallothionein-2 (mtl-2), a commonly observed responsive gene to the metal toxicities (conserved in C. elegans and mammals) (Caito et al, 2012;Cui et al, 2007;Roh, Lee & Choi, 2006;Kumar et al, 2015;Anbalagan et al, 2012), was up-regulated in these groups (FDR =0.002 for Ag, FDR = 0.043 for SiO2), which further confirmed the effectiveness of the model. Ag and SiO 2 nanoparticles have been shown to affect locomotion velocity in C. elegans N2, as previously described (Jung et al, 2015).…”

“…Furthermore, gene enrichment in GO and newly determined terms were carried out using GOATOOLS (Klopfenstein et al, 2018) and WormExp (Yang, Dierking & Schulenburg, 2016), respectively. Differentially expressed genes in the toxicity groups (compared to control) were further searched to ascertain whether they were reported in metal toxicity based on previous studies (Caito et al, 2012;Cui et al, 2007;Roh, Lee & Choi, 2006;Kumar et al, 2015;Anbalagan et al, 2012).…”

Cell Biology of the Mitochondrion

“…The precise changes depended on coexposure to other secondary toxins (UVC and hydrogen peroxide), and whether the mercury was presented in organic or inorganic form. Caito and Aschner also showed that organic mercury (MeHg) caused mitochondrial dysfunction, decreased mitochondrial mass and mtDNA copy number (Caito et al 2012(Caito et al , 2013. Interestingly, they also showed that the effects were NAD + dependent and could be alleviated by pretreatment of the nematodes with exogenous NAD + .…”

Mixture effects of copper, cadmium, and zinc on mortality and behavior ofCaenorhabditis elegans

“…It is well known that metals can cause neurotoxicity, alter neuronal excitability, and impair chemosensation, and that they are involved in neurodegenerative diseases . Furthermore, free radicals and reactive oxygen species generated by metals can induce protein and deoxyribonuclease (DNA) oxidation and lipid peroxidation . They also disrupt cellular homeostasis by impairing DNA repair, inhibiting enzyme activity, and affecting protein binding .…”