Molecular analysis of somatic mutations at the HPRT locus in lymphocytes of human population exposed to chronic high background natural radiation

Populations residing in high-level natural radiation areas (HLNRA) along the monazite-rich coastal belt of Kerala, India, are chronically exposed to low-dose ionizing radiation, with lifetime cumulative doses exceeding 1000 mGy. Although the biological effects of acute high-dose exposures are well established, the long-term health consequences of chronic low-dose or low-dose-rate ionizing radiation (LDIR) remain poorly understood. To address this knowledge gap, we examined the frequency and molecular spectrum of somatic mutations at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus-a sensitive biomarker of mutagenesis-in peripheral blood lymphocytes from 37 healthy adults residing in normal-level (NLNRA, N = 12) and high-level (HLNRA, N = 25) natural radiation areas. Using a T-lymphocyte cloning assay, PCR-based molecular profiling, and sequence-tagged site (STS) analysis, we found no significant difference in HPRT mutant frequency (p = 0.43), mutation spectrum (p = 0.52), or deletion subtype distribution (p = 0.69) between HLNRA and NLNRA groups. The extent of genomic deletions, spanning 0.09-1.19 Mb, was also comparable between HLNRA and NLNRA populations. However, gene expression profiling revealed significant alterations in DNA repair genes, including KU80, DDB2, MSH6, PCNA, and RAD50, suggesting that HPRT mutation may influence DNA damage response pathways. Our findings indicate that chronic exposure to natural background radiation does not elevate somatic mutation frequency or induce large-scale genomic alterations but may modulate DNA damage response and repair gene regulation. This study provides critical human data for refining low-dose radiation risk models and understanding mechanisms of genome stability and adaptation in chronically exposed populations.