Dose-response modeling reveals multifaceted molecular responses to low-dose radiation in human white blood cells

The current radiation protection framework extrapolates health risks from high-dose exposures based on a linear, no-threshold model. However, empirical data on molecular effects below 0.1 Gy are lacking, creating uncertainties in risk assessments. To address this, we used benchmark dose (BMD) modeling, commonly applied in chemical hazard assessment, to analyze gene and protein expression changes in human white blood cells, providing insights into dose-response relationships following low-dose radiation (LDR) exposure.

Blood samples were collected from 14 participants (6 females, 8 males). Lymphocytes were isolated, cultured, and exposed to X-irradiation at nine doses (0-6 Gy) at 0.05 Gy/min. Transcriptomic and proteomic changes were assessed 24 h post-exposure. BMD modeling was applied to each endpoint, and the data were grouped into distinct dose-response patterns. Pathway analysis identified cellular functions associated with these patterns, offering insight into the biological effects of LDR.

BMD modeling identified 1,204 genes and 168 proteins with dose-response relationships, with median BMD lower confidence limits (BMDLs) of 1.38 Gy and 0.21 Gy, respectively. Transcriptional and proteomic responses exhibited complex patterns, including exponential, biphasic, and hypersensitivity responses, with peak activity between 0.05-0.25 Gy, followed by a decline or plateau. Pathway analysis revealed changes in genes and proteins related to DNA damage, cell cycle, cellular stress, metabolism, immune function, and cancer, with DNA damage response genes showing BMDLs below 0.1 Gy.

This study shows that molecular dose-response relationships can be complex and non-linear, emphasizing the need for further research to better understand the effects of LDR.