Cadmium hijacks the high zinc response by binding and activating the HIZR-1 nuclear receptor

Cadmium is an environmental pollutant and significant health hazard that is similar to the physiological metal zinc. In C. elegans high zinc homeostasis is regulated by the HIZR-1 nuclear receptor transcription factor. To define relationships between high zinc homeostasis and the response to cadmium, we identified 145 cadmium-regulated genes. hizr-1 was necessary for activation of a subset of genes, indicating there are at least two mechanisms of cadmium-regulated transcription. Cadmium directly bound HIZR-1, promoted nuclear accumulation of HIZR-1 in intestinal cells, and activated HIZR-1-mediated transcription via the HZA enhancer. Thus, cadmium binding promotes HIZR-1 activity, indicating that cadmium acts as a zinc mimetic to hijack the high zinc response. To elucidate the relationships between high zinc and cadmium detoxification, we analyzed three pathways: the phytochelatin pathway strongly promoted cadmium resistance but not high zinc resistance, the hizr-1 pathway strongly promoted high zinc resistance but not cadmium resistance, and the mek-1/sek-1 pathway promoted resistance to high zinc and cadmium. These studies identify resistance pathways that are specific for high zinc and cadmium as well as a shared pathway. Overall design: Two Caenorhabditis elegans strains, wild type and a hizr-1 loss-of-function mutant were independtly exposed to toxic cadmium conditions and compared to basal growing conditions. Two biological samples each strain and each condition were used.