Cadmium is an environmental pollutant and significant health hazard that is similar to the physiological metal zinc. In Caenorhabditis elegans, high zinc homeostasis is regulated by the high zinc activated nuclear receptor (HIZR-1) transcription factor. To define relationships between the responses to high zinc and cadmium, we analyzed transcription. Many genes were activated by both high zinc and cadmium, and hizr-1 was necessary for activation of a subset of these genes; in addition, many genes activated by cadmium did not require hizr-1, 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 high zinc activation (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 genes that function in three pathways: the pcs-1/phytochelatin pathway strongly promoted cadmium resistance but not high zinc resistance, the hizr-1/HZA pathway strongly promoted high zinc resistance but not cadmium resistance, and the mek-1/sek-1/kinase signaling 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.

镉是一种环境污染物，对健康有重大危害，与生理金属锌相似。在秀丽隐杆线虫中，高锌稳态受高锌激活核受体 (HIZR-1) 转录因子的调节。为了确定对高锌和镉的反应之间的关系，我们分析了转录。许多基因被高锌和高镉激活，hizr-1是激活这些基因子集所必需的；此外，许多被镉激活的基因不需要hizr-1，表明至少有两种镉调控的转录机制。镉直接结合 HIZR-1，促进 HIZR-1 在肠细胞中的核积累，并通过高锌活化 (HZA) 增强剂激活 HIZR-1 介导的转录。因此，镉结合促进了 HIZR-1 活性，表明镉充当锌模拟物来劫持高锌反应。为了阐明高锌和镉解毒之间的关系，我们分析了在三个途径中起作用的基因：pcs-1 /phytochelin 途径强烈促进镉抗性但不促进高锌抗性，hizr-1 /HZA 途径强烈促进高锌抗性但不抗镉，而mek-1/sek-1/激酶信号通路促进对高锌和高镉的抵抗。这些研究确定了特定于高锌和镉的抗性途径，以及共同途径。