Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Innovation Center in Zhejiang University, State Key Laboratory of Component-Based Chinese Medicine, Hangzhou 310058, China.
ACS Nano. 2021 May 25;15(5):8225-8243. doi: 10.1021/acsnano.0c07323. Epub 2021 May 3.
The intensive application of nanomaterials in the food industry has raised concerns about their potential risks to human health. However, limited data are available on the biological safety of nanomaterials in food, especially at the epigenetic level. This study examined the implications of two types of synthetic amorphous silica (SAS), food-grade precipitated silica (S200) and fumed silica Aerosil 200F (A200F), which are nanorange food additives. After 28-day continuous and intermittent subacute exposure to these SAS via diet, whole-genome methylation levels in mouse peripheral leukocytes and liver were significantly altered in a dose- and SAS type-dependent manner, with minimal toxicity detected by conventional toxicological assessments, especially at a human-relevant dose (HRD). The 84-day continuous subchronic exposure to all doses of S200 and A200F induced liver steatosis where S200 accumulated in the liver even at HRD. Genome-wide DNA methylation sequencing revealed that the differentially methylated regions induced by both SAS were mainly located in the intron, intergenic, and promoter regions after 84-day high-dose continuous exposure. Bioinformatics analysis of differentially methylated genes indicated that exposure to S200 or A200F may lead to lipid metabolism disorders and cancer development. Pathway validation experiments indicated both SAS types as potentially carcinogenic. While S200 inhibited the p53-mediated apoptotic pathway in mouse liver, A200F activated the HRAS-mediated MAPK signaling pathway, which is a key driver of hepatocarcinogenesis. Thus, caution must be paid to the risk of long-term exposure to food-grade SAS, and epigenetic parameters should be included as end points during the risk assessment of food-grade nanomaterials.
纳米材料在食品工业中的广泛应用引起了人们对其潜在健康风险的关注。然而，关于食品纳米材料的生物安全性，特别是在表观遗传水平上的数据有限。本研究检测了两种合成无定形二氧化硅（SAS），即食品级沉淀二氧化硅（S200）和气相法二氧化硅 Aerosil 200F（A200F）的生物学效应，这两种物质都是纳米级食品添加剂。通过饮食连续和间歇性亚急性暴露于这两种 SAS28 天后，小鼠外周血白细胞和肝脏的全基因组甲基化水平以剂量和 SAS 类型依赖的方式显著改变，而传统毒理学评估检测到的毒性最小，特别是在人类相关剂量（HRD）下。所有剂量的 S200 和 A200F 连续 84 天亚慢性暴露均导致肝脏脂肪变性，即使在 HRD 下 S200 也在肝脏中积累。全基因组 DNA 甲基化测序显示，两种 SAS 诱导的差异甲基化区域主要位于 84 天高剂量连续暴露后的内含子、基因间区和启动子区域。差异甲基化基因的生物信息学分析表明，暴露于 S200 或 A200F 可能导致脂质代谢紊乱和癌症发展。途径验证实验表明，这两种 SAS 类型均具有潜在致癌性。虽然 S200 抑制了小鼠肝脏中的 p53 介导的凋亡途径，但 A200F 激活了 HRAS 介导的 MAPK 信号通路，这是肝癌发生的关键驱动因素。因此，必须注意长期暴露于食品级 SAS 的风险，并且在食品级纳米材料的风险评估中应将表观遗传参数作为终点。
