Abstract
Phthalates, ubiquitous environmental contaminants, pose substantial risks to neurodevelopment, yet the mechanisms underlying their toxicity remain largely unknown. This study demonstrates that developmental exposure to mono-(2-ethylhexyl) phthalate (MEHP: 0, 10, and 50 mg/kg), the bioactive metabolite of di-(2-ethylhexyl) phthalate (DEHP), induced neurobehavioral deficits in adolescent offspring rats. Behavioral assessments revealed that the MEHP exposure provoked anxiety-like behaviors at postnatal days (PND) 14 and 21, concurrently manifested as spatial memory impairments at PND35. Histopathological analysis demonstrated significant neurodegenerative alterations in the hippocampus of MEHP-exposed offspring, including reduced Nissl body density in the 50 mg/kg group. Transcriptomic profiling identified a robust dose-dependent dysregulation pattern, with high-dose exposure (50 mg/kg) eliciting substantially more differentially expressed genes (542 DEGs) than low-dose exposure (393 DEGs). Analysis revealed suppression of cytochrome P450 (CYP450) pathways, characterized by the downregulation of Cyp2a1, Cyp2f4, Cyp2g1, and Cyp1a2. Strikingly, these effects occurred independently of canonical xenobiotic-sensing receptors, indicating direct CYP450 transcriptional inhibition as a potential novel mechanism. Taken together, our findings determine MEHP as a potent developmental neurotoxicant, with CYP450 dysregulation identified as a critical mediator of phthalate-induced neurotoxicity, with significant implications for environmental risk assessment.