The Metabolomic Responses of <i>Caenorhabditis elegans</i> to Cadmium Are Largely Independent of Metallothionein Status, but Dominated by Changes in Cystathionine and Phytochelatins

Cadmium is a widely distributed toxic environmental pollutant. Using proton NMR spectroscopy and UPLC-MS, we obtained metabolic profiles from the model organism <i>Caenorhabditis elegans</i> exposed to sublethal concentrations of cadmium. Neither in the presence nor absence of cadmium did the metallothionein status (single or double <i>mtl</i> knockouts) markedly modulate the metabolic profile. However, independent of strain, cadmium exposure resulted in a decrease in cystathionine concentrations and an increase in the nonribosomally synthesized peptides phytochelatin-2 and phytochelatin-3. This suggests that a primary response to low levels of cadmium is the differential regulation of the <i>C. elegans</i> trans-sulfuration pathway, which channels the flux from methionine through cysteine into phytochelatin synthesis. These results were backed up by the finding that phytochelatin synthase mutants (<i>pcs-1</i>) were at least an order of magnitude more sensitive to cadmium than single or double metallothionein mutants. However, an additive sensitivity toward cadmium was observed in the <i>mtl-1; mtl-2; pcs-1</i> triple mutant.