Developmental EDC exposures alter hippocampal lipids and metabolites linked to long-term behavioral impairments in rats

Early-life exposure to endocrine-disrupting chemicals (EDCs) can interfere with brain development and contribute to long-term cognitive impairments. This study investigated whether hippocampal metabolite alterations at postnatal day 6 (PND6) are associated with behavioral outcomes in early adulthood following perinatal exposure to four EDCs: bisphenol F (BPF), butyl benzyl phthalate (BBzP), triphenyl phosphate (TPHP), and diisononyl cyclohexane-1,2-dicarboxylate (DINCH). Male and female rats were exposed in utero and during lactation, and hippocampal tissue was collected at PND6 for targeted metabolomics and untargeted lipidomics. Behavioral testing in adulthood using the Morris water maze assessed spatial learning (acquisition) and cognitive flexibility (reversal). BBzP exposure impaired acquisition learning, and BPF disrupted reversal performance in males. In females, both DINCH and TPHP led to increased latency during reversal. A multi-layered analytical framework was applied to explore associations between early metabolite and lipid profiles and later behavioral performance, including group-based comparisons, correlation analyses, and evaluation of biologically informed ratios. Results revealed sex- and domain-specific alterations in steroid and thyroid hormones, neurotransmitters, and PUFA-containing lipid classes, as well as changes in functional ratios and metabolite–metabolite coordination. These early metabolic disruptions were associated with increased escape latency in adulthood, suggesting long-term impacts on hippocampal function. • Males with acquisition impairments showed reduced levels of corticosterone, T3, and testosterone, and increased GABA, suggesting delayed GABAergic maturation. • Females with reversal impairments had increased PREG-S, DHEA-S, and GABA levels, indicating prolonged excitatory GABA signaling. • Disrupted hormone–neurotransmitter and DHA:AA lipid ratios were linked to long-term impairments in learning and cognitive flexibility