Low-Dose Exposure to Ionizing Radiation Deregulates the Brain-Specific MicroRNA-134 in Interventional Cardiologists
Editorial, see p 2417
In recent years, there has been growing concern about the health risks for contemporary interventional cardiologists who have high and unprecedented levels of occupational ionizing radiation exposure.1
MicroRNAs (miRNAs), a class of short and highly conserved noncoding RNA molecules (≈22 nucleotides), have been shown to become dysregulated in many human diseases.2 The stability and tissue specificity of circulating miRNAs make them ideal biomarkers to explore the molecular mechanisms underlying the association between chronic low-dose radiation exposure and potential disease risk. The purpose of this study was to apply a miRNome-wide microarray to characterize the plasma miRNA profiles in interventional cardiologists professionally exposed to ionizing radiation.
The study consisted of 3 stages: discovery, selection, and validation. In the discovery stage, a microarray analysis (Agilent Human miRNA Microarray 8×60K Release 19.0 platform containing 2006 human miRNA probes) was performed on plasma from 10 interventional cardiologists (6 men; age, 54±5.4 years) and 10 age- and sex-matched unexposed control subjects (6 men; age, 53.2±5.5 years).
In the selection stage, all dysregulated miRNAs were evaluated in another 80 plasma samples (40 from interventional cardiologists and 40 from unexposed subjects) by quantitative real-time polymerase chain reaction.
In the validation stage, the confirmed differentially expressed miRNAs were further investigated in an expanded cohort of 132 interventional cardiologists (102 men; age, 46.3±9 years) and 83 unexposed control subjects (51 men; age, 47.9±8 years). Interventional cardiologists were considered eligible for inclusion in the study if they had been employed for >1 year in the catheterization laboratory. For comparison, unexposed subjects (clinical cardiologists and other professional researchers) were randomly selected and had never experienced occupational exposure to ionizing radiation. Exposed cardiologists and control subjects were similar in terms of age, smoking habits, educational level, and health status. The prevalence of male subjects was significantly higher in the exposed than in the unexposed group (P=0.01). Subjects with a history of cancer or cardiovascular disease were excluded from the study. Forty-one interventional cardiologists had a complete lifetime dosimetric reconstruction (median exposure, 16 years; interquartile range, 9–22 years) with a median individual effective dose of 19 mSv (interquartile range, 11–43 mSv).
Each participant gave written informed consent to enter the study, and the study was approved by the institutional Ethical Research Committee.
Microarray analysis revealed 4 differentially expressed miRNAs (miR-134, miR-575, miR-127, and miR-2392) between interventional cardiologists and unexposed control subjects (all downregulated with a fold change>2 and false discovery rate–adjusted P<0.001).
In the selection stage, brain-specific miR-134 (P=0.002) and miR-2392 (P=0.003) were reproducibly found to be significantly downregulated.
Significant downregulation of brain-specific miR-134 and miR-2392 expression profiles (both P<0.0001) was validated in the expanded validation cohort (Figure). We did not detect significant correlations between the levels of the selected 2 miRNAs and demographic and life habits characteristics. In a multiple regression model, only radiation exposure emerged as a significant predictor of both circulating miR-134 (β=−0.246; P<0.0001) and miR-2392 (β=−0.233; P=0.0003) levels after adjustment for age, sex, smoking, and body mass index. When interventional cardiologists were divided into low (n=20) or high (n=21) exposure on the median of recorded cumulative effective dose (≥19 mSv), brain-specific miR-134 circulating levels were also significantly downregulated in high-exposure interventional cardiologists (P=0.004; Figure).
Bioinformatic analysis (Kyoto Encyclopedia of Genes and Genomes pathway analysis) revealed 4 significantly enriched pathways (false discovery rate–adjusted P≤0.05) targeted by the coexpression of miR-134 and miR-2392, including 3 significant brain pathways (GABAergic synapse, morphine addiction, and glutamatergic synapse) and 1 cancer pathway (proteoglycans in cancer). GABAergic synapse, the most abundant inhibitory neurotransmitter in the mammalian central nervous system, was the most significantly enriched pathway (false discovery rate–adjusted P=0.01).
This study revealed that circulating brain miR-134 and miR-2392 expression profiles were significantly downregulated in interventional cardiologists compared with controls.
Although the exact function of miR-2392 is currently unknown, a recent study showed that miR-2392 was downregulated in gastric cancer cell lines and tissues, and its overexpression inhibited in vitro and in vivo tumor cell invasion and metastasis.3
miR-134 was first identified as a brain-specific miRNA that is involved in synapse development and directly implicated in learning and memory.4 It has been previously dysregulated in mesial temporal lobe epilepsy, Alzheimer disease, bipolar disorder, oligodendrogliomas, and glioblastomas.5
Therefore, the highly dysregulated brain-specific miR-134 strongly suggests that brain damage is one of the main potential long-term risks of unprotected head irradiation in interventional cardiologists, with possible long-lasting consequences on cognitive impairment.
However, our results do not provide direct proof of the involvement of these 2 miRNAs in the potential health effects of long-term low-dose exposure, and they should be interpreted with caution given the exploratory hypothesis-generating nature of this study.
Additional studies are needed to validate these findings and to further explore the existing potential of circulating miRNAs to be used clinically as novel biomarkers for identifying early, disease-related perturbations caused by long-term radiation exposure in interventional cardiologists.
Andrea Borghini, MSc, PhD
Cecilia Vecoli, MSc, PhD
Antonella Mercuri, MSc
Clara Carpeggiani, MD
Emanuela Piccaluga, MD
Giulio Guagliumi, MD
Eugenio Picano, MD, PhD
Maria Grazia Andreassi, MSc, PhD
The authors thank the Italian Association of Invasive Cardiology for long-term support for the Healthy Cath Laboratory project. They also thank all the cardiologists and control subjects who participated in this study.
Sources of Funding
This research was partially funded by National Research Council grant Progetto di Interesse “Invecchiamento.”
The podcast and transcript are available as an online-only Data Supplement at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.117.031251/-/DC1.
The data sets generated and analyzed during the present study are not publicly available but are available from the corresponding author on reasonable request.
Circulation is available at http://circ.ahajournals.org.
- © 2017 American Heart Association, Inc.
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