Developmental Mono(2-ethylhexyl) Phthalate Exposure Impairs Offspring Neurobehavior through Suppression of CYP450 Transcriptional Pathways

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 <i>Cyp2a1</i>, <i>Cyp2f4</i>, <i>Cyp2g1</i>, and <i>Cyp1a2</i>. 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.