Examining the homeostatic distribution of metals and Zn isotopes in Göttingen minipigs

Abstract

The role of metals in biologic systems is manifold, and understanding their behaviour in bodily processes, especially those relating to neurodegenerative diseases, is at the forefront of medical science. The function(s) of metals - such as the transition metals - and their utility in both the diagnosis and treatment of diseases in human beings, is often examined via the characterization of their distribution in animal models, with porcine models considered exceptional proxies for human physiology. To this end, we have investigated the homeostatic distribution of numerous metals (Mg, K, Ca, Mn, Fe, Cu, Zn, Rb and Mo), the non-metal P, and Zn isotopes in the organs and blood (red blood cells, plasma) of Göttingen minipigs. These results represent the first set of data outlining the homeostatic distribution of metals and Zn isotopes in Göttingen minipigs, and indicate a relatively homogeneous distribution of alkali/alkaline earth metals and P among the organs, with generally lower levels in the blood, while indicating more heterogeneous and systematic abundance patterns for transition metals. In general, the distribution of all elements analysed is similar to that found in humans. Our elemental abundance data, together with data reported for humans in the literature, suggest that element-to-element ratios, e.g. Cu/Mg, show potential as simple diagnostics for diseases such as Alzheimer's. Isotopic data indicate a heterogeneous distribution of Zn isotopes among the organs and blood, with the liver, heart and brain being the most depleted in heavy Zn isotopes, and the blood the most enriched, consistent with observations in other animal models and humans. The Zn isotopic composition of Göttingen minipigs displays a systematic offset towards lighter δ66Zn values relative to mice and sheep models, suggesting physiology that is more closely aligned with that of humans. Cumulatively, these observations strongly suggest that Göttingen minipigs are an excellent animal model for translational research involving metals, and these data provide a strong foundation for future research.

High‐Precision Zinc Isotopic Measurement of Certified Reference Materials Relevant to the Environmental, Earth, Planetary and Biomedical Sciences

“…Biologically derived reference materials are applicable to multiple research disciplines, including biomedicine. However, reference Zn isotope values are generally underreported, despite recent amplification in the number of Zn isotope studies with a biological focus (Ohno et al 2005, B€ uchl et al 2008, Larner et al 2015, Moynier et al 2017a, Mahan et al 2018. Here, we report new d 66 Zn values for a range of modern ocean marine biota, including the reference materials BCR-414, BCR-279, DOLT-4 and DOLT-5 that display wide-ranging signatures varying from -1.02 to +0.53‰.…”

“…In animals and humans, Zn isotopes also have the potential to improve understanding of the processes that impact on Zn homeostasis (Krebs et al 1995) in nutritional and dietary studies (Ohno et al 2005, B€ uchl et al 2008, Mahan et al 2018, and as a novel biomarker for human diseases such as breast cancer (Larner et al 2015) and Alzheimer's dementia (Moynier et al 2017a). As the biomedical applications of the Zn isotope system continue to expand, there is a need to expand the availability of wellcharacterised biological reference materials.…”

Serum and brain natural copper stable isotopes in a mouse model of Alzheimer’s disease

“…Therefore, it will be important to test other AD animal models (e.g. minipigs 43 ) as well as human patients.…”

Inter-comparison of stable iron, copper and zinc isotopic compositions in six reference materials of biological origin

“…Zinc isotopes in plants are fractionated between the organs, including roots [22,36]. Zinc isotopes are also fractionated between the organs of animals [37,38]. In humans, the blood and urine Zn isotopic composition have been suggested to reveal dietary habits [39] and more genrally, the Zn status in human [40].…”