Alterations in epigenetic marks and expression of genes related to stress regulation: an exploratory study among newborns after fetal repair of spina bifida aperta

Fetal repair of spina bifida aperta (fSBA) is an established intervention that improves neurological and neurodevelopmental outcomes. The present exploratory study examines whether molecular signatures related to stress regulation are detectable in newborns following this procedure. Specifically, we investigated DNA methylation and gene expression of two stress-regulatory genes, <i>NR3C1</i> and <i>FKBP5</i>. Within a clinical trial (ID: NCT04027374), we analyzed postpartum saliva samples from newborns who had undergone fSBA repair (fSBA group; <i>n</i> = 30) and compared them with two control groups: newborns exposed to antenatal glucocorticoids for lung maturation (LMI group; <i>n</i> = 12) and healthy controls (HC group; <i>n</i> = 27). Pyrosequencing and qRT-PCR were used for epigenetic and transcriptional analyses. Significant group differences were observed in <i>FKBP5</i> methylation, particularly at intron 7 CpG sites 5-7. The fSBA group showed lower methylation at site 5 but higher methylation at sites 6-7 compared to controls. No significant methylation differences were detected for <i>NR3C1</i>. Conversely, <i>NR3C1</i> gene expression was elevated in the fSBA group, whereas <i>FKBP5</i> expression did not differ between groups. These findings suggest gene- and site-specific molecular variation in newborns following fetal surgery. Given the exploratory nature of the study, the results are not suited to draw specific clinical implications but may inform future work aimed at understanding stress-related molecular alterations surrounding fetal interventions. Larger and longitudinal studies are warranted to clarify the robustness, developmental course, and potential clinical relevance of these molecular patterns.