Cationic gold nanoparticles elicit mitochondrial dysfunction: a multi-omics study

Abstract

Systems biology is increasingly being applied in nanosafety research for observing and predicting the biological perturbations inflicted by exposure to nanoparticles (NPs). In the present study, we used a combined transcriptomics and proteomics approach to assess the responses of human monocytic cells to Au-NPs of two different sizes with three different surface functional groups, i.e., alkyl ammonium bromide, alkyl sodium carboxylate, or poly(ethylene glycol) (PEG)-terminated Au-NPs. Cytotoxicity screening using THP-1 cells revealed a pronounced cytotoxicity for the ammonium-terminated Au-NPs, while no cell death was seen after exposure to the carboxylated or PEG-modified Au-NPs. Moreover, Au-NR3+ NPs, but not the Au-COOH NPs, were found to trigger dose-dependent lethality in vivo in the model organism, Caenorhabditis elegans. RNA sequencing combined with mass spectrometry-based proteomics predicted that the ammonium-modified Au-NPs elicited mitochondrial dysfunction. The latter results were validated by using an array of assays to monitor mitochondrial function. Au-NR3+ NPs were localized in mitochondria of THP-1 cells. Moreover, the cationic Au-NPs triggered autophagy in macrophage-like RFP-GFP-LC3 reporter cells, and cell death was aggravated upon inhibition of autophagy. Taken together, these studies have disclosed mitochondria-dependent effects of cationic Au-NPs resulting in the rapid demise of the cells.

Multiparametric Profiling of Engineered Nanomaterials: Unmasking the Surface Coating Effect

“…However, we reported in a previous study on a set of Au ENMs that proteomics can be applied to detect changes at doses corresponding to EC 50 and found a good concordance between transcriptomics and proteomics approaches in THP-1 cells. [12] In line with the latter findings, a recent proteomics study of metal oxide ENMs (SiO 2 and TiO 2 ) and GO showed no effects in a lung epithelial cell line at low doses (≤ 1 µg cm −2 ) while doses of 10 µg cm −2 yielded significant changes. [47] It is interesting to note that three ENMs (Au-20-PEG, QD-COOH, and QD-PEG) were noncytotoxic as shown by conventional toxicity assays, yet they were found to elicit significant changes in gene expression in THP-1 cells.…”

“…Indeed, it appears that toxicologists often apply the same "paradigm" for all ENMs rather than seeking to understand biological responses to ENMs in all their complexity (which is not to say that ENMs necessarily trigger novel responses-the pathways gene expression. [11,12] Such studies serve to complement, but cannot replace, toxicological studies using conventional assays.…”

An Engineered Gene Nanovehicle Developed for Smart Gene Therapy to Selectively Inhibit Smooth Muscle Cells: An In Vitro Study

“…On the other hand, PKCδ could be activated by LPS stimulation, which also induces the mitochondrial apoptosis pathway. These two mitochondria apoptosis pathways may be the cause of the enhancement of the selective inhibition effect of the PEI-Au/CHC/phEGR1-PKCδ complex on SMCs under the LPS stimulation condition [21,22]. The PrestoBlue assay suggested that the SMC-specific inhibition of proliferation under inflammation condition was realized via using the PEI-Au/CHC/phEGR1-PKCδ complex.…”

Nanotoxicity: a challenge for future medicine

“…In vitro testing methods might require assessment of multiple challenging steps such as physicochemical properties of nanomaterials, the environment-target cell, cellular uptake and epigenetic interaction [153]. Omic approaches; next generation sequencing, transcriptomics and proteomics, have provided considerably more information regarding the toxicity of the complex cellular processes triggered by interaction of nanomaterials with the microenvironment [154,155]. Also, an important point is personalized toxicology.…”