Expose to high doses of folic acid during pregnancy causes adolescent anxiety- and depression-like behaviors in offspring mice

The effects of high doses of folic acid (FA) during pregnancy on anxiety- and depression-like behaviors in adolescent offspring mice were determined and the potential underlying mechanisms were elucidated. Pregnant C57BL/6 mice were randomly assigned to Control (2 mg/kg in feed), high FA (20 mg/kg in feed), and ultrahigh FA (40 mg/kg in feed) groups. The physiological development of the offspring, their preweaning neurobehavioral milestones, and adolescent behaviors indicative of anxiety and depression were assessed. High doses of FA during pregnancy delayed key developmental milestones such as pinna detachment, fur appearance, and incisor eruption. Furthermore, it triggered anxiety-like behavior in the passive avoidance test and led to depression-like behavior, as reflected by reduced movement distance in the center zone and decreased shuttling frequency in the light-dark box test and open field test. Additionally, brain tissues of the offspring exhibited increased expression of the microglia marker ionized calcium-binding adaptor molecule 1 and the Nod-like receptor protein 3 inflammasome. These findings suggest that high doses of FA during pregnancy may impair physiological development and increase the susceptibility of the offspring to anxiety- and depression-like behaviors, potentially mediated through the induction of low-grade inflammation in the brain.