Gestational NO₂ exposure induces anxiety- and depression-like behaviors in mice via hippocampal PTGDS-PGD2 activation and tryptophan metabolism reprogramming.

Depression is a growing threat to adolescent health worldwide. NO2 potentially contributes to depression onset. A knowledge gap exists in the characterization of neurotoxicity in early life caused by prenatal NO2 exposure. In this study, pregnant C57BL/6 mice were exposed to NO2 throughout the gestational period. On postnatal day 22, we evaluated neurobehavioral changes, hippocampal disruption, and transcriptional alterations in pups to elucidate the neurodevelopmental toxicity of NO2. The results showed that prenatal NO2 exposure induced significantly decreased exploration in the open field test and elevated plus maze test, and increased despair time in the tail suspension and forced swimming tests. The transcriptomic alterations were enriched in neuroinflammation and neurotransmission, as well as diversified catabolic and metabolic processes. Elevated hippocampal microglial density, neuroinflammation, and the PTGDS-PGD2 pathway were observed in both genders. We identified a hippocampal shift in tryptophan metabolism from serotonin biosynthesis toward the kynurenine pathway, driven by the upregulation of indoleamine 2,3-dioxygenase 1 (IDO1), resulting in reduced serotonin synthesis. These findings demonstrate the intergenerational detrimental effects of maternal NO₂ exposure on offspring psychiatric health and elucidate underlying mechanisms involving multiple biological pathways. This insight aids in refining ambient pollution control strategies and personal protective measures during the perinatal period.