Organic elements make up 99% of an organism but without the remaining inorganic bioessential elements, termed the metallome, no life could be possible. The metallome is involved in all aspects of life, including charge balance and electrolytic activity, structure and conformation, signaling, acid-base buffering, electron and chemical group transfer, redox catalysis energy storage and biomineralization. Here, we report the evolution with age of the metallome and copper and zinc isotope compositions in five mouse organs. The aging metallome shows a conserved and reproducible fingerprint. By analyzing the metallome in tandem with the phenome, metabolome and proteome, we show networks of interactions that are organ-specific, age-dependent, isotopically-typified and that are associated with a wealth of clinical and molecular traits. We report that the copper isotope composition in liver is age-dependent, extending the existence of aging isotopic clocks beyond bulk organic elements. Furthermore, iron concentration and copper isotope composition relate to predictors of metabolic health, such as body fat percentage and maximum running capacity at the physiological level, and adipogenesis and OXPHOS at the biochemical level. Our results shed light on the metallome as an overlooked omic layer and open perspectives for potentially modulating cellular processes using careful and selective metallome manipulation.

Ageing is accompanied by important chemical deregulations that could serve as biomarkers of premature ageing conditions.

Selenium 0 (Se⁰) is a powerful anti-proliferative agent in cancer research. We investigated the impact of sub-toxic concentrations of Se⁰ functionalized nanoparticles (SeNPs) on prostate cancer PC-3 cells and determined their intracellular localization and fate. An in-depth characterization of functionalized selenium nanoparticles composition is proposed to certify that no chemical bias relative to synthesis issues might have impacted the study. Selenium is an extremely diluted element in the biological environment and therefore requires high-performance techniques with a very low detection limit and high spatial resolution for intracellular imaging. This was explored with state-of-the-art techniques, but also with cryopreparation to preserve the chemical and structural integrity of the cells for spatially resolved and speciation techniques. Monodisperse solutions of SeNPs capped with bovine serum albumin (BSA) were shown to slow down the migration capacity of aggressive prostate cancer cells compared to polydisperse solutions of SeNPs capped with chitosan. BSA coating could prevent interactions between the reactive surface of the nanoparticles and the plasma membrane, mitigating the generation of reactive oxygen species. The intracellular localization showed interaction with mitochondria and also a localization in the lysosome-related organelle. The SeNPs-BSA localization in mitochondria constitute a possible explanation for our result showing a very significant dampening of the PC-3 cell proliferation capabilities. The purpose of the use of sublethal compound concentrations was to limit adverse effects resulting from high cell death to best evaluate some cellular changes and the fate of these SeNPs on PC-3. Our findings provide new insight to further study the various mechanisms of cytotoxicity of SeNPs.

Volcanic eruptions release particles in a range of sizes that can chronically affect the health of communities within tens of kilometers of the volcano. Many years after an eruption, resuspension of volcanic ash can exacerbate the health impact of primary eruptive events. So far, our global understanding of the health effects triggered by chronic exposure to volcanic particles at the whole-body scale is limited. Recently, it has been shown that mice chronically exposed to metal-rich volcanic ash deposits present metallome deregulations associated with pathophysiological changes. These deregulations preferentially impact the reproductive functions, questioning about the impact of ash on fertility. This work aims to further assess the mechanisms driving the ash-related fertility disorders and develop predictive biomarkers. For that, elemental concentrations and Cu-Zn-Fe isotope measurements coupled to metabolomic, proteomic and transcriptomic analyses were measured in blood, liver and two organs of the male reproductive system (testis, seminal vesicle). The samples were collected on wild-type and mice exposed over two months to volcanic ash. Mice exposed to ash are characterized by (i) significant metallomic deregulations, (ii) higher oxidative stress correlating with isotopic variations of redox-sensitive elements and (iii) testicular and hepatic alterations, marked by gains in organ mass, hepatic lipid accumulation and circulating bile acids overload, all of which might exacerbate testicular defects. Together, these results demonstrate that prolonged exposure to metal-rich ash is a threat for male reproduction and that investigating redox-sensitive isotopes might help identifying early signs of oxidative stress-related testicular injuries, with future implications for hepato-testicular disease prevention.