Comparative proteomic analysis of human peripheral blood mononuclear cells indicates adaptive response to low-dose radiation in individuals from high background radiation areas of Kerala.

Abstract

There remain significant uncertainties in estimation of risks with low doses of radiation. The small coastal belt in the southwestern state of Kerala, India, extending from Neendakara in the south to Purakkad in the north is one of the most extensively studied high-level natural background radiation areas (HLNRAs) of the world to address these concerns. The natural radioactivity here is due to occurrence of monazite sand bearing placer deposits along the coastline. In this study, proteomic approach was employed to study the response of human peripheral blood mononuclear cells (PBMCs) from individuals residing in HLNRA (N = 10; mean radiation dose: 15.60 ± 3.04 mGy/y) vis-à-vis responses in individuals from adjoining normal-level natural background radiation areas (NLNRA; N = 10; mean radiation dose: ≤1.50 mGy/y) using two-dimensional gel electrophoresis coupled with mass spectrometry. A total of 15 proteins were found to be statistically altered in individuals from HLNRA when compared to individuals from NLNRA (P ≤ 0.05). Most of the changes in expression were small. The mean coefficient of variation for the differentially altered proteins was found to be ~34%. Pathway enrichment analysis with Database for Annotation, Visualization and Integrated Discovery distinguished 44 biological processes significantly (P ≤ 0.05) modulated in HLNRA samples. More importantly, when challenged with an ex vivo dose of 2 Gy, HLNRA PBMCs responded with an up-regulation of many protective pro-survival proteins such as protein disulfide-isomerase A1 (PDIA1), peroxiredoxin 6 (PRDX6) and glucose-regulated protein 78 kDa (GRP78). PDIA1 and PRDX6 are known to play an important role in redox homeostasis. GRP78 is considered the master regulator of unfolded protein response that aims to restore endoplasmic reticulum homeostasis and thus, regulate cell survival. Principal component analysis identified clear clusters based on radiation dose. The expression changes of key proteins were validated by western blotting using additional samples from HLNRA and NLNRA. This indicates that the human cells respond to low dose of ionising radiation through dynamic changes in the proteome to maintain adaptive homeostasis. These findings emphasise that the dose-response relationship at low doses of radiation may not be linear and, thus, provide mechanistic challenge to the linear-no-threshold hypothesis.