Wednesday afternoon’s Symposium Session during the 2022 SOT Annual Meeting and ToxExpo entitled, “Competitive Displacement of Physiologic Metals as a Mechanism of Toxicity,” highlighted how displacement of a “good metal” by a “bad metal” could lead to toxicologic pathologies.
Research by Dr. Jim Liu showed that the “good metal” is zinc in the zinc finger protein poly(ADP-ribose) polymerase-1 (PARP-1) that performs the DNA repair when DNA damage occurs. However, Dr. Liu’s studies have demonstrated that the trivalent arsenite selectively interacted with the zinc finger motif of this DNA-repairing PARP-1 protein (i.e., its 3 cysteine residues). Upon displacement of zinc by arsenite, the structure and function of PARP-1 was adversely modified: PARP-1 was no longer capable of binding the damaged part of DNA and thus failed to perform the DNA repair. This alteration led to excessive accumulation of ultraviolet (UV)–induced DNA damage and enhanced mutation. Through revelation of such a metal displacement mechanism, arsenic was thus recognized as a potent carcinogen and co-carcinogen to other environmental factors.
However, based on arsenic’s selectivity in displacing zinc, is arsenic always a “bad metal”? The answer is no. One zinc finger protein called cytoplasmic linker protein 170 was known to facilitate the tumor cell migration and invasion through microtubules dynamics. When low- and non-cytotoxic-level arsenic was applied, its selectivity in displacing zinc was found to inhibit the tumor spread and recurrence. Of note, much data regarding the competitive displacement of metals were acquired using in vitro systems (i.e., purified proteins or cell models) but were later verified with in vivo models. Therefore, Dr. Liu’s research also is a fantastic example for how in vitro evidence finally advanced our understanding of the toxic metals’ mechanism in human health.
This session repeatedly highlighted zinc as a “good metal” in multiple specific mechanisms, but can zinc and zinc-related proteins be proposed as a more general mechanism serving to protect our health? Dr. Lu Cai’s answer is yes. His research focusing on the metallothionein, a seven zinc-containing and zinc-inducible protein, demonstrated that this metallothionein protein, upon overexpression in a transgenic mouse model, contributed to better outcomes in diabetic cardiomyopathy, as compared with controls. However, although cadmium, a toxic metal, also can induce increased expression of metallothionein, the displacement of zinc by cadmium in metallothionein failed to protect the heart as zinc did.
Researchers in this Symposium Session are the pioneers that significantly advanced our understanding of metal toxicity. With the development of new experimental approaches (i.e., biophysical method or sensitive fluorescent probes with high metal specificity), we hope to provide more mechanistic studies to reveal toxic metal–induced adverse effects.
This blog was prepared by an SOT Reporter and represents the views of the author. SOT Reporters are SOT members who volunteer to write about sessions and events in which they participate during the SOT Annual Meeting and ToxExpo. SOT does not propose or endorse any position by posting this article. If you are interested in participating in the SOT Reporter program in the future, please email Giuliana Macaluso.
On-demand recordings of all Featured and Scientific Sessions delivered during the 2022 SOT Annual Meeting and ToxExpo will be available to meeting registrants in the SOT Event App and Online Planner after their conclusion, through July 31, 2022.
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