Parental folate deficiency induces birth defects in mice accompanied with increased de novo mutations

Abstract

Dietary folate deficiency (FD) is associated with the occurrence of birth defects. However, the mechanisms underlying this association remain elusive. In particular, how FD affects genome stability is unknown. To examine whether a folate-deficient diet can affect genome stability, C57BL/6 mice were maintained on a synthetic diet lacking of folic acid (FA) for two generations. F0 mice received the FD diet beginning at 3 weeks of age, and their offspring (F1) began the FD diet after weaning. Both male and female F1 mice fed the FD diet were intentionally crossed with F1 mice fed the normal diet to produce F2 mice. F2 embryos were dissected and collected at E14.5 and E18.5. The malformation ratio was significantly increased in F2 embryos fed the FD diet for two generations compared to those fed the normal diet. Whole-genome sequencing of multiple sibship with F1 males on the FD diet showed that the de novo mutation (DNM) rate in F2 embryos was three times of the reported spontaneous rate in mice. Furthermore, many DNMs observed in the F2 mice exhibited an allele ratio of 1:3 instead of 2:2, suggesting that these mutations are likely to accumulate in gamete cells as a form of mismatch in the DNA duplex. Our study indicated that FD for two generations significantly enhances DNM accumulation during meiosis, which might contribute to the increased negative birth outcomes among F2 mice. Not only maternal but also paternal FA supplementation is probably also necessary and beneficial to prevent birth defects.

Parental Folate Deficiency Inhibits Proliferation and Increases Apoptosis of Neural Stem Cells in Rat Offspring: Aggravating Telomere Attrition as a Potential Mechanism

“…Based on the above, the effect of parental folate status on the proliferation and apoptosis of NSCs may be mediated by telomerase activity and telomere integrity. Folic-acid-deficient diets during pregnancy could lead to negative reproductive outcomes and brain development [ 27 ]. The process of the proliferation and apoptosis of NSCs is critical for developing the brain and for plasticity and repair in the CNS [ 13 ].…”

The impact of maternal dietary folic acid or choline deficiencies on cerebral blood flow, cardiac, aortic, and coronary function in young and middle-aged female mouse offspring following ischemic stroke

“…Investigations of maternal perinatal folate deficiencies have revealed reduced hippocampal proliferation, impaired vesicular transport and synaptic plasticity, as well as poor neurite outgrowth (46), modified cellular neocortex composition, and diminished complexity and arborization of projection neurons (47) in offspring. In addition to these structural observations, both genetic and epigenetic modifications have been observed; maternal folate deficiencies reduced expressions levels of brain derived neurotropic factor (BDNF) and H3K9me2 in the fetal hippocampus, and folic acid deficiency for two generations, significantly enhancing de novo mutations accumulation during meiosis (48). Choline, another one-carbon cofactor implicated in a number of diverse biological processes (49), has yielded variable results in animal models of neurodevelopment.…”