Deciphering low-dose radiation-induced cytotoxic effects:The application of integrative transcriptomics and metabolomics analysis in lung organoid-based 3D in vitro model

Abstract

Although the adverse effects induced by acute high-dose radiation from nuclear accidents have been intensively explored, the biological effects of low-dose radiation remain unclear. This study aimed to identify the role of low-dose radiation in three-dimensional (3D) lung organoids using transcriptomic and metabolomic analyses. An irradiation dose of 0 01 Gy was utilized to simulate environmental radiation exposure. Lung organoids were included in the study. Through metabolomic analysis, compared to the control, 290, 284, and 492 metabolites were significantly up-regulated, while 150, 605, and 310 metabolites were significantly down-regulated in the 0.01 Gy, 0.05 Gy, and 2 Gy groups, respectively. However, only the metabolites in the glycerophospholipid metabolism pathway increased significantly in the group treated with 0. 01 Gy radiation, with the lipid substances Carnitine C18:0(Car (18: 0)), palmitoylcarnitine, and PE (18: 3 (9 Z, 12 Z, 15 Z)/P- 16: 0) showing the most significant increase. Significantly, compared to the control, lipid metabolism can be affected by 0.01 Gy radiation. Furthermore, these altered lipid metabolites, such as triglycerides and sterols, were enriched in pathways related to cell signaling and affected cell proliferation, differentiation, and death after bioinformatics analysis. Through transcriptomic analysis, compared with the 0 Gy group, the expression of 19 genes in the 0.01 Gy group was up-regulated, while the expression of 6 genes was down-regulated. The 0.01 Gy irradiation affects the cardiac muscle contraction pathway and glycerolipid metabolism pathway. Moreover, using lung epithelial cells, we further identified that compared with the control group, there was no significant change in cystine uptake capacity, lipid peroxide levels, or mitochondrial membrane potential under irradiation conditions of 0.01 Gy and 0.05 Gy. In summary, our combined transcriptomic and metabolomic analysis of lung organoids provides an effective approach to understanding the biological effects of low-dose radiation exposure.