Integrated Profiling of DEHP-Induced Hippocampal Neurotoxicity in Adult Female Rats Based on Transcriptomic and Neurobiological Analyses

Di-2-ethylhexyl phthalate (DEHP) is a widely used plasticizer with recognized sex-dependent neurotoxicity. However, research on adult neurotoxicity is scarce, especially in females. In this study, adult female rats were exposed to a high-dose experimental model of DEHP (500 mg/kg/day) for 28 days to systematically evaluate hippocampal neurotoxicity. We found that DEHP exposure significantly impaired spatial learning and memory. Transcriptomics revealed enrichment in oxidative stress, complement activation, and neurodegenerative pathways. Specifically, cellular and molecular analyses showed that DEHP induced mitochondrial structural defects and elevated markers of oxidative damage (8-OHdG and 3-NT). While the upregulation of mitochondrial and antioxidant proteins (COX4I1, SOD2, and NQO1) indicated an attempted compensatory response, it remained inadequate to restore redox homeostasis. Under this neurotoxic microenvironment, DEHP triggered early neurogenesis, marked by the upregulation of SOX2 and DCX; however, NeuN levels remained unchanged, suggesting that this compensatory effort failed to expand the mature neuronal population. Ultimately, these pathological processes culminated in neurodegeneration, as evidenced by reduced synaptic proteins, suppressed Olig1/2 expression, and increased tau phosphorylation. Collectively, this study provides a comprehensive neurotoxic profile of DEHP in adult female rats, filling a research gap in this field.