Abstract Selenium (Se) is an essential trace element with a narrow dietary requirement range in humans (55–90 µg/day), and its deficiency is associated with significant health consequences including skeletal disease, cancer susceptibility, thyroid disorders, and impaired fertility. In plants Se is not essential, however it can impact plant health positively through protecting against abiotic stress and negatively due to enhanced reactive oxygen species activity. The inherent toxicity of Se at elevated concentrations has necessitated its formulation in nanoparticulate formats (SeNPs), which offer improved safety profiles and controlled delivery. This review examines recent advances in understanding the role of SeNPs in modulating epigenetic processes in both human and plant systems. Beyond their established effects on DNA methylation, SeNPs have been shown to modulate histone methylation by influencing the expression of specific histone methyltransferases (HMTs) such as EZH2, SETD7, and SUV39H2/KMT1B, and by altering the S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio through the transsulfuration pathway. SeNPs have also been shown to regulate levels of selenoproteins, including glutathione peroxidases (GPX) and thioredoxin reductase (TrxR). The modulation of selenoprotiens, not only by SeNPs, is increasingly recognised as a determinant of cellular homeostasis, ferroptosis, and cancer vulnerability. In plant systems, Se exposure, including when delivered as SeNP, is beginning to reveal epigenetic effects that may have implications for biofortification strategies and crop development. Environmental Se (not SeNP) availability, strongly influenced by climate change and anthropogenic activities, is predicted to decline globally, compounding Se deficiency in approximately one billion people, and thus where SeNP administration could be beneficial. Advanced analytical approaches, including HERFD-XAS and NanoSIMS, are presented as essential tools for deciphering the molecular landscape of Se, including determining the fate of SeNPs, in biological systems. SeNPs represent a versatile platform for health nanotechnology, capable of reducing Se-associated systemic toxicity while modulating key epigenetic mechanisms relevant to cancer prevention, selenoprotein regulation, and plant biofortification. A multi-modal analytical strategy is required to fully elucidate the role of this biologically unique element in health and disease.

At physiological levels, the trace element selenium plays a key role in redox reactions through the incorporation of selenocysteine in antioxidant enzymes. Selenium has also been evaluated as a potential anti-cancer agent, where selenium nanoparticles have proven effective, and are well tolerated in vivo at doses that are toxic as soluble Se. The use of such nanoparticles, coated with either serum albumin or the naturally occurring alkaline polysaccharide chitosan, also serves to enhance biocompatibility and bioavailability. Here we demonstrate a novel role for selenium in regulating histone methylation in ovarian cancer cell models treated with inorganic selenium nanoparticles coated with serum albumin or chitosan. As well as inducing thioredoxin reductase expression, ROS activity and cancer cell cytotoxicity, coated nanoparticles caused significant increases in histone methylation. Specifically, selenium nanoparticles triggered an increase in the methylation of histone 3 at lysines K9 and K27, histone marks involved in both the activation and repression of gene expression, thus suggesting a fundamental role for selenium in these epigenetic processes. This direct function was confirmed using chemical inhibitors of the histone lysine methyltransferases EZH2 (H3K27) and G9a/EHMT2 (H3K9), both of which blocked the effect of selenium on histone methylation. This novel role for selenium supports a distinct function in histone methylation that occurs due to a decrease in S-adenosylhomocysteine, an endogenous inhibitor of lysine methyltransferases, the metabolic product of methyl-group transfer from S-adenosylmethionine in the one-carbon metabolism pathway. These observations provide important new insights into the action of selenium nanoparticles. It is now important to consider both the classic antioxidant and novel histone methylation effects of this key redox element in its development in cancer therapy and other applications.

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.

High dose selenium acts as a cytotoxic agent, with potential applications in cancer treatment. However, clinical trials have failed to show any chemotherapeutic value of selenium at safe and tolerated doses (<90 μg/day). To enable the successful exploitation of selenium for cancer treatment, we evaluated inorganic selenium nanoparticles (SeNP), and found them effective in inhibiting ovarian cancer cell growth. In both SKOV-3 and OVCAR-3 ovarian cancer cell types SeNP treatment resulted in significant cytotoxicity. The two cell types displayed contrasting nanomechanical responses to SeNPs, with decreased surface roughness and membrane stiffness, characteristics of OVCAR-3 cell death. In SKOV-3, cell membrane surface roughness and stiffness increased, both properties associated with decreased metastatic potential. The beneficial effects of SeNPs on ovarian cancer cell death appear cell type dependent, and due to their low in vivo toxicity offer an exciting opportunity for future cancer treatment.

Selenium (Se) is an essential micronutrient present in human diet, entering in the composition of selenoproteins as selenocysteine (Se-Cys) amino acid. At the thyroid level, these proteins play an important role as antioxidant and in hormone metabolism. Selenoproteins are essential for the balance of redox homeostasis and antioxidant defense of mammalian organisms, while the corresponding imbalance is now recognized as the cause of many diseases including cancer. The food chain is the main source of Se in human body. Dietary intake is strongly correlated with Se content in soil and varies according to several factors such as geology and atmospheric input. Both Se deficiency and toxicity have been associated with adverse health effects. This review synthesizes recent data on the transfer of Se from soil to humans, Se U-shaped deficiency and toxicity uptake effects and particularly the impact of Se deficiency on thyroid cancer.

Background: Ovarian cancer diagnosis is currently based on imaging and circulating CA-125 concentrations with well-known limits to sensitivity and specificity. New biomarkers are required to complement CA-125 testing to increase effectiveness. Increases in sensitivity of isotopic separation via multi collector inductively coupled plasma-mass spectrometry have recently allowed highly accurate measurement of copper (Cu) isotopic variations. Studies in breast cancer patients have revealed changes of serum copper isotopic composition demonstrating the potential for development as a cancer biomarker. Evaluating Cu-65/Cu-63 ratios (delta Cu-65) in serum samples from cancer patients has revealed a strong correlation with cancer development. In this study blood samples from forty-four ovarian cancer patients, and 13 ovarian biopsies were investigated. Results: Here we demonstrate that changes in Cu isotopes also occurs in ovarian cancer patients. Copper composition determined by multiple collector inductively coupled plasma mass spectrometry revealed that the copper isotopic ratio delta Cu-65 in the plasma of 44 ovarian cancer patient cohort was significantly lower than in a group of 48 healthy donors, and indicated that serum was enriched for Cu-63. Further analysis revealed that the isotopic composition of tumour biopsies was enriched for Cu-65 compared with adjacent healthy ovarian tissues. Conclusions: We propose that these changes are due to increase lactate and Cu transporter activities in the tumour. These observations demonstrate that, combined with existing strategies, delta Cu-65 could be developed for use in ovarian cancer early detection.

Bio-géochimie du cancer : Utilisation des nanoparticules de sélénium dans le traitement et des isotopes du cuivre dans la détection des cancers ovariens Le cancer des ovaires est le septième cancer le plus commun chez les femmes dont le taux de survie à 5 ans est en deçà de 45% et dont le taux de détection des premiers stades de développement est inférieur à 20%. Avant d’arriver à un traitement, de nombreux défis restent à relever.Le développement de nouveaux traitements ciblant spécifiquement les cellules cancéreuses en réduisant les effets secondaires liés au traitement est nécessaire. Pour cela, le Sélénium a été étudié et a démontré à forte doses d’être efficace contre les cellules cancéreuses in vitro. De plus, les essais cliniques ont montré que l’utilisation de doses tolérables de sélénium (<90µg/jour) n’avait pas d’effet thérapeutique contre le cancer. Le développement de nouvelles formes de sélénium afin d’augmenter les doses administrées est donc nécessaire afin d’atteindre l’effet thérapeutique souhaité. Au cours de cette thèse j’ai mesuré l’effet de formes agrégées de sélénium appelées nanoparticules et démontré leur capacité à inhiber la croissance de cellules cancéreuses ovariennes. Dans les lignées cellulaires cancéreuses ovariennes SKOV-3 et OVCAR-3, le traitement aux SeNPs a déclenché la mort cellulaire. La mesure des propriétés nanomécaniques de ces deux lignées cellulaires après traitement a démontré un effet différent des SeNPs en fonction du type cellulaire. Les cellules OVCAR-3 ont vu diminuer leur rugosité de surface ainsi que leur rigidité cellulaire alors que les cellules SKOV-3 ont augmenté leur rigidité et leur rugosité, ces deux caractéristiques étant liées à une diminution de leur potentiel métastatique. De plus, le traitement aux SeNPs a augmenté de manière considérable la méthylation de trois lysines de l’histone 3 H3K4, H3K27 et H3K9. Cette méthylation a pu être bloquée par l’utilisation d’inhibiteurs de méthyltransférases spécifiques de ces marqueurs. L’étude du profil d’expression des deux lignées cellulaires après traitement a démontré le fait que le sélénium induit des modifications d’expression des méthyltransférases nous permettant de suggérer un mécanisme d’action du sélénium. De plus les SeNPs ont démontré leur impact sur l’expression marqueurs cancéreux comme l’activation de la réparation de l’ADN, la réponse aux espèces réactives de l’oxygène, la réorganisation de la matrice extracellulaire. L’effet des SeNPs semble dépendant du type cellulaire cependant leur bonne tolérabilité in vivo offre de bonnes perspectives d’utilisation en tant que traitement du cancer.Enfin, dans la continuité de récentes études sur le cancer du sein le cancer colorectal s’intéressant à la mesure des isotopes du cuivre (rapport 63Cu/65Cu) et démontrant leur potentiel dans la détection du développement de ces cancers, j’ai pu mesurer le contenu isotopique de biopsies et de prélèvements sanguins issus de patientes atteintes de cancers ovariens. J’ai pu mesurer une diminution significative du rapport des isotopes du cuivre dans le sérum des patientes cancéreuses en comparaison avec des témoins sains démontrant l’efficacité de détection des cancers par la mesure des isotopes du cuivre dans le sang.