Quantified Chronic High-Radon Exposure is Associated with Compartment-Specific Alteration of Peripheral Blood hsa_circ_0040573: A Cross-Sectional Study

Chronic exposure to geogenic radon, an important naturally occurring element, is a public health concern, yet our knowledge regarding alterations of human circular RNA (circRNA) remains limited. We conducted a cross-sectional study of 94 residents (exposed group, n = 46, with regular bathing in a high-radon hot spring environment; control group, n = 48, without hot-spring-related high-radon exposure) to evaluate associations between quantified chronic radon exposure and peripheral blood hsa_circ_0040573 expression. We measured radon concentrations in the bathing microenvironments using solid-state nuclear track detectors (CR-39) and estimated individual cumulative effective doses from measured concentrations and bathing patterns. Hsa_circ_0040573 expression was quantified in plasma and the peripheral blood cellular fraction. We used multivariable linear regression to assess exposure-response associations. Bioinformatics analysis and targeted quantitative reverse transcription PCR (qRT-PCR) were used to explore a putative hsa_circ_0040573-centered ceRNA axis. The mean radon concentration in the primary bathing areas was 2.28 × 10 4 Bq/m 3 , corresponding to an estimated individual cumulative dose of 70.22 mSv (IQR: 29.17–109.71 mSv) among exposed participants. Compared with controls, hsa_circ_0040573 expression was higher in plasma but lower in the peripheral blood cellular fraction in the exposed group. After multivariable adjustment, cumulative radon dose was inversely associated with hsa_circ_0040573 expression in the peripheral blood cellular fraction (standardized β = –0.304, 95% CI: –0.537 to –0.072). Bioinformatics analysis prioritized hsa-miR-338-3p within a hsa_circ_0040573-centered competing endogenous RNA (ceRNA network), with enrichment in vascular endothelial growth factor receptor signaling. Targeted validation in the peripheral blood cellular fraction showed decreased ATP1A2 and increased hsa-miR-338-3p among exposed participants. These findings indicate that quantified chronic high-radon exposure is associated with compartment-specific alteration of peripheral blood circRNA signals and provide human molecular evidence for a radon-related response, with preliminary support for a candidate hsa_circ_0040573/hsa-miR-338-3p/ATP1A2 regulatory axis.