Gestational folic acid supplement prevents vitamin D deficiency-induced depression-like behavior by reversing cortical DNA hypomethylation in adult offspring.

Depression is a common mental disorder with an increasing incidence. Several studies have demonstrated that cortical DNA hypomethylation is associated with depression-like behaviors. This study aims to investigate whether maternal vitamin D deficiency (VDD) induces depression-like behaviors and to explore the effects of folic acid supplement on VDD-induced cortical DNA hypomethylation in adult offspring. Female mice were fed with a VDD diet, beginning at 5 weeks of age and throughout pregnancy. Depression-like behaviors were evaluated, and cortical 5-methylcytosine (5mC) content was detected in adult offspring. Results showed that depression-like behaviors were observed in adult offspring of the VDD group. Cortical Ache and Oxtr mRNAs were upregulated in female offspring of the VDD group. Cortical Cpt1a and Htr1b mRNAs were increased in male offspring of the VDD group. Moreover, cortical 5mC content was reduced in offspring of VDD-fed dams. The additional experiment showed that serum folate and cortical S-adenosylmethionine (SAM) contents were decreased in the offspring of the VDD group. Folic acid supplement attenuated VDD-induced SAM depletion and reversed cortical DNA methylation. Moreover, folic acid supplement attenuated VDD-induced upregulation of depression-related genes. In addition, folic acid supplement alleviated maternal VDD-induced depression-like behaviors in adult offspring. These results suggest that maternal VDD induces depression-like behavior in adult offspring by reducing cortical DNA methylation. The gestational folic acid supplement prevents VDD-induced depression-like behavior by reversing cortical DNA hypomethylation in adult offspring.

Relationship between Maternal Vitamin D Levels and Adverse Outcomes.

Vitamin D (VD), a fat-soluble vitamin, has a variety of functions that are important for growth and development, including regulation of cell differentiation and apoptosis, immune system development, and brain development. As such, VD status during pregnancy is critical for maternal health, fetal skeletal growth, and optimal pregnancy outcomes. Studies have confirmed that adverse pregnancy outcomes, such as preeclampsia, low birth weight, neonatal hypocalcemia, poor postnatal growth, skeletal fragility, and increased incidence of autoimmune diseases, can be associated with low VD levels during pregnancy and infancy. Thus, there is growing interest in the role of VD during pregnancy. This review summarizes the potential adverse health outcomes of maternal VD status during pregnancy for both mother and offspring (gestational diabetes mellitus, hypertensive gestational hypertension, intrauterine growth restriction, miscarriage, stillbirth, and preterm birth) and discusses the underlying mechanisms (regulation of cytokine pathways, immune system processing, internal secretion, placental function, etc.) of VD in regulating each of the outcomes. This review aims to provide a basis for public health intervention strategies to reduce the incidence of adverse pregnancies.