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Background: Tumor development and progression is a long and complex process influenced by a combination of intrinsic (eg, gene mutation) and extrinsic (eg, environmental pollution) factors. As a detoxification organ, the liver plays an important role in human exposure and response to various environmental pollutants including nanomaterials (NMs). Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and remains a serious threat to human health. Whether NMs promote liver cancer progression remains elusive and assessing long-term exposure to subtoxic doses of nanoparticles (NPs) remains a challenge. In this study, we focused on the promotional effects of nano zinc oxide (nZnO) on the malignant progression of human HCC cells HepG2, especially aged nZnO that has undergone physicochemical transformation., Methods: In in vitro experiments, we performed colony forming efficiency, soft agar colony formation, and cell migration/invasion assays on HepG2 cells that had been exposed to a low dose of nZnO (1.5 μg/mL) for 3 or 4 months. In in vivo experiments, we subcutaneously inoculated HepG2 cells that had undergone long-term exposure to nZnO for 4 months into BALB/c athymic nude mice and observed tumor formation. ZnCl 2 was administered to determine the role of zinc ions., Results: Chronic low-dose exposure to nZnO significantly intensified the malignant progression of HCC cells, whereas aged nZnO may exacerbate the severity of malignant progression. Furthermore, through transcriptome sequencing analysis and in vitro cellular rescue experiments, we demonstrated that the mechanism of nZnO-induced malignant progression of HCC could be linked to the activation of Claudin-2 (CLDN2), one of the components of cellular tight junctions, and the dysregulation of its downstream signaling pathways., Conclusion: Long-term exposure of fresh and aged nZnO promotes hepatocellular carcinoma malignancy by up-regulating CLDN2. The implications of this work can be profound for cancer patients, as the use of various nanoproducts and unintentional exposure to environmentally transformed NMs may unknowingly hasten the progression of their cancers., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Yu et al.)

Zinc oxide nanoparticles (ZnO NPs) are commonly used in industrial and household applications, prompting the assessment of their associated health risks. Previous studies indicated that ZnO NPs can induce somatic cell mutations, while the aging process appears to increase the mutagenicity of ZnO NPs. However, little is known about the influence of ZnO NPs on genome stability of germ cells, and non-exposed progeny. Here we show that 20 nm ZnO NPs exposure disrupts germ cell development, and elevates the overall mutation frequency of germ cells in Caenorhabditis elegans (C. elegans). We observed that pristine ZnO NPs elicit germ cell apoptosis to a greater extent than the 60-day aged ZnO NPs. By treating parental worms with ZnO NPs for seven successive generations, whole-genome sequencing data revealed that, although the frequency of point mutations is kept unchanged, large deletions are significantly increased in F8 worms. Furthermore, we found that the mutagenicity of ZnO NPs might be partially attributed to the release of Zn 2+ ions. Together, our results demonstrate the genotoxic effects of ZnO NPs on germ cells, and the possible underlying mechanism. These findings suggest that germ cell mutagenicity is worthy of consideration for the health risk assessment of engineered NPs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Zinc oxide nanoparticles (ZnO NPs) are used in a wide range of applications including industry, commercial products and medicine field. Numerous mechanistic studies for ZnO NPs' toxicity were performed on pristine (fresh) NPs. However, the cytotoxicity induced by the transformed (aged) ZnO NPs and the underlying mechanisms remain unclear. Here, we observed the physicochemical transformation of ZnO NPs underwent over time, followed by evaluating the cytotoxicity of fresh and aged NPs. We found that fresh ZnO NPs induced higher apoptosis level than their aged counterparts. Accordingly, RNA sequencing data from aged ZnO NP-treated human–hamster hybrid (AL) cells showed that p53, PI3k–Akt, FoXO, Glutathione, ErbB, HIF-1, Oxytocin and Jak-STAT signaling pathways were enriched but no apoptosis pathway. Quantitative PCR results revealed the significantly higher mRNA level of IL1B and CD69 in fresh NP-treated groups compared to that of aged ZnO NP- and zinc chloride-treated groups. The above results indicated that the lower cytotoxicity of aged ZnO NPs is partially attributed to their reduced potency in inducing apoptosis. The transcriptional regulation of multiple signal pathways activated by aged NPs may help to build the cellular homeostasis. Taken together, our findings highlight the influence of aging (environmental transformation) process of ZnO NPs on their toxicities and biological consequences. [ABSTRACT FROM AUTHOR]