Environmental phthalate exposure impairs cognition in aged males by coupling myelin injury to synaptic dysfunction via Nogo-A/S1PR2 signaling.

Di-(2-ethylhexyl) phthalate (DEHP) is a widespread environmental contaminant linked to endocrine disruption, neurotoxicity, and cognitive aging. However, its effects on hippocampal function in aging populations remain unclear. In this study, 22-month-old male C57BL/6J mice were orally exposed to DEHP (0.2, 20, or 200  mg/kg/day) for 5 weeks to model environmentally relevant and toxicological exposure scenarios. Cognitive performance was evaluated using the Morris water maze and novel object recognition tests, while hippocampal alterations were assessed through histology, immunofluorescence, and molecular analyses. DEHP exposure at higher doses impaired spatial learning and memory, whereas the lowest dose induced subtle molecular changes. Mechanistically, DEHP reduced oligodendrocyte maturation and myelin integrity, inhibited oligodendrocyte precursor cell (OPC) differentiation, and induced local thyroid hormone disruption and neuroinflammation. Notably, DEHP activated the Nogo-A/S1PR2 pathway and its downstream RhoA/ROCK2 signaling, contributing to synaptic deficits marked by decreased PSD95 expression. In summary, subacute DEHP exposure disrupts hippocampal homeostasis in aged male mice by impairing myelin integrity, glial function, and synaptic stability. Activation of the Nogo-A/S1PR2 axis represents a key mechanistic link underlying these effects, providing insight into how environmental phthalates may accelerate age-related cognitive decline.