Behavioral and transcriptomic analyses reveal neurotoxicity and mechanism of action of DEHP in female pubertal mice with or without type 2 diabetes mellitus.

Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer that is widely used and is present in the environment and can be readily absorbed from inhalation or oral exposure. Previous studies have demonstrated that individuals with type 2 diabetes mellitus (T2DM) exhibit heightened sensitivity to environmental pollutants. Given the escalating prevalence of T2DM among adolescents, there is a growing concern regarding the impact of pollutants on this specific population. Consequently, researchers are increasingly focusing their attention on investigating the relationship between pollutants and individuals with diabetes. This paper investigates the toxicity and mechanism of action of DEHP exposure on the nervous system of female pubertal T2DM mice. The study found that DEHP had a significant impact on behavioral indicators including total distance, CW rotation count, residence time in the target quadrant, and latency in locating the platform, in T2DM mice. Transcriptomics analysis revealed that DEHP exposure significantly affected the expression of genes related to synapses and behavior, specifically those involved in the 5-hydroxytryptamine synapse and the signaling pathways associated with neuroactive ligand receptors and neuroreceptors in T2DM mice. Western blotting analyses indicated that DEHP treatment led to inhibition of the cAMP-PKA-ERK1/2-CREB pathway and increased levels of Ca2+ , CaM, and p-CaMKII, which negatively affected the nervous system. Furthermore, factorial analysis demonstrated that DEHP had a greater neurotoxicity in T2DM mice. In conclusion, DEHP impaired exploration and learning memory in female pubertal T2DM mice through the calcium signaling pathway and the cAMP-PKA-ERK1/2-CREB signaling pathway. Additionally, female pubertal T2DM mice were found to be more susceptible to DEHP toxicity compared to healthy mice.