ABSTRACT: Chronic psychological stress become synonymous with modern life. It can disrupt homeostasis and lead to numerous health risks. However, the molecular basis is still in its infancy. Here, we employed a chronic restraint stress (CRS) mouse model to investigate the effects of psychological stress on metabolism, behavior, and fertility. Subsequently, we conducted a transcriptome analysis on the liver, brain, and testes, aiming to understand the molecular basis of CRS-induced physiological and behavioral alterations. The results showed that two consecutive weeks of CRS treatment led to delayed growth in mice, abnormalities in blood glucose metabolism, anxiety-like behaviors, and a decline in semen quality. Transcriptome analysis of 18 samples obtained from liver, brain and testis of both control and CRS-treated micerevealed significant changes in gene expression in the liver, brain, and testes. Gene function enrichment analysis, protein and protein interaction analysis, and gene set enrichment analysis highlighted that differentially expressed genes (DEGs) in the liver were primarily involved in the synthesis, metabolism, and transport of fatty acids and ribose, closely associated with glucose metabolism, insulin resistance, the synthesis and secretion of growth hormones, and extensively linked to adaptive immune responses. In the brain, DEGs were not only related to hormone secretion and cognitive function alterations but also played a part in regulating insulin secretion and the development of the reproductive system, closely linked to abnormalities in blood sugar metabolism and semen parameters. In the testes, DEGs mainly concerned immune responses, DNA damage, and hormone regulation, closely associated with abnormalities in semen parameters. These observations suggested that the multitude of health risks stemming from psychological stress-induced homeostatic imbalance could be mediated through the impact on gene expression profiles across various tissues. Despite the challenges in investigating the effects of psychological stress on human tissues and organs, with a reliance on animal models for insights, the role of psychological stress as a contributing factor to male metabolism issues, emotional disturbances, and infertility issues is undeniable. Highlighting its health implications among humans is essential. The study emphasizes the need for further research to explore the broader implications of stress on human health and the potential for intergenerational effects of stress-induced disorders.
