Folate Deficiency May Affect Subsequent Generations Through Epigenetics

Erica D. Watson, PhD Lecturer in Reproductive Biology Centre for Trophoblast Research Dept Physiology, Development and Neuroscience University of Cambridge Physiology Building, Downing Site Cambridge, CB2 3EG, United Kingdom Interview with:
Erica D. Watson, PhD
Lecturer in Reproductive Biology Centre for Trophoblast Research Dept Physiology, Development and Neuroscience University of Cambridge, United Kingdom  What are the main findings of the study?

Dr. Watson: It has been known for decades that maternal folate deficiency increases the risk for a diverse range of health problems in her children, such as spina bifida, heart defects and growth restriction. Despite this, the molecular mechanism of folate during development was not well understood. Our study is important because it shows that the inability to break down folate due to a mutation in the gene Mtrr can affect the health not only in the immediate offspring but also of the next generation.

We used mice for the study as they metabolize folate similarly to humans and because folic acid deficiency or mutations in the genes required to break down folate in humans result in similar developmental abnormalities and diseases in mice. This enabled us to explore how the molecular mechanism of folate deficiency impacted development, thereby causing health problems.  Were any of the findings unexpected?

Dr. Watson: The results were very unexpected. We found that when the maternal grandmother or maternal grandfather had this Mtrr mutation, their grandchildren were at risk of a wide spectrum of developmental abnormalities, even if the mutated gene was not inherited by the next generations. These abnormalities were also seen in the fourth and fifth generations of mice. This suggested that defects caused by the Mtrr mutation were not genetically-inherited but rather inherited through epigenetic mechanisms.

Epigenetics is a system which turns genes on and off. It occurs when chemical modifications (e.g., methyl groups) bind to the DNA at specific locations to control gene expression. Interestingly, the folate cycle is required to make sure that the cell has enough methyl groups for normal gene expression. Epigenetic inheritance refers to the passing of these epigenetic modifications from one generation to the next – despite the epigenome, for the most part, being ‘wiped clean’ after each generation.

We hypothesize that, for a yet unknown reason, some of these abnormal epigenetic marks caused by the Mtrr mutation may escape this normal erasure and are inherited by the next generation. If these abnormal epigenetic marks are inherited, then these generations may develop abnormalities as a result of the wrong genes being turned on or off.  What should clinicians and patients take away from your report?

Dr. Watson: This work emphasizes the importance for both women and men to ingest sufficient levels of folate during their reproductive years to reduce the risk of health problems in their children, grandchildren and even great grandchildren. It also suggests that the effects of folate fortification programs may not become apparent for more than one generation.  What recommendations do you have for future research as a result of this study?

Dr. Watson: This research shows that disease in general can be inherited through epigenetic means rather than genetic means, which has huge implications for human health. Environmental factors that influence epigenetic patterns – e.g., diet, epigenetic disruptors in the environment such as chemicals, etc. – may also have long term, multigenerational effects. Future studies must be carefully designed to further explore this phenomenon and the mechanisms behind epigenetic inheritance.


Mutation in Folate Metabolism Causes Epigenetic Instability and Transgenerational Effects On Development
Nisha Padmanabhan, Dongxin Jia, Colleen Geary-Joo, Xuchu Wu, Anne C. Ferguson-Smith, Ernest Fung, Mark C. Bieda, Floyd F. Snyder, Roy A. Gravel, James C. Cross, Erica D. Watson

Cell – 26 September 2013 (Vol. 155, Issue 1, pp. 81-93)

Last Updated on February 17, 2015 by Marie Benz MD FAAD