NAC's protective capacity against Engineered Nanoparticles (ENPs) toxicity

Another great study on N-acetylcysteine

PLEASE CHECK OUT THIS STUDY:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599212/pdf/ijn-14-4573.pdf

Abstract

Introduction: Engineered nanoparticles (ENPs) are one of the most widely used types of nanomaterials. Recently, ENPs have been shown to cause cellular damage by inducing ROS (reactive oxygen species) both directly and indirectly, leading to the changes in DNA methylation levels, which is an important epigenetic mechanism. In this study, we investigated the effect of ENP-induced ROS on DNA methylation.

Here are some of the highlights:

Conclusion:

The global DNA methylation that is observed in cells exposed to ENPs is associated with methylation of the Alu elements. However, the change in DNA methylation levels following ENP exposure is specific to particular ENP and cell types and independent of ROS, being induced indirectly through disruption of the oxidative defense process.

Introduction

Nanotechnology has been receiving growing interest across a number of fields, with engineered nanoparticles (ENPs) being one of the most highly used nanomaterials for a range of applications, such as cosmetics, food additives, and biomedicine, because of their special physicochemical properties.

However, it has previously been shown that many kinds of ENPs are toxic to organisms, causing cyto- and genotoxicity, including inflammation, oxidative stress, immunotoxicity, and DNA damage,^1–3 with the level of toxicity often depending on the physicochemical properties of the ENP, such as the size, shape, charge, and chemical composition.^4–6

In addition, exposure to ENPs has been shown to cause epigenetic changes,⁷ whereby gene expression is altered without any change in the DNA sequences, by inducing histone modification and changes miRNA expression and global DNA methylation, with the latter being particularly well studied due to its potential importance for maintaining genome stability.⁸

Recent studies have demonstrated that ENPs can induce changes in not only the global DNA methylation level but also the DNA methylation level of transposable elements (TEs), including long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs), respectively, both in vitro and in vivo using an inhalation exposure model.⁹ Furthermore, because TEs (particularly LINE-1 and Alu) account for 30% of the genome, it has been argued that their methylation levels can be used as an indicator of global DNA methylation levels.¹⁰ Full-length LINE-1 contains approximately 6,000 base pairs and accounts for 17% of the human genome, with approximately 600,000 copies being dispersed throughout it. In contrast, Alu is the most abundant SINE in the human genome, with around 1 million copies making up approximately 11% of the genome.

It has previously been reported that changes in the DNA methylation levels of LINE-1 and Alu are correlated with diseases, particularly various types of cancers and autoimmune diseases.¹¹ Moreover, such changes have been observed in models following exposure to various environmental toxicants, such as lead, benzene, and ultrafine air pollution particles.^12–14

However, the mechanisms by which ENPs induce changes in DNA methylation levels remain unclear.

Several previous studies have found that ENPs can increase the level of ROS, which has been shown to cause intracellular macromolecular damage, induce an inflammatory response, and potentially have an impact on epigenetic changes.^1,15–18

In this study, we gained new insights into the epigenotoxicity of ENPs, demonstrating that they alter global DNA methylation levels and DNA methylation levels of TEs via a mechanism that is independent of oxidative stress. Moreover, we proved that NAC can attenuate ENP-induced DNA hypomethylation.

Epigenetic modifications have been reported to play critical roles in many cellular processes, and the effects of nanomaterials on epigenetic mechanisms continue to receive attention.

In addition to inducing intracellular ROS production, ENPs have been shown to interfere with the oxidative stress balance by depleting the antioxidant capacity of cells.⁴ Glutathione (GSH) plays a critical role in the cellular defense mechanism against oxidative stress and has been shown to become unbalanced in cells that have been exposed to ENPs.³ However, the protective effects of antioxidants on DNA methylation in ENP-exposed cells have not previously been investigated. Although we did not directly measure the concentration of GSH in the present study, we did find that the pretreatment of HaCaT cells with NAC, which is a precursor of GSH, before they were challenged with ENPs prevented DNA hypomethylation of the Alu elements. ENPs may induce the production of intracellular ROS and deplete GSH levels. Interestingly, it should also be noted that the production of GSH directly influences DNA methylation levels by altering pools of the methyl donor S-adenosyl methionine (SAM). Under normal conditions, homocysteine is converted into methionine via the methionine cycle and used in the synthesis of SAM. However, when cells require a greater production of antioxidants such as GSH for defense against cellular oxidative stress, homocysteine is pushed into the GSH synthesis pathway, decreasing the level of SAM. In addition, the genome-wide methylome also affects the global DNA hypomethylation level.⁴² These findings suggest that ENPs induce changes in DNA methylation levels indirectly by disturbing the cellular oxidative defense process and that NAC represents a candidate protective drug where there is a high risk of ENP exposure.

Protect yourself with NAC and other antioxidants!