Cai, X., Wu, S., Weng, M., Chu, J., Yin, K., Hu, J., Chen, X., Hou, F., Xu, D., Wei, T., Zhao, L. (2025). Early-life DEHP exposure disrupts adult male drosophila sleep homeostasis via Kyat-KYNA-NMDAR pathway in the brain.  J. Hazard. Mater. 495(): 139146.

FBrf0263302

Research paper

Sleep quality is associated with exposure to environmental chemicals, and model organisms such as fruit flies are ideal for studying the genetic basis of sleep. Using the Drosophila melanogaster model, this study innovatively explores the long-term effects of early-life exposure to the plasticizer di-(2-ethylhexyl) phthalate (DEHP) on adult sleep quality and the underlying mechanisms. Results showed that early-life DEHP exposure reduced adult fruit fly total sleep time and increased sleep number, with more significant sleep phenotype changes in males. Through non-targeted metabolomics and Elisa experiments, it was discovered that the concentration of kynurenic acid (KYNA) specifically increased in the brains of male fruit flies in the exposure group. Western blotting and brain-specific gene silence experiments confirmed that the increase in KYNA was due to upregulated expression of kynurenine aminotransferase (Kyat), a key enzyme in its synthesis. Molecular docking analysis revealed that KYNA can bind to multiple active sites of the ionotropic glutamate receptor, N-methyl-D-aspartate receptor (NMDAR), hindering normal NMDAR channel opening and calcium ion influx. Notably, in a fruit fly model with brain-specific Kyat knockdown, this operation partially reversed the DEHP-induced KYNA accumulation and sleep homeostasis imbalance. This study clarifies that early-life DEHP exposure can promote KYNA accumulation by increasing Kyat activity, disrupt NMDAR calcium flow regulation, and induce adult sleep disorders. These findings shed light on the association between environmental chemical exposure and sleep disorders and may offer potential therapeutic targets for the prevention and treatment of such sleep disorders.