Perinatal neurodevelopmental effects of endocrine disruptors: Insights from metabolome mapping in the rat hippocampus

Metabolism is critical for neurodevelopment, yet the mechanisms by which endocrine-disrupting chemicals (EDCs) contribute to neurodevelopmental disorders remain poorly defined. Using a rat model, we investigated hippocampal metabolomic responses at postnatal day 6 following maternal exposure to six structurally diverse EDCs (bisphenol F, permethrin, butyl benzyl phthalate, triphenyl phosphate, perfluorooctane sulfonic acid, and DINCH) from pre-mating through lactation. Targeted steroid, thyroid, and neurosteroid hormones, neurotransmitters, and untargeted lipidomics were profiled to map disrupted pathways. The analysis revealed sex-specific, chemical-specific, and shared metabolic signatures of developmental neurotoxicity. Key affected endpoints across chemicals included corticosterone, pregnenolone sulfate, and N-acylethanolamine lipids, confirming hormonal disruption while uncovering novel non-EATS (estrogen, androgen, thyroid, and steroidogenesis) pathways and mechanisms of action. These findings provide new insights into EDC-mediated disruption of hippocampal development and identify potential molecular biomarkers that may support future mechanistic research and chemical risk assessment.