Endoplasmic reticulum stress and oxidative stress are involved in ZnO nanoparticle-induced hepatotoxicity

Abstract

Zinc oxide nanoparticles (Nano-ZnO) are widely used in sunscreens, clothes, medicine and electronic devices. However, the potential risks of human exposure and the potential for adverse health impacts are not well understood. Previous studies have demonstrated that exposure to Nano-ZnO caused liver damage and hepatocyte apoptosis through oxidative stress, but the molecular mechanisms that are involved in Nano-ZnO-induced hepatotoxicity are still unclear. Endoplasmic reticulum (ER) is sensitive to oxidative stress, and also plays a crucial role in oxidative stress-induced damage. Previous studies showed that ER stress was involved in many chemical-induced liver injuries. We hypothesized that exposure to Nano-ZnO caused oxidative stress and ER stress that were involved in Nano-ZnO-induced liver injury. To test our hypothesis, mice were gavaged with 200 mg/kg or 400 mg/kg of Nano-ZnO once a day for a period of 90 days, and blood and liver tissues were obtained for study. Our results showed that exposure to Nano-ZnO caused liver injury that was reflected by focal hepatocellular necrosis, congestive dilation of central veins, and significantly increased alanine transaminase (ALT) and aspartate transaminase (AST) levels. Exposure to Nano-ZnO also caused depletion of glutathione (GSH) the liver tissues. In addition, our electron microscope results showed that ER swelling and ribosomal degranulation were observed in the liver tissues from mice treated with Nano-ZnO. The mRNA expression levels of ER stress-associated genes (grp78, grp94, pdi-3, xbp-1) were also up-regulated in Nano-ZnO-treated mice. Nano-ZnO caused increased phosphorylation of RNA-dependent protein kinase-like ER kinase (PERK) and eukaryotic initiation factor 2α (eIF2α). Finally, we found that exposure to Nano-ZnO caused increased ER stress-associated apoptotic protein levels, such as caspase-3, caspase-9, caspase-12, phosphorylation of JNK, and CHOP/GADD153, and up-regulation of pro-apoptotic genes (chop and bax). These results suggest that oxidative stress and ER stress-induced apoptosis are involved in Nano-ZnO-induced hepatotoxicity in mice.

Zinc Oxide Nanoparticles: The Hidden Danger

“…The effect of ZnO-NPs on serum ALT, AST, albumin, total protein and liver MDA indicated that the liver is one of the target organs of such NPs toxicity. Similar effects of ZnO-NPs on serum ALT, AST, and MDA levels were reported [4,34,50,58]. Also, the significant decrease of the total serum proteins and albumin caused by ZnO-NPs agreed with Wang et al (2010) [57] and Al-Rasheed et al (2012) [2].…”

“…Similar effects on the serum albumin and total protein levels were demonstrated by Wang et al (2010) [57] and AlRasheed et al (2012) [2]. Also similar effects on serum ALT and AST were reported [2,57,58,62]. Furthermore, serum total proteins and albumin levels in spite of elevation were still significantly lower than those of the control group and vitamin E control group, while serum ALT and AST levels reached non-significant levels compared to the control group and vitamin E control group.…”

“…This results in cytotoxicity, oxidative stress, and mitochondrial dysfunction [7,9,11,53,56]. Mansouri et al (2015) [34] and Yang et al (2015) [33], reported higher Zn concentration in the liver tissues of rodents orally administered ZnO-NPs and showed elevated serum AST and ALT. In addition, it was reported that liver damage could be induced by excess oral Zn salt [10] and oral nanoscale zinc powder [55].…”

Engineered nanoparticles induce cell apoptosis: potential for cancer therapy

“…Zinc oxide nanoparticles (Nano-ZnO), which are widely used in daily commodities, have been reported to induce hepatotoxicity through ER stress. ER swelling and ribosomal degranulation were also observed by TEM in the liver tissues treated with Nano-ZnO [26]. Obvious ER aggregation and the associated swelling were also observed in nano-ZnO treatment of human umbilical vein endothelial cells (HUVECs) [27].…”

α-Lipoic acid protects HAECs from high glucose-induced apoptosis via decreased oxidative stress, ER stress and mitochondrial injury

“…Oxidative stress, the inhibition of protein glycosylation, a reduction in disulde bond formation, calcium depletion and accumulation of unfolded proteins in the ER lumen may disrupt the ER function, and trigger the unfolded protein response (UPR), also known as "ER-stress". 46 Recently, ROS have emerged as important regulators of ER function and UPR activation in several diseased conditions. 47 GRP78 protein was widely known as an ER stress marker.…”