Endoplasmic Reticulum Stress Induced by Zinc Oxide Nanoparticles Is an Earlier Biomarker for Nanotoxicological Evaluation

Abstract

Zinc oxide nanoparticles (ZnO NPs) have been widely used in cosmetics and sunscreens, advanced textiles, self-charging and electronic devices; the potential for human exposure and the health impact at each stage of their manufacture and use are attracting great concerns. In addition to pulmonary damage, nanoparticle exposure is also strongly correlated with the increase in incidences of cardiovascular diseases; however, their toxic potential remains largely unclear. Herein, we investigated the cellular responses and endoplasmatic reticulum (ER) stress induced by ZnO NPs in human umbilical vein endothelial cells (HUVECs) in comparison with the Zn2+ ions and CeO2 NPs. We found that the dissolved zinc ion was the most significant factor for cytotoxicity in HUVECs. More importantly, ZnO NPs at noncytotoxic concentration, but not CeO2 NPs, can induce significant cellular ER stress response with higher expression of spliced xbp-1, chop, and caspase-12 at the mRNA level, and associated ER marker proteins including BiP, Chop, GADD34, p-PERK, p-eIF2α, and cleaved Caspase-12 at the protein levels. Moreover, ER stress was widely activated after treatment with ZnO NPs, while six of 84 marker genes significantly increased. ER stress response is a sensitive marker for checking the interruption of ER homeostasis by ZnO NPs. Furthermore, higher dosage of ZnO NPs (240 μM) quickly rendered ER stress response before inducing apoptosis. These results demonstrate that ZnO NPs activate ER stress-responsive pathway and the ER stress response might be used as an earlier and sensitive end point for nanotoxicological study.

In situquantification of diverse titanium dioxide nanoparticles unveils selective endoplasmic reticulum stress-dependent toxicity

“…wed in Djur n D (Zhang et al 2012, Chen et al 2014, Yu, Chang, et al 2015. Our data show that the internalization of titanium (TiO 2 NPs), besides increasing the cell calcium content, does also induce the expression of CHOP (ATF4 pathway) and activates (i) the ER stress in HUVEC cells and (ii) differentiation in keratinocytes.…”

“…Recent studies report the endoplasmic reticulum stress (ER stress) as a common response in NPs related toxicity with studies on TiO 2 NPs (Zhang et al 2012, Chen et al 2014, Yu, Chang, et al 2015. The endoplasmic reticulum (ER) is an important organelle, which plays a role in folding and assembling of cellular proteins, in synthesis of lipids and sterols, and in regulating the balance of the intracellular calcium homeostasis, processes which are all dependent on the ER internal homeostasis.…”

Gold nanoparticle interactions with endothelial cells cultured under physiological conditions

“…Several studies have previously shown induced endoplasmic reticulum (ER) stress in different cell types after treatment with silverdoped silica NPs, 40 silver NPs 41,42 or polystyrene nanospheres. 43 Chen et al showed that zinc oxide NPs triggered ER stress in HUVEC 44 and gold NPs were shown to induce stress signaling in K562 cells. 45 However, previous studies show that AuNPs of three different sizes and four detection of ER stress markers, which constitute components of the Unfolded Protein Response (UPR).…”

Airborne Nanoparticle Pollution in a Wire Electrical Discharge Machining Workshop and Potential Health Risks

“…The airborne particles can be classified as ambient airborne particulate material (PM) which usually is categorized into coarse, fine, and ultrafine particles with aerodynamic diameters between 2.5 and 10 µm, < 2.5 µm (PM 2.5 ), and < 0.1 µm (PM 0.1 ), respectively (Hinds, 1999). It had been found that particles at the nanoscale level pose more adverse health effects than larger particles with the same materials (Nalwa and Zhao, 2007;Qu et al, 2011;Chen and Chen, 2012;Gorbunov et al, 2013;Chen et al, 2014). Understanding the health risks of aerosol particles under different environmental conditions, is of major necessity for improving exposure estimates, to develop efficient control strategies, to reduce human exposure and adverse health risks.…”