Dietary Chelators in Metal Homeostasis

About This Grant

SUMMARY Trace metal nutrients are essential for fundamental biological processes like cell signaling, metabolism, and survival. However, the absorption of heavy metals through food, water, and air disrupts these critical functions, posing a significant threat to human health. Maintenance of physiological function requires control of metal homeostasis, which involves tight regulation of adequate availability of essential trace metals while minimizing accumulation of toxic heavy metals. Controlling this delicate balance is vital to preserve cellular function and prevent disease. Despite its central importance, our understanding of metal homeostatic systems is limited. A major gap in understanding lies in the involvement of small molecule thiols in metal disposition, despite acknowledgement that abundant, endogenous thiols are engaged in such activities. A new opportunity to study these interactions with metal homeostasis has presented in our recent discovery of phytochelatins (PyCs) in human samples. PyCs are short, thiol-containing peptides produced in plants, where they act as potent metal chelators. PyCs are ubiquitous in the diets, but their presence and influence on human metal homeostasis was only recently discovered. We hypothesize that dietary PyCs are key regulators of human metal homeostasis. Testing this hypothesis from multiple angles will provide critical opportunities to address significant gaps in our understanding of small molecule regulation of metal dynamics. This research not only uncovers a previously unrecognized class of molecules involved in metal homeostasis but also opens new avenues to develop dietary interventions for modifying nutrient bioavailability and excretion of toxic heavy metals, with implications for preventing and mitigating metal-associated diseases. The proposed project will explore these interactions using a suite of molecular and multi-omic analytical techniques to answer core questions about PyC activity in humans. 1) This project will reveal mechanisms of transport of PyC and PyC-metal complexes by absorbing and excretory epithelia using labeled PyC standards. 2) It will explore PyCs as a dietary means of modifying nutrient metal absorption and distribution in in vivo experiments involving mineral-deficient mouse models. Complementary studies will investigate PyCs as a dietary means to promote heavy metal excretion using both in vitro and in vivo models. 3) Finally, methods for reliable detection of PyC and PyC-metal complexes in human samples, using established analytical methods from the plant sciences and PyC-biased re-extraction of preexisting human metabolomics data, will be explored and optimized. Successful completion of this project will lay the foundation for a new topic of study within metal homeostasis research. A fundamental understanding of PyC and PyC-metal uptake, distribution and excretion will be established, and key methodology for subsequent clinical translational research on PyCs as dietary modifiers of metal homeostasis will be provided. More widely, this project will highlight small molecule actors in regulation of metal availability and distribution that have thus far gone unnoticed and may be key to any number of future developments in metal homeostasis research.