Evaluation of Vortioxetine on Global DNA Methylation in Maternal and Offspring Rats and In Silico Molecular Docking to Key Epigenetic Enzymes.

Mothers face high depression risks during pregnancy, and untreated depression can harm both mother and baby. Vortioxetine is a novel antidepressant with a multimodal mechanism, unlike traditional ones. However, little is known about its safety and effectiveness in pregnancy due to limited preclinical and clinical data. This study investigated how maternal vortioxetine exposure during pregnancy affects DNA methylation in the brain tissue of mother and offspring rats. It also explored putative structural interactions of vortioxetine through molecular docking with key epigenetic enzymes to provide a hypothesis-generating context. Fifty female Sprague-Dawley rats were screened using a repeated forced-swim paradigm to characterize a passive stress-coping phenotype. They were then mated and randomly assigned to five groups (n = 10 each): vortioxetine at 0.5, 1.0, 2.0 mg/kg/day orally, saline control, and escitalopram (2.6 mg/kg/day orally) as a comparison. Treatments were given throughout pregnancy. On the day of cesarean section (G20), brain tissue was collected from both the mother and fetus. Global 5-mC levels were measured with ELISA (three replicates). The binding affinities and interaction motifs of vortioxetine and escitalopram with TET2, DNMT3A, and DNMT3B were analyzed via molecular docking. Global 5-mC levels in brain tissue did not differ between groups. However, a significant decrease in overall methylation was observed in offspring given the highest dose of vortioxetine (2.0 mg/kg/day). Docking analyses revealed that vortioxetine and escitalopram could bind strongly to TET2 and DNMT3A/3B; the observed reduction in global 5-mC was compatible with the hypothesis of altered de novo methylation pathways. The results show a specific dose threshold for the fetus. Low to moderate maternal exposures were not associated with detectable differences in global 5-mC under the current assay conditions, whereas high exposure was associated with hypomethylation in offspring. These findings underscore the importance of careful dose selection and mechanism validation for vortioxetine.