Evaluation of natural chronic low dose radiation exposure on telomere length and transcriptional response of shelterin complex in individuals residing in Kerala coast, India

IF 1.5 4区医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis Pub Date : 2022-07-01 DOI:10.1016/j.mrfmmm.2022.111797

Divyalakshmi Saini , Vinay Jain , Birajalaxmi Das

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引用次数: 2

Abstract

The high level natural radiation areas (HLNRA) of Kerala coast provide unique opportunity to study the biological effect of chronic low dose ionizing radiation (LDIR) on human population below 100 mSv. The radiation level in this area varies from < 1.0–45 mGy /year due to patchy distribution of monazite in the sand, which contains ²³²Th (8–10%), ²³⁸U (0.3%), and their decay products. Telomere length attrition has been correlated to DNA damage due to genotoxic agents. The objective of the present study is to evaluate the effect of natural chronic LDIR exposure on telomere length and transcriptional response of telomere specific and DNA damage repair genes in peripheral blood mononuclear cells (PBMCs) of individuals from normal level natural radiation areas (NLNRA) and HLNRA of Kerala coast, southwest India. Blood samples were collected from 71 random male donors (24–80 years) from NLNRA (≤1.50 mGy/year; N = 19) and two HLNRA dose groups [1.51–10 mGy/year (N = 17); > 10 mGy/year, (N = 35)]. Genomic DNA was isolated from PBMCs and relative telomere length (RTL) was determined using real time q-PCR. Radio-adaptive response (RAR) study was carried out in PBMCs of 40 random males from NLNRA (N = 20) and HLNRA (>10 mGy/year; N = 20), where PBMCs were given a challenged dose of 2.0 Gy gamma radiation at 4 h. Transcriptional profile of telomere specific (TRF1, TRF2, POT1, TIN2, TPP1, RAP1), DNA damage response (RAD17, ATM, CHEK1) and base excision repair pathway (BER) (OGG1, XRCC1, NTH1, NEIL1, MUTYH, MBD4) genes were analysed at basal level and after a challenge dose of 2.0 Gy at 4 h. Our results did not show any significant effect of chronic LDR on RTL among the individuals from NLNRA and two HLNRA groups (p = 0.195). However, influence of age on RTL was clearly evident among NLNRA and HLNRA individuals. At basal level, TRF1, TRF2, TIN2, MBD4, NEIL1 and RAD17 showed significant up-regulation, whereas XRCC1 was significantly down regulated in HLNRA individuals. After a challenge dose of 2.0 Gy, significant transcriptional up-regulation was observed at telomere specific (TRF2, POT1) and BER (MBD4, NEIL1) genes in HLNRA individuals as compared to NLNRA suggesting their role in RAR. In conclusion, elevated level of natural chronic LDR exposure did not have any adverse effect on telomere length in Kerala coast. Significant transcriptional response at TRF2, MBD4 and NEIL1 at basal level and with a challenge dose of 2.0 Gy suggested their active involvement in efficient repair and telomere maintenance in individuals from HLNRA of Kerala coast.

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天然慢性低剂量辐射照射对印度喀拉拉邦海岸居民端粒长度和庇护复合体转录反应的影响

喀拉拉邦海岸高水平自然辐射区为研究100毫西弗以下慢性低剂量电离辐射(LDIR)对人群的生物学效应提供了独特的机会。这个地区的辐射水平从<1 - 45 mGy /年，主要是由于单独居石在沙中呈斑片状分布，其中含有232Th(8-10%)、238U(0.3%)及其衰变产物。端粒长度磨损与基因毒性物质引起的DNA损伤有关。本研究的目的是评估自然慢性LDIR暴露对印度西南部喀拉拉邦海岸正常水平自然辐射区(NLNRA)和HLNRA个体外周血单个核细胞(PBMCs)端粒长度和端粒特异性转录反应和DNA损伤修复基因的影响。从NLNRA随机采集71例男性献血者(24-80岁)的血液样本(≤1.50 mGy/年;N = 19)和2个HLNRA剂量组[1.51 ~ 10 mGy/年](N = 17);比;10 mGy/年，(N = 35)]。从pbmc中分离基因组DNA，用实时q-PCR测定相对端粒长度(RTL)。对来自NLNRA (N = 20)和HLNRA (>10 mGy/年;N = 20)，其中PBMCs在4 h时给予2.0 Gy γ辐射的挑战剂量。端粒特异性(TRF1, TRF2, POT1, TIN2, TPP1, RAP1)， DNA损伤反应(RAD17, ATM, CHEK1)和碱基切除修复途径(BER) (OGG1, XRCC1, NTH1, NEIL1, MUTYH，在基础水平和2.0 Gy攻毒4 h后分析MBD4)基因。我们的结果没有显示NLNRA和两个HLNRA组个体的慢性LDR对RTL有任何显著影响(p = 0.195)。然而，年龄对RTL的影响在NLNRA和HLNRA个体中是明显的。在基础水平上，TRF1、TRF2、TIN2、MBD4、NEIL1和RAD17显著上调，而XRCC1在HLNRA个体中显著下调。在2.0 Gy攻毒剂量后，与NLNRA相比，HLNRA个体的端粒特异性基因(TRF2, POT1)和BER (MBD4, NEIL1)的转录显著上调，提示它们在RAR中的作用。综上所述，自然慢性LDR暴露水平升高对喀拉拉邦沿海地区的端粒长度没有任何不利影响。TRF2、MBD4和NEIL1在基础水平和2.0 Gy攻击剂量下的显著转录应答表明，它们积极参与喀拉拉邦沿海HLNRA个体的有效修复和端粒维持。

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来源期刊

Mutation Research-Fundamental and Molecular Mechanisms of Mutagenesis 生物-毒理学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

51 days

期刊介绍： Mutation Research (MR) provides a platform for publishing all aspects of DNA mutations and epimutations, from basic evolutionary aspects to translational applications in genetic and epigenetic diagnostics and therapy. Mutations are defined as all possible alterations in DNA sequence and sequence organization, from point mutations to genome structural variation, chromosomal aberrations and aneuploidy. Epimutations are defined as alterations in the epigenome, i.e., changes in DNA methylation, histone modification and small regulatory RNAs. MR publishes articles in the following areas: Of special interest are basic mechanisms through which DNA damage and mutations impact development and differentiation, stem cell biology and cell fate in general, including various forms of cell death and cellular senescence. The study of genome instability in human molecular epidemiology and in relation to complex phenotypes, such as human disease, is considered a growing area of importance. Mechanisms of (epi)mutation induction, for example, during DNA repair, replication or recombination; novel methods of (epi)mutation detection, with a focus on ultra-high-throughput sequencing. Landscape of somatic mutations and epimutations in cancer and aging. Role of de novo mutations in human disease and aging; mutations in population genomics. Interactions between mutations and epimutations. The role of epimutations in chromatin structure and function. Mitochondrial DNA mutations and their consequences in terms of human disease and aging. Novel ways to generate mutations and epimutations in cell lines and animal models.