AbstractRespiratory and emotional responses to blood-acidifying inhalation of CO₂ are markers of some human anxiety disorders, and can be enhanced by repeatedly cross-fostering (RCF) mouse pups from their biological mother to unrelated lactating females. Yet, these dynamics remain poorly understood. We show RCF-associated intergenerational transmission of CO₂ sensitivity in normally-reared mice descending from RCF-exposed females, and describe the accompanying alterations in brain DNA methylation patterns. These epigenetic signatures were compared to DNA methylation profiles of monozygotic twins discordant for emotional reactivity to a CO₂ challenge. Altered methylation was consistently associated with repeated elements and transcriptional regulatory regions among RCF-exposed animals, their normally-reared offspring, and humans with CO₂ hypersensitivity. In both species, regions bearing differential methylation were associated with neurodevelopment, circulation, and response to pH acidification processes, and notably included the ASIC2 gene. Our data show that CO₂ hypersensitivity is associated with specific methylation clusters and genes that subserve chemoreception and anxiety. The methylation status of genes implicated in acid-sensing functions can inform etiological and therapeutic research in this field.