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

Abstract

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.

Effects of Cadmium Exposure on Gut Villi in Danio rerio

“…As expected, the damage is more extended at the lower concentration; the same evidence was obtained in the retina and kidney tubules [13,15]. Higher toxicity at a lower concentration can be explained considering that cadmium is a calcium and zinc mimetic and, by entering the cell at a low concentration, it may remain invisible to the detoxifying mechanisms [46,47]. Indeed, in villi of 25 µM Cd-treated animals, metallothioneins remain concentrated in the enterocyte's cytoplasm as in control villi, while MTs reduce significantly after 100 µM Cd exposure, presumably since it was used to detoxify the mucosa.…”

Chemical Genetics in C. elegans Identifies Anticancer Mycotoxins Chaetocin and Chetomin as Potent Inducers of a Nuclear Metal Homeostasis Response

“…42,77 C. elegans has additional metal-responsive signaling mechanisms because numr-1/2 and many other genes can be strongly activated by cadmium independently of HIZR-1. 42 Repression of metallothionein genes by chaetocin and chetomin is also consistent with a distinct mechanism (Figures 3 and 7 and Figures S3 and S5). 77 Redox imbalance has been measured in cancer cells exposed to ETPs, 16,19,78 which is consistent with activation of HMOX1 and unfolded protein responses that we observed in HCT116 cells (Figure S6).…”

The association between serum cadmium and diabetes in the general population: A cross-sectional study from NHANES (1999–2020)

“…We speculated that cadmium might play a physiological role at low levels somewhat, although it has not yet been discovered. Cadmium is chemically similar to zinc since they belong to group 12 of the periodic table and both elements are divalent d-block elements ( 44 ). Previous studies have shown that serum zinc levels are negatively correlated with diabetes and have positive glucose control outcomes ( 45 ).…”