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Updated: Sep 11, 2025
Author Spotlight: Studying the Impact of Maternal Dietary Deficiencies on Long-Term Offspring Health Outcomes
Published on: June 28, 2024
Low Dietary Folate Increases Developmental Delays in the Litters of Mthfr677TT Mice
Karen E Christensen1,2, Marie-Lou Faquette1,2, Vafa Keser1,2
1Departments of Human Genetics and Pediatrics, McGill University, Montreal, QC H3A 0C7, Canada.
Insights
Mice with the MTHFR 677TT genotype and low folate diets experienced increased homocysteine and developmental delays during pregnancy. This mouse model helps study MTHFR gene variants and folate intake effects on embryonic development.
Area of Science:
- Genetics and Developmental Biology
- Nutritional Science
- Biochemistry
Background:
- Low folate intake during pregnancy is linked to neural tube defects.
- The MTHFR 677C>T gene variant may exacerbate risks associated with poor folate status.
- Understanding these interactions is crucial for optimizing maternal and fetal health.
Purpose of the Study:
- To evaluate the impact of the MTHFR 677TT genotype and varying folate intake levels on embryonic development.
- To assess MTHFR protein expression and metabolic markers in pregnant mice with different MTHFR genotypes and diets.
- To establish a mouse model for studying MTHFR gene variants and folate deficiency during gestation.
Main Methods:
- BALB/cJ Mthfr 677CC and 677TT mice were fed diets with 2, 1, or 0.3 mg folic acid/kg.
- Maternal plasma methyltetrahydrofolate (methylTHF) and total homocysteine (tHcy) were measured.
- Embryonic development was assessed, and MTHFR protein expression was analyzed in maternal liver tissue.
Main Results:
- The MTHFR 677TT genotype and low folate diets reduced methylTHF and increased tHcy levels.
- MTHFR protein expression was lower in MTHFR 677TT mice and responded differently to folate intake compared to controls.
- Embryonic developmental delays were more frequent in MTHFR 677TT mice on low folate diets.
Conclusions:
- The Mthfr 677C>T mouse model effectively mimics the human MTHFR 677TT genotype's effects.
- This model demonstrates folate responsiveness and is valuable for studying MTHFR variants and folate intake during pregnancy.
- Findings highlight the combined risks of MTHFR genotype and low folate on embryonic development.
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.
