Integrative functional transcriptomic analyses implicate specific molecular pathways in pulmonary toxicity from exposure to aluminum oxide nanoparticles

Abstract

Gene expression profiling has developed rapidly in recent years and it can predict and define mechanisms underlying chemical toxicity. Here, RNA microarray and computational technology were used to show that aluminum oxide nanoparticles (Al₂O₃ NPs) were capable of triggering up-regulation of genes related to the cell cycle and cell death in a human A549 lung adenocarcinoma cell line. Gene expression levels were validated in Al₂O₃ NPs exposed A549 cells and mice lung tissues, most of which showed consistent trends in regulation. Gene-transcription factor network analysis coupled with cell- and animal-based assays demonstrated that the genes encoding PTPN6, RTN4, BAX and IER play a role in the biological responses induced by the nanoparticle exposure, which caused cell death and cell cycle arrest in the G2/S phase. Further, down-regulated PTPN6 expression demonstrated a core role in the network, thus expression level of PTPN6 was rescued by plasmid transfection, which showed ameliorative effects of A549 cells against cell death and cell cycle arrest. These results demonstrate the feasibility of using gene expression profiling to predict cellular responses induced by nanomaterials, which could be used to develop a comprehensive knowledge of nanotoxicity.

Keywords:

• Aluminum oxide nanoparticle
• cell cycle
• cell death
• microarray
• nanotoxicology

Acknowledgements

We thank Nanjing Milestone Biotechnology Co. LTD for the analysis of mRNA microarray profile.

Declaration of interest

The authors declare no conflicts of interests.

This work was financially supported by National Natural Science Foundation of China (Grant No. 81472938), the Fund of the Distinguished Talents of Jiangsu Province (BK20150021), the Natural Science Foundation of Jiangsu Province (BK20151418), the fund of the Distinguished Professor of Jiangsu Province, the Open Research Fund of State Key Laboratory of Bioelectronics, Southeast University and the Fundamental Research Funds for the Central Universities.

Supplementary material available online

Supplementary Figure S1–S5 and Table S1–S9