The effect of paternal dietary folic acid on male fertility and embryo development in Balb/c mice

In 1998, Canada fortified white flour with folic acid targeting women of childbearing age to reduce the incidence of neural tube defects. Resultantly, FA intake in men increased. This study investigated the effect of paternal FA intake on male fertility, embryo development, and methylation dependent gene expression in unexposed descendants of Balb/c mice. Folate deficiency resulted in a higher number of embryos with congenital anomalies and developmental delay, and a lower prevalence of ossification in bones of the skull. Placenta size was higher with higher FA intake. BiSulfite Amplicon Sequencing was used to characterize methylation changes in heritable epigenetically regulated genes for which hepatic expression was dependent on grand-paternal FA exposure during early development or post-weaning. CpG islands in promoters of three genes had subtle diet-induced methylation changes. This study highlights the importance of adequate paternal FA intake, emphasizing that fortification can directly impact embryo development and affect future generations.