Prenatal exposure to indoor VOCs impairs synaptic plasticity and cognitive function in mouse offspring via retinol metabolism disorder

Prenatal exposure to indoor volatile organic compounds (VOCs) poses a substantial yet underestimated threat to fetal brain development. We developed a realistic mouse model to investigate how gestational exposure to such formaldehyde-free paint VOCs mixture disrupts synaptic maturation and cognitive function in postnatal offspring, revealing a novel role for retinol metabolism. Pregnant C57BL/6 J mice inhaled filtered air (control; 0.15 ± 0.01 ppm) or VOCs (0.68 ± 0.06 ppm) from embryonic day 0-21. Exposed postnatal offspring showed deficits in exploratory behavior, recognition memory, and spatial learning, alongside neurodegeneration, reduced dendritic complexity, and lower levels of synaptic proteins (PSD-95, synaptophysin). We identified through transcriptomic and biochemical analyses significant retinol metabolism pathway enrichment, with downregulation of key genes (Aldh1a2, Crabp2) and their protein products. Our findings reveal that prenatal VOCs exposure disrupts synaptic development and cognition by interfering with retinol metabolism. This challenges the assumed safety of "low-VOCs" or "green" building materials in real-world scenarios. These results underscore the critical need to minimize maternal exposure to indoor air pollutants and to consider retinoid pathways as potential targets for intervention.