Zinc oxide (ZnO) nanomaterials are used in a wide range of products ranging from cosmetics to fabric and electronic devices. In addition, some ZnO-derived nano and microparticles have been demonstrated to exert antibacterial properties. For their increased exposure, their potential harm to human health needs to be carefully investigated.
Our hypothesis is that treatment of tumor and non tumor cells with ZnONR causes a vicious pathogenetic circuit triggered and maintained by the following players: HIF-1a, activated by ZnRO coating and by ROS; and HMGB1, released by damaged and dying cells and acting as a paracrine cytokine.The link between HIF-1a and HMGB1 is represented by membrane receptors binding to HMGB1 and whose transcription is increased by HIF-1a.
To demonstrate it, in this study, we will use ZnO nanorods (ZnONR) obtained through the thermal decomposition method, to initially, determine their uptake, increase of intracellular Zn++ and ROS production. Next, we will determine the release of HMGB1 from damaged or dying cells, HIF-1a activation, as well as HIF-1a-dependent gene expression and metabolic reprogramming. In order to correlate ZnONR effects with tumor grade, we will use HaCat cells, a human immortalized keratinocyte cell line, and two breast cancer cell lines i.e. the non-metastatic and more differentiated MCF7 and the metastatic and poorly differentiated MDA-MB-231.
In conclusion, our study will delineate the mechanism of action of ZnONR on tumor and non tumor cells that will help to understand their safety for human health and rationalize their use in medicine.
The world of nanotechnology is quickly growing, and nanomaterials are used in different areas such as fabrics, food processing, medical systems, etc. In fact, millions of tons of nanoparticles are produced every year and ZnO nanoparticles play a major role being the third highest nanometal produced (1). ZnO nanoparticles are present in sun lotions, ointments, paints, food supplements for live stock, antibacterial products, etc (1). This means that they are dispersed in the environment and that we are constantly exposed to them. Notwithstanding this, we have a very scarce information and knowledge on the toxic effects of nanoparticles in general and ZnO in particular. However, some studies have revealed health problems with ZnO nanoparticles in animals and plants after the use of ZnO as food supplement (1). In particular, it has been shown that ZnO treatment is accompanied by release of Zn++, ROS accumulation and cell death in different cellular systems (2). Moreover, ZnO can cross the blood brain barrier (BBB) thereby representing a trigger for neuroinflammation (3). It is therefore, important to continue and to strat new studies aimed to unravel the pathogenic potential of ZnO nanoparticles in order to suggest a wise use of them.
In this context our study aims to unravel a new pathogenetic mechanism triggered by exposing cells to ZnO nanoparticles in the form of nanorods (NR). In fact, we suggest that ZnONR can adhere to the plasmamembrane of the cells creating a "hypoxia-like" condition to which the cell respond by activating an hypoxia response with HIF-1a activation. Such HIF-1a activation, in turn, would increase cellular survival but also metabolic reprogramming and de novo expression of membrane receptors for alarmins such as HMGB1 release by damaged or dying cells. These series of events is depicted in Figure 1 and represents our hypothesis of the possible pathogenetic mechanism triggered by ZnONR.
In conclusion, once proved, this new mechanism will provide a scientific rationale unifying the different effects of ZnO nanoparticles described so far and that could be used also for other nanoparticles.
1) Swain PS, Rao SBN, Rajendran D, Dominic G, Selvaraju S. Anim Nutr. 2016;2:134-141. doi: 10.1016/j.aninu.2016.06.003.
2) Singh S. Toxicol Mech Methods. 2019;29:300-311. doi: 10.1080/15376516.2018.1553221.
3) Hu YL, Gao JQ. Int J Pharm. 2010;394:115-21. doi: 10.1016/j.ijpharm.2010.04.026.