Adaptive Changes in Human Leukocytes in Response to a Long-Term Stay in Antarctica

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Abstract

Oxidative stress and aging are known to alter the copy number (CN) of satellite III repeat (1q12) (SatIII(1q)) and telomeric repeat (TR) in the DNA of human cells. The extreme conditions of Antarctica could potentially affect the CN of these repeats in human blood cells, which may be associated with inhibition of the antioxidant system and activation of apoptosis. In this work, we analyzed the CN of ribosomal DNA (rDNA), SatIII(1q), and TR repeats in the leukocytes of 11 male members of the expedition to Vostok station in 2019–2020. To observe dynamic changes in the number of repeating elements of the genome and the degree of their oxidation, six blood samples were taken: before arrival in Antarctica, after 27, 85, 160, 270, and 315 days of wintering. To analyze adaptive changes, the expression levels of the BAX, BCL2, NOX4, NRF2, SOD1, and HIF1 genes were measured. We detected a decrease in SatIII(1q) CN and an increase in TR CN against the background of a stable rDNA CN in human blood cells during wintering. These changes, along with a decrease in the 8-oxodG in DNA, are associated with an increase in the activity of the NOX4 gene, a decrease in the activity of the NRF2 gene, and an increase in the expression of the proapoptotic protein BAX. Thus, wintering in Antarctica stimulates an adaptive response in the human body, which includes increased elimination from the bloodstream of “ballast” cells with a high level of DNA oxidation, a high SatIII(1q) content, and a low TR content. An increase in ROS levels due to chronic activation of the NOX4 gene along with the blocked NRF2 gene may play a significant role in the development of the response.

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N. N. Veiko

Medical Genetic Research Center, Russian Academy of Medical Sciences

Email: shmarov.v.a@gmail.com
Russian Federation, Moscow

E. S. Ershova

Medical Genetic Research Center, Russian Academy of Medical Sciences

Email: shmarov.v.a@gmail.com
Russian Federation, Moscow

E. M. Malinovskaya

Medical Genetic Research Center, Russian Academy of Medical Sciences

Email: shmarov.v.a@gmail.com
Russian Federation, Moscow

E. A. Savinova

Medical Genetic Research Center, Russian Academy of Medical Sciences

Email: shmarov.v.a@gmail.com
Russian Federation, Moscow

J. M. Chudakova

Medical Genetic Research Center, Russian Academy of Medical Sciences

Email: shmarov.v.a@gmail.com
Russian Federation, Moscow

J. I. Eliseeva

Medical Genetic Research Center, Russian Academy of Medical Sciences

Email: shmarov.v.a@gmail.com
Russian Federation, Moscow

S. V. Kostyuk

Medical Genetic Research Center, Russian Academy of Medical Sciences

Email: shmarov.v.a@gmail.com
Russian Federation, Moscow

A. A. Sadova

Institute of Biomedical Problems, RAS

Email: shmarov.v.a@gmail.com
Russian Federation, Moscow

V. A. Shmarov

Institute of Biomedical Problems, RAS

Author for correspondence.
Email: shmarov.v.a@gmail.com
Russian Federation, Moscow

M. P. Rykova

Institute of Biomedical Problems, RAS

Email: shmarov.v.a@gmail.com
Russian Federation, Moscow

N. Yu. Osetskiy

Institute of Biomedical Problems, RAS

Email: shmarov.v.a@gmail.com
Russian Federation, Moscow

S. A. Ponomarev

Institute of Biomedical Problems, RAS

Email: shmarov.v.a@gmail.com
Russian Federation, Moscow

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2. Fig. 1. General scheme of the experiment.

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3. Fig. 2. Changes in the content of three tandem repeats in DNA isolated from the blood cells of winterers. A – SatIII(1q) repeat content in DNA samples isolated from the blood cells of each winterer (a), and analysis of changes in SatIII(1q) content in winterers under working conditions at the station compared to the period before arrival at the station (b); B – TR repeat content in DNA samples isolated from the blood cells of each winterer (a), and analysis of changes in TR repeat content under working conditions at the station compared to the period before arrival at the station (b); C – rDNA content in DNA samples isolated from the blood cells of each winterer (a), and analysis of changes in rDNA content under working conditions at the station compared to the period before arrival at the station (b); D – changes in repeat content in cells obtained from winterers at points I–V compared to the control (CA). Points I–IV: N = 11 DNA samples; V: N = 9. * – the content of repeats in group I–V differs from the content in the control group (p < 0.01). D – dependence of the content (a) and content change (b) of TR in DNA on the content and content change of the SatIII(1q) repeat. Spearman correlation analysis data (Rs and p) are presented. Figures A–C show the mean value for three measurements and the measurement error (SE). Dark gray columns indicate blood samples obtained before arrival at the station (sample CA). Gray color indicates samples obtained during the polar day. Black color indicates samples obtained during the polar night. In Figures A–C, white color in the tables indicates that the parameter value has not changed (p > 0.05, U-test); gray indicates that the parameter value differs from the control (p < 0.05).

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4. Fig. 3. DNA damage in blood cells of winterers. A – content of the 8-oxodG oxidation marker in DNA samples isolated from the blood cells of each winterer (a), changes in the 8-oxodG content in DNA samples at points I–V compared to the control (CA) (b), analysis of 8-oxodG changes under working conditions at the station compared to the period before arrival at the station (c). B – dependence of changes in SatIII(1q) content (a) and TR content (b) in DNA on changes in the 8-oxodG oxidation marker level. Spearman correlation analysis data (Rs and p) are presented. B – SATIII(1q) RNA content in RNA samples isolated from blood cells of each winterer (a), changes in SATIII(1q) RNA content in RNA samples at points I–V, compared to the control (CA) (b), analysis of changes in SATIII(1q) RNA content under working conditions at the station compared to the period before arrival at the station (c). Graphs A, a and B, a show the mean values ​​for three measurements and the measurement error (SE). Dark gray bars indicate blood samples obtained before arrival at the station (sample CA), light gray bars indicate samples obtained during the polar day, black bars indicate samples obtained during the polar night. In graphs A, b and B, b points I–IV: N = 11 samples; V: N = 9, * – the content of repeats in group I–V differs from the content in the control group (p < 0.01). White color in tables (A, b and B, b) – the parameter value did not change (p > 0.05, U-test); dark – increased; * indicates samples in which the parameter decreased.

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5. Fig. 4. Changes in the RNA level of genes controlling the level of oxidative stress and cell death. A – changes in the amount of RNA of the NOX4, NRF2 (NFE2L2), SOD1 and HIF1A genes, regulating the level of ROS in cells, at points I–V compared to the control (see Table 1). B – changes in the amount of RNA of the BAX, BCL2 genes, regulating apoptosis in cells, and the RNA ratio (BAX/BCL2) at points I–V compared to the control (see Table 2). C – correlation analysis (according to Spearman) of the relationships between changes in the genes analyzed in the work. D – dependence of changes in the RNA ratio (BAX/BCL2) on changes in RNA NOX4. D – correlation analysis of the relationships between the parameters of DNA and RNA SATIII(1q), isolated from cells, and changes in the RNA amount of the genes analyzed in the work. E – analysis of correlations between changes in the level of SATIII(1q) RNA and changes in the level of SOD1 RNA (a) and HIF1 RNA (b), dependence of changes in TR content on the indicator reflecting the level of apoptosis (c).

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6. Fig. 5. Scheme illustrating changes in the content of SatIII(1q) and TR repeats in the blood cells of overwinterers.

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