Circular RNA circ_Cabin1 promotes DNA damage in multiple mouse organs via inhibition of non-homologous end-joining repair upon PM 2.5 exposure

Fine particulate matter (PM 2.5 ) 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 PM 2.5 exposure remains unclear. In this study, male ICR mice were exposed to PM 2.5 at a daily mean concentration of 382.18 μg/m 3 for 3 months in an enriched-ambient PM 2.5 exposure system in Shijiazhuang, China, and PM 2.5 collected form Shijiazhuang was applied to RAW264.7 cells at 100 µg/mL for 48 h. The results indicated that exposure to PM 2.5 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 PM 2.5 . PM 2.5 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 PM 2.5 -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.