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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    • "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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