Abstract
Fine particulate matter (PM2.5) has been shown to induce DNA damage. Circular RNAs (circRNAs) have been implicated in various disease processes related to environmental chemical exposure. However, the role of circRNAs in the regulation of DNA damage response (DDR) after PM2.5 exposure remains unclear. In this study, male ICR mice were exposed to PM2.5 at a daily mean concentration of 382.18 μg/m3 for 3 months in an enriched-ambient PM2.5 exposure system in Shijiazhuang, China, and PM2.5 collected form Shijiazhuang was applied to RAW264.7 cells at 100 µg/mL for 48 h. The results indicated that exposure to PM2.5 induced histopathological changes and DNA damage in the lung, kidney and spleen of male ICR mice, and led to decreased cell viability, increased LDH activity and DNA damage in RAW264.7 cells. Furthermore, circ_Cabin1 expression was significantly upregulated in multiple mouse organs as well as in RAW264.7 cells upon exposure to PM2.5. PM2.5 exposure also resulted in impairment of non-homologous end joining (NHEJ) repair via the downregulation of Lig4 or Dclre1c expression in vivo and in vitro. Importantly, circ_Cabin1 promoted PM2.5-induced DNA damage via inhibiting of NHEJ repair. Moreover, the expression of circ_Cabin1 and Lig4 or Dclre1c was strongly correlated in multiple mouse organs, as well as in the blood. In summary, our study provides a new perspective on circRNAs in the regulation of DDR after environmental chemical exposure.
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This study was supported by the National Natural Science Foundation of China (81872652, 91643204 to JY), and Guangdong Natural Science Foundation (2018B030311019 to JY).
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YGJ, HXZ and QHH designed the research. HXZ, QHH, MZL, YFL, YHL and QQD performed the experiments. HXZ, MZL, YTS, XL and RZ constructed the animal model. HXZ, MZL, YTS, HZ, MYQ and JLZ collected PM2.5. HXZ analyzed the data and wrote the manuscript. YGJ planned, projected, supervised, and coordinated the overall research work.
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Zeng, H., Li, M., Hua, Q. et al. Circular RNA circ_Cabin1 promotes DNA damage in multiple mouse organs via inhibition of non-homologous end-joining repair upon PM2.5 exposure. Arch Toxicol 95, 3235–3251 (2021). https://doi.org/10.1007/s00204-021-03138-5
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DOI: https://doi.org/10.1007/s00204-021-03138-5