Size-Dependent Cytotoxicity and Reactive Oxygen Species

source:Dovepress

Nanomaterials have unique properties, such as small size and enlarged surface area, that enhance regenerative and catalytic enzyme activities and, consequently, their biological effects. Cerium (Ce), a critical rare earth element with a unique f-electron configuration that gives its compounds special properties, has been called a universal new material.1 In cerium oxide nanoparticles (CeO2 NPs), there are two valence states-Ce3+ (reduced state) and Ce4+ (oxidation state)—and these two states can be converted to each other. The transition between Ce4+/Ce3+ on the crystal surface results in catalytic and antioxidant effects. Pezzini et al reported that CeO2 NPs serve as antioxidants in primary cultured skin fibroblasts. As free radical scavengers, CeO2 NPs can treat various diseases induced by oxidative stress. Recent studies have found that CeO2 NPs act as ROS scavengers in diabetic nephropathy, rheumatoid arthritis, and ischemic stroke.Furthermore, CeO2 NPs are widely used in single-phase or multiphase drug carriers or delivery devices to solve cancer drug resistance and mistargeting, and to achieve a synergistic anti-tumor activity with drugs. In addition, some studies have reported that CeO2 NPs are used in the treatment of eye diseases, such as to reduce light-induced retinal degeneration and photoreceptor death rate. Moreover, CeO2 NPs have been reported to act as antioxidants in the retina and protect against retinal nerve damage induced by high-intensity light exposure.

Therefore, the widespread use of CeO2 NPs has raised human health concerns. It has been suggested that CeO2 NPs lead to ROS generation, DNA damage, and apoptosis in human lung cells. Moreover, CeO2 NPs induce cytotoxicity of the human hepatoma cell line SMMC-7721 through oxidative stress and activation of the MAPK signaling pathway. In addition, CeO2 NPs induce cytotoxicity and oxidative stress in human skin keratinocytes and genotoxicity in human intestinal Caco-2 cells. However, despite being an important and sensitive organ, the eyes have been ignored in evaluating the toxicity of CeO2 NPs; whether or not CeO2 NPs exert toxicity to other organs is largely unknown.

ROS are natural byproducts of normal oxidative metabolism and of free radicals such as the highly reactive hydroxyl radical (·OH) or superoxide anion radical (O2·–). ROS are unstable and highly reactive compounds that can strip electrons from nearby molecules and induce significant oxidative damage to cellular structures if the amount of ROS exceeds the system’s antioxidant capacity. The cytotoxicity effect is referred to as “oxidative stress,” which leads to a change in the mitochondrial membrane potential. In the whole life cycle of cells, mitochondria use oxidable substrates to produce an electrochemical proton gradient on the mitochondrial membrane, which is used to produce ATP and generate energy for cellular activities. The evaluation of the mitochondrial membrane potential (ΔΨ m) of intact cells can provide the necessary information to assess their physiological and pathological status.

This study evaluated the toxicity of CeO2 NPs with different particle sizes in ARPE-19 cells, which are a type of human retinal pigment epithelial cell. We also determined the role of CeO2 NPs in ROS generation. In addition, we explored the change in mitochondrial membrane potential in response to CeO2 NPs treatment.