Acute hypobaric hypoxia induces coordinated DNA methylation alterations and immune cell redistribution in lowlanders

Yuta Inaba; Takayuki Nishimura; Midori Motoi; Hideo Toyoshima; Fumi Kishida; Sora Shin; Hiroaki Arima; Takafumi Takafumi Katsumura; Hiroki Oota; Shigekazu Higuchi; Takafumi Maeda; Kazuhiro Nakayama

doi:10.20330/AnthropKozl.2026.67s.92

Yuta Inaba University of Tokyo, Department of Integrated Biosciences, Graduate School of Frontier Sciences, Tokyo, Japan
Takayuki Nishimura Kyushu University, Faculty of Design, Department of Human Life Design and Science, Fukuoka, Japan
Midori Motoi Kyushu University, Faculty of Design, Department of Human Life Design and Science, Fukuoka, Japan
Hideo Toyoshima Fukuoka Urasoe Clinic, Cyuou-Ku, Fukuoka, Japan
Fumi Kishida Junshin Gakuen University, Faculty of Health Sciences, Department of Medical Laboratory Science, Fukuoka, Japan
Sora Shin Virginia Polytechnic Institute and State University, Department of Human Nutrition, Foods, and Exercise, Blacksburg, USA
Hiroaki Arima Nagasaki University, Institute of Tropical Medicine, Department of International Health and Medical Anthropology, Nagasaki, Japan
Takafumi Takafumi Katsumura Kyushu University, Faculty of Design, Department of Human Life Design and Science, Fukuoka, Japan
Hiroki Oota Department of Biological Sciences, University of Tokyo, Tokyo
Shigekazu Higuchi Kyushu University, Faculty of Design, Department of Human Life Design and Science, Fukuoka, Japan
Takafumi Maeda Kyushu University, Faculty of Design, Department of Human Life Design and Science, Fukuoka, Japan;
Kazuhiro Nakayama Kyushu University, Faculty of Design, Department of Human Life Design and Science, Fukuoka, Japan

DOI: https://doi.org/10.20330/AnthropKozl.2026.67s.92

Keywords: Acute hypobaric hypoxia, Epigenetics, Cell composition deconvolution, DNA methylome, Remodelling, Innate-adaptive immune axis

Abstract

Background: Acute hypobaric hypoxia rapidly affects oxygen transport, endocrine regulation, and immune function. However, how short-term hypoxic stress links immune cell redistribution with changes in blood DNA methylation remains unclear.

Objectives: We aimed to characterize coordinated immune and DNA methylation responses to acute hypobaric hypoxia in lowlanders and to distinguish methylation changes caused by altered blood cell composition from potentially cell-intrinsic responses.

Subjects and methods: 18 healthy lowlanders were exposed to simulated altitude (3,500 m) for 75 minutes. Blood samples collected before and after exposure underwent genome-wide DNA methylation analysis using Illumina EPIC arrays. Differential methylation, functional enrichment, and immune cell deconvolution analyses were performed, and EPIC v1 and v2 datasets were integrated to identify methylation changes independent of blood cell composition.

Results: Acute hypobaric hypoxia induced widespread blood DNA methylation changes, particularly in immune-related pathways. Most signals reflected shifts in immune cell composition, with increased neutrophils and decreased lymphocytes. After adjustment, only a few hypoxia-associated loci remained, including an enhancer region of ECE1, a gene involved in vascular responses to hypoxia.

Conclusions: Even brief hypobaric hypoxia induces coordinated immune redistribution and detectable changes in blood DNA methylation. These findings highlight the importance of accounting for blood cell composition and support DNA methylation as a sensitive molecular indicator of acute hypoxic stress.

References

References: None.