Acute wood smoke exposure is associated with cell-specific hippocampal transcriptomic responses in an accelerated ovarian failure mouse model.

Background: Wildfire events are increasing in frequency and intensity, and it is well-known that aging individuals are more susceptible to air pollution exposures, and that air pollution exposures result in neurological sequelae. Despite this, it is unclear how declining levels of ovarian hormones that naturally occur in aging females influence brain vulnerability to air pollution. Menopause and the menopausal transition represent a period of profound physiological change that affects cardiovascular, neurological, and immune health. Methods: We tested whether perimenopausal-like hormonal status amplifies hippocampal responses to acute wood smoke (WS) using an ovary-intact, 4-vinylcyclohexene diepoxide (VCD) model of moderate accelerated ovarian failure (AOF) in female C57BL/6 mice. Animals were exposed to HEPA-filtered air (FA) or WS for 4 h/day over 2 consecutive days (∼0.5 mg/m³). Exposure characterization confirmed a complex mixture of combustion products with significant levels of both trace metals and gas release during WS exposure. Results: Spatial transcriptomics (10x Visium; (n=4 sections/group) with automated cell-type annotation identified astrocytes, GABAergic and glutamatergic neurons, oligodendrocytes, revealed cell type-specific transcriptional alterations following WS exposure. Distinct transcriptional patterns were observed across all identified neuronal and glial cell populations. Conclusion: Together, these findings define a cell type-resolved transcriptional framework linking WS exposure and ovarian hormone decline and identify potential cellular pathways relevant to hippocampal vulnerability.