Low Dietary Folate Increases Developmental Delays in the Litters of Mthfr677TT Mice

TL;DR

Low folate diets in mice with a specific MTHFR gene variant lead to developmental delays in their offspring and changes in folate-related metabolism.

Contribution

A new mouse model is introduced to study how the MTHFR 677TT genotype interacts with low folate intake during pregnancy.

Findings

MTHFR protein expression was lower in the liver of Mthfr677TT mice compared to Mthfr677CC mice.

Developmental delays in embryos were increased in Mthfr677TT mice fed low folate diets.

Low folate diets and the Mthfr677TT genotype led to higher total homocysteine levels in maternal plasma.

Abstract

Background/Objectives: Low folate intake before and during pregnancy increases the risk of neural tube defects and other adverse outcomes. Gene variants such as MTHFR 677C>T (rs1801133) may increase risks associated with suboptimal folate intake. Our objective was to use BALB/cJ Mthfr677C>T mice to evaluate the effects of the TT genotype and low folate diets on embryonic development and MTHFR protein expression in pregnant mice. Methods: Female 677CC (mCC) and 677TT (mTT) mice were fed control (2 mg folic acid/kg (2D)), 1 mg folic acid/kg (1D) and 0.3 mg folic acid/kg (0.3D) diets before and during pregnancy. Embryos and maternal tissues were collected at embryonic day 10.5. Embryos were examined for developmental delays and defects. Methyltetrahydrofolate (methylTHF) and total homocysteine (tHcy) were measured in maternal plasma, and MTHFR protein expression was evaluated in maternal liver. Results: MethylTHF decreased due to the experimental diets and mTT genotype. tHcy increased due to 0.3D and mTT genotype; mTT 0.3D mice had significantly higher tHcy than the other groups. MTHFR expression was lower in mTT liver than mCC. MTHFR protein expression increased due to low folate diets in mCC mice, whereas in mTT mice, MTHFR expression increased only due to 1D. Developmental delays were increased in the litters of mTT mice fed 1D and 0.3D. Conclusions: The Mthfr677C>T mouse models the effects of the MTHFR 677TT genotype in humans and provides a folate-responsive model for examination of the effects of folate intake and the MTHFR 677C>T variant during gestation.

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