Zinc (Zn2+) is a crucial trace element with diverse biological roles, including catalytic and structural functions in proteins and immune system modulation. Its bioavailability is tightly regulated by ZnT (export) and Zip (import) transporter proteins. ZnT8, for example, imports Zn2+ into β-cell vesicles for insulin storage and co-release. Recent studies have shown that glucose-stimulated zinc secretion (GSZS) can be imaged in vivo using Zn-responsive MRI contrast agents, successfully visualizing pancreatic islets and differentiating response rates. The human prostate has the highest Zn2+ concentration of any tissue, significantly reduced in malignant tissue. This prompted the investigation of GSZS MRI to differentiate healthy and cancerous prostate tissue. Hypointense foci (lack of Zn2+ secretion) were observed in TRAMP mice and dogs with benign prostatic hyperplasia (BPH). SR-XRF confirmed that glucose stimulates Zn2+ movement from the glandular lumen to stromal/interstitial spaces, where it interacts with the MRI contrast agent. While the mechanism remains unclear, studies in PNT1A cells show that high glucose causes zinc transporter rearrangement, resulting in Zn2+ export via ZnT1 and lysosomal storage via ZnT4. Glycolytic flux is necessary for in vivo GSZS. This study aimed to assess the impact of altered dietary Zn2+ on prostate tissue zinc content (SR-XRF) and GSZS (MRI) in healthy and TRAMP mice to understand how varying zinc intake might affect the accuracy of prostate cancer detection using this method.

The literature review extensively covers the essential role of zinc in various biological processes, emphasizing its involvement in metalloenzymes, transcription factors, and immune regulation. The dynamic nature of Zn2+ interactions in cells is highlighted, alongside the role of ZnT and Zip transporters in maintaining cytosolic Zn2+ levels. The existing knowledge on ZnT8 in insulin secretion and the development of Zn-responsive MRI contrast agents for imaging GSZS in the pancreas are discussed. Previous research on the high zinc content of the healthy prostate and its reduction in malignant tissues is reviewed, alongside studies showing the potential of GSZS MRI to differentiate between these states in animal models. The mechanisms underlying glucose-stimulated Zn2+ secretion are explored, including the influence of glucose on zinc transporter rearrangement in prostate epithelial cells.

Wild-type (WT) and TRAMP mice were fed diets with low (0.05 ppm), normal (30 ppm), or high (150 ppm) zinc for 21 days. Animals were fasted overnight before imaging. GSZS was induced by glucose injection with the Zn2+-responsive MRI contrast agent GdL1. GdL1 binds to Zn2+ and albumin, increasing T1 relaxivity, which is detected as increased image intensity in T1-weighted MRI. MRI scans were acquired before and after GdL1 and glucose/saline injection. After imaging, mice were euthanized, and prostates were collected for SR-XRF. Blood samples were analyzed for Gd and Zn using ICP-MS. SR-XRF generated elemental maps of prostate lobes, and data was quantified using PyMCA software. Statistical analysis included one-way ANOVA, Tukey's test, and Student's t-test. Body weight, blood glucose, and serum zinc levels were also measured. The study design included a workflow combining in vivo MRI, ex vivo SR-XRF, and blood analysis to investigate systemic and prostatic responses to altered dietary zinc.

Zinc deficiency caused weight loss in both WT and TRAMP mice. WT mice on a zinc-deficient diet showed higher serum zinc levels than TRAMP mice, suggesting impaired zinc redistribution in TRAMP mice. GdL1 injection alone slightly decreased blood glucose in mice on high-zinc diets. SR-XRF revealed that dietary zinc did not significantly impact total prostate zinc content, but zinc distribution varied among lobes. GSZS MRI showed increased zinc efflux in WT mice with increasing dietary zinc. In contrast, TRAMP mice showed minimal changes in GSZS irrespective of dietary zinc, indicating impaired zinc regulation. There was a significant increase in the index of zinc efflux (difference in signal intensity between saline and glucose injections) in WT animals that were directly proportional to increased dietary zinc levels. This trend was not observed in the TRAMP animals.

The findings demonstrate that zinc deficiency leads to systemic and organ-level dysregulation, affecting weight and zinc bioavailability differently in healthy and cancerous prostate tissue. The lack of significant changes in total prostate zinc content with varying dietary zinc intake highlights the importance of dynamic imaging methods like GSZS MRI in assessing functional aspects of zinc metabolism. The observed difference in GSZS response to dietary zinc between WT and TRAMP mice underscores the altered zinc homeostasis in prostate cancer. The inability of TRAMP mice to efficiently regulate zinc efflux suggests that dietary zinc supplementation before GSZS MRI could potentially enhance image contrast between healthy and malignant prostate tissue by exploiting this difference, thereby improving diagnostic accuracy. Additional studies are needed to further investigate the mechanism of GSZS and optimize GSZS MRI for prostate cancer detection in humans.

This study demonstrates the impact of dietary zinc on GSZS in healthy and malignant mouse prostates. Zinc deficiency causes systemic dysregulation, while healthy mice exhibit increased zinc efflux with higher dietary zinc, unlike TRAMP mice. This suggests that dietary zinc supplementation before GSZS MRI could improve prostate cancer detection. Future research should focus on optimizing this approach for clinical translation and investigating the underlying mechanisms of altered zinc homeostasis in prostate cancer.

The study used a mouse model, which may not fully reflect human physiology. The small sample sizes in some experimental groups limit the statistical power of the findings. The study did not include a control experiment using a non-zinc-responsive Gd-based agent to fully account for variations in tissue vascularity between healthy and malignant tissues. Further research with larger sample sizes and additional control experiments are needed to validate the findings.