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Folic acid deficiency may impact later generations

Posted:  Tuesday, October 08, 2013

Deficiencies in folic acid dating back up to five generations could have an impact on developmental risk factors and later risk of disease, according to new research in mice. Writing in Cell, the research team reveal that epigenetic risk markers for disease caused by folic acid deficiency can be passed on to later generations, leading to an increased risk of disease and developmental disorders.

"Although our research focused on genetic mutations which disrupts the break down and metabolism of folic acid, we believe that folic acid deficiency in the diet would have a similar multi-generational impact on health," explained Dr Erica Watson from the University of Cambridge, who led the study.

The researchers found that when either the maternal grandmother or the maternal grandfather had a specific genetic mutation (known as Mtrr mutation) that caused a folic acid deficiency, their genetically normal grandchildren who did not have the genetic mutation and did not suffer from folic acid deficiency were still at risk of a spectrum of developmental abnormalities.

"It surprised us to find that the great, great grandchildren of a parent who has had a folic acid deficiency could have health problems as a result -- suggesting that the 'sins of your maternal grandparents' can have an effect on your development and your risk for disease," said Watson.

"More importantly, our 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,” she said.

Folic acid fortification

The detrimental effects of folic acid deficiency on development are quite well known, and can include developmental problems such as spina bifida, heart defects and placental abnormalities. However, until now, very little was known about how folic acid deficiency caused the diverse range of health problems in offspring.

As a result, many countries have implemented folate fortification programmes which require folic acid to be added to cereal products.

"Fortification programmes have reduced the risk of health effects but not eliminated them completely," said Watson. "Based on our research, we now believe that it may take more than one generation to eliminate the health problems caused by folate deficiency."

Inherited epigenetics

Through another experiment which involved transferring the embryo from the third generation into a normal healthy female mouse, the team discovered that the developmental abnormalities seen in later generation were not passed down genetically.

Instead, the serious defects were the result of epigenetic changes which had been inherited, said the authors.

Epigenetic inheritance refers to the passing of these epigenetic marks from one generation to the next - despite the epigenome, for the most part, being 'wiped clean' after each generation, explained Watson.

The team suggested that, for a yet unknown reason, some of these abnormal epigenetic marks caused by the Mtrr mutation, or indeed dietary folic acid deficiency, may escape this normal eradication and are inherited by the next generation.

If these abnormal epigenetic markers that regulate genes important for development are inherited, then subsequent generations may develop abnormalities as a result of the wrong genes being turned on or off, they said.

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, Mutation in Folate Metabolism Causes Epigenetic Instability and Transgenerational Effects on Development, Cell, Volume 155, Issue 1, 26 September 2013, Pages 81-93

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