Role of MTL-1, MTL-2, and CDR-1 in Mediating CadmiumSensitivity in Caenorhabditis elegans

Biomolecular Screening Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709, USA.
Toxicological Sciences (Impact Factor: 3.85). 05/2012; 128(2):418-26. DOI: 10.1093/toxsci/kfs166
Source: PubMed


Cadmium is an environmental toxicant whose exposure is associated with multiple human pathologies. To prevent cadmium-induced toxicity, organisms produce a variety of detoxification molecules. In response to cadmium, the nematode Caenorhabditis elegans increases the steady-state levels of several hundred genes, including two metallothioneins, mtl-1 and mtl-2, and the cadmium-specific response gene, cdr-1. Despite the presumed importance in metal detoxification of mtl-1 and mtl-2, knockdown of their expression does not increase cadmium hypersensitivity, which suggests that these genes are not required for resistance to metal toxicity in C. elegans. To determine whether cdr-1 is critical in metal detoxification and compensates for the loss of mtl-1 and/or mtl-2, C. elegans strains were generated in which one, two, and all three genes were deleted, and the effects of cadmium on brood size, embryonic lethality, the Bag phenotype, and growth were determined. Growth at low cadmium concentrations was the only endpoint in which the triple mutant displayed more sensitivity than the single and double mutants. A lack of hypersensitivity in these strains suggests that other factors may be involved in the response to cadmium. Caenorhabditis elegans produces phytochelatins (PCs) that are critical in the defense against cadmium toxicity. PC levels in wild type, cdr-1 single, mtl-1, mtl-2 double, and triple mutants were measured. PC levels were constitutively higher in the mtl-1, mtl-2 double, and triple mutants compared with wild type. Following cadmium exposure, PC levels increased. The lack of cadmium hypersensitivity when these genes are deleted may be attributed to the compensatory effects of increases in PCs.

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    • "In addition, GSH is involved in cellular removal of Cd and is discussed later. Phytochelatins (PCs), which are formed from condensation of glutathione molecules, have recently been discovered in invertebrate species[110]and are also believed to function as a Cd detoxification system[111]. In contrast to Cd-MT, Cd-PC complexes taken up with the food have been shown to not co-localize with lysosomes[105]which might hint at different storage and excretion routes of PCs and MTs. "

    Preview · Article · Jan 2016 · International Journal of Molecular Sciences
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    • "As the name suggests, they were originally thought to be found only in plants, but two independent studies demonstrated that the PCS from the nematode C. elegans produced PCs when cloned into an appropriate microbial host and that a C. elegans PCS knockout was hypersensitive to cadmium [10,11]. Treating C. elegans with cadmium also led to an increase in tissue concentrations of PC2 and PC3 [12,13]. More recently, a functional PCS has been demonstrated in a second animal phylum (Platyhelminthes), as the Schistosoma mansoni PCS is also cadmium-responsive when cloned into baker’s yeast [14], although PC production has not yet been observed in the S. mansoni flukes themselves [15]. "
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    ABSTRACT: Phytochelatins are small cysteine-rich non-ribosomal peptides that chelate soft metal and metalloid ions, such as cadmium and arsenic. They are widely produced by plants and microbes; phytochelatin synthase genes are also present in animal species from several different phyla, but there is still little known about whether these genes are functional in animals, and if so, whether they are metal-responsive. We analysed phytochelatin production by direct chemical analysis in Lumbricus rubellus earthworms exposed to arsenic for a 28 day period, and found that arsenic clearly induced phytochelatin production in a dose-dependent manner. It was necessary to measure the phytochelatin metabolite concentrations directly, as there was no upregulation of phytochelatin synthase gene expression after 28 days: phytochelatin synthesis appears not to be transcriptionally regulated in animals. A further untargetted metabolomic analysis also found changes in metabolites associated with the transsulfuration pathway, which channels sulfur flux from methionine for phytochelatin synthesis. There was no evidence of biological transformation of arsenic (e.g. into methylated species) as a result of laboratory arsenic exposure. Finally, we compared wild populations of earthworms sampled from the field, and found that both arsenic-contaminated and cadmium-contaminated mine site worms had elevated phytochelatin concentrations.
    Full-text · Article · Nov 2013 · PLoS ONE
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    ABSTRACT: Phytochelatins are sulfur-rich metal-binding peptides, and phytochelatin synthesis is one of the key mechanisms by which plants protect themselves against toxic soft metal ions such as cadmium. It has been known for a while now that some invertebrates also possess functional phytochelatin synthase (PCS) enzymes, and that at least one species, the nematode Caenorhabditis elegans, produces phytochelatins to help detoxify cadmium, and probably also other metal and metalloid ions including arsenic, zinc, selenium, silver, and copper. Here, we review recent studies on the occurrence, utilization, and regulation of phytochelatin synthesis in invertebrates. The phytochelatin synthase gene has a wide phylogenetic distribution, and can be found in species that cover almost all of the animal tree of life. The evidence to date, though, suggests that the occurrence is patchy, and even though some members of particular taxonomic groups may contain PCS genes, there are also many species without these genes. For animal species that do possess PCS genes, some of them (e.g. earthworms) do synthesize phytochelatins in response to potentially toxic elements, whereas others (e.g. Schistosoma mansoni, a parasitic helminth) do not appear to do so. Just how (and if) phytochelatins in invertebrates complement the function of metallothioneins remains to be elucidated, and the temporal, spatial, and metal specificity of the two systems is still unknown.
    Full-text · Article · Jun 2014 · Metallomics
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