Kovvuru Prasad, Mancilla Patrick E, Shirode Amit B, Murray Thomas M, Begley Thomas J, Reliene Ramune
Department of Environmental Health Sciences, University at Albany, State University of New York , Albany, NY , USA .
Nanotoxicology. 2015 Mar;9(2):162-71. doi: 10.3109/17435390.2014.902520. Epub 2014 Apr 9.
Silver nanoparticles (AgNPs) are widely used in consumer and medical products. However, most AgNP toxicity data are based on in vitro studies. Only a few studies were performed in mammals and no studies systematically assessed cancer risk of AgNPs. In this study, we examined whether oral exposure to polyvinylpyrrolidone (PVP)-coated AgNPs induces DNA damage and permanent genome alterations, and modulates DNA repair gene expression in vivo in mice. We found that AgNPs induced large DNA deletions in developing embryos, irreversible chromosomal damage in bone marrow, and double strand breaks and oxidative DNA damage in peripheral blood and/or bone marrow. DNA Repair RT Profiler PCR Array showed that AgNPs altered expression of 36 of the 84 genes from which 24 genes were downregulated and 12 genes were upregulated. In particular, AgNPs downregulated a significant proportion of base excision repair (BER) genes. We hypothesized that downregulation of BER by AgNPs contributes to oxidative DNA damage and subsequent genomic instability, which predicts that BER defects enhance sensitivity to AgNPs. We tested this hypothesis in mice deficient in MutY homologue (Myh). Myh excises adenine mispaired with 8-oxoguanine to counteract its promutagenic activity and also has a role in cell cycle check points and apoptosis. MYH mutations are common in humans and predispose to colorectal and other types of cancer. Myh deficient mice were hypersensitive to AgNP-induced chromosomal damage. In summary, oral ingestion of AgNPs induces permanent genome alterations and may therefore cause cancer. In addition, BER defects, especially, Myh mutations, enhance sensitivity to AgNPs.
银纳米颗粒（AgNPs）广泛应用于消费品和医疗产品中。然而，大多数AgNP毒性数据基于体外研究。仅有少数研究在哺乳动物中进行，且尚无研究系统评估AgNPs的癌症风险。在本研究中，我们检测了经口暴露于聚乙烯吡咯烷酮（PVP）包覆的AgNPs是否会在小鼠体内诱导DNA损伤和永久性基因组改变，并调节DNA修复基因表达。我们发现，AgNPs在发育中的胚胎中诱导了大片段DNA缺失，在骨髓中导致了不可逆的染色体损伤，在外周血和/或骨髓中造成了双链断裂和氧化性DNA损伤。DNA修复RT Profiler PCR阵列显示，AgNPs改变了84个基因中的36个基因的表达，其中24个基因下调，12个基因上调。特别是，AgNPs下调了相当一部分碱基切除修复（BER）基因。我们推测，AgNPs对BER的下调导致了氧化性DNA损伤及随后的基因组不稳定，这预示着BER缺陷会增强对AgNPs的敏感性。我们在MutY同源物（Myh）缺陷的小鼠中验证了这一假设。Myh可切除与8-氧鸟嘌呤错配的腺嘌呤以抵消其促诱变活性，并且在细胞周期检查点和细胞凋亡中也起作用。MYH突变在人类中很常见，易患结直肠癌和其他类型的癌症。Myh缺陷小鼠对AgNP诱导的染色体损伤高度敏感。总之，经口摄入AgNPs会诱导永久性基因组改变，因此可能致癌。此外，BER缺陷，尤其是Myh突变，会增强对AgNPs的敏感性。
