Chronic Occupational Exposure to Ionizing Radiation Induces Alterations in the Structure and Metabolism of the Heart: A Proteomic Analysis of Human Formalin-Fixed Paraffin-Embedded (FFPE) Cardiac Tissue

Abstract

Epidemiological studies on workers employed at the Mayak plutonium enrichment plant have demonstrated an association between external gamma ray exposure and an elevated risk of ischemic heart disease (IHD). In a previous study using fresh-frozen post mortem samples of the cardiac left ventricle of Mayak workers and non-irradiated controls, we observed radiation-induced alterations in the heart proteome, mainly downregulation of mitochondrial and structural proteins. As the control group available at that time was younger than the irradiated group, we could not exclude age as a confounding factor. To address this issue, we have now expanded our study to investigate additional samples using archival formalin-fixed paraffin-embedded (FFPE) tissue. Importantly, the control group studied here is older than the occupationally exposed (>500 mGy) group. Label-free quantitative proteomics analysis showed that proteins involved in the lipid metabolism, sirtuin signaling, mitochondrial function, cytoskeletal organization, and antioxidant defense were the most affected. A histopathological analysis elucidated large foci of fibrotic tissue, myocardial lipomatosis and lymphocytic infiltrations in the irradiated samples. These data highlight the suitability of FFPE material for proteomics analysis. The study confirms the previous results emphasizing the role of adverse metabolic changes in the radiation-associated IHD. Most importantly, it excludes age at the time of death as a confounding factor.

Data-Independent Acquisition Proteomics Reveals Long-Term Biomarkers in the Serum of C57BL/6J Mice Following Local High-Dose Heart Irradiation

“…Considering causal biological processes in the development of the disease, persistent inflammation and oxidative stress, fibrosis, and pre-mature endothelial senescence are thought to be salient (7)(8)(9). Recently, the role of mitochondrial dysfunction and related metabolic perturbations has become more and more evident (10)(11)(12).…”

“…Proteomics represents a promising global technology to discover new types of biomarkers for radiation-induced cardiac injury (11,24). However, identification and quantification of serum/plasma proteins remains an analytical challenge, mainly due to the dominance of albumins and immunoglobulins and the high dynamic range of protein abundances (25).…”

Expert consultation is vital for adverse outcome pathway development: a case example of cardiovascular effects of ionizing radiation

“…Knowledge gaps in the area of low dose and low dose-rate (<100 mGy, <5 mGy/h) irradiation were highlighted, emphasizing the need for more studies in the context of the cellular communication where the interplay of cardiac cells contributes to heart injury following exposure (Tapio et al 2021). Moreover, the retrospective studies on archival autopsies such as collected from nuclear workers can be a better alternative for animal or cellular models to investigate the late and lasting effect of low dose, chronic radiation exposure on the human heart (Rybkina et al 2014;Azimzadeh, Azizova, et al 2017;Azimzadeh et al 2020).…”

“…In terms of cardiomyocytes, thoughts within the working group noted that the effect of radiation exposure on cardiomyocytes would be centered on mitochondrial dysfunction, leading to metabolic changes due to the impairment of the peroxisome proliferator-activated receptor (PPAR)-alpha pathway and energy production (Azimzadeh et al 2013;Barjaktarovic et al 2013;Subramanian et al 2017;Azimzadeh, Azizova et al 2017;Subramanian et al 2018;Azimzadeh et al 2020). This energy deposition subsequently affects heart contraction, leading to myocardium injury and pathology.…”

Advanced Omics and Radiobiological Tissue Archives: The Future in the Past

“…These methods aim to optimise reproducible, cost-effective and efficient protocols that are compatible with omics techniques. Analytical protocols for the profiling of FFPE samples have been also established, optimized and used in radiation biology studies [12][13][14]. In this review, we describe the characteristics of radiobiological archives with available FFPE samples and the recent advances in omics analysis on FFPE tissues in radiation research.…”