Folic acid deficiency can cause severe health problems in offspring, including heart defects and placental abnormalities, Cambridge researchers have found.
A new study has revealed that a mutation in a gene necessary for the metabolism of folic acid not only impacts the immediate offspring but can also have detrimental health effects on the next several generations.
"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," said Dr Erica Watson, who led the study.
"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," said Watson.
The researchers, from the Universities of Cambridge and Calgary, used mice for the study as they metabolise folic acid very similarly to humans and because folic acid deficiency or mutations in the same genes required to break down folic acid in humans result in similar developmental abnormalities and diseases in mice.
This enabled the researchers to explore how the molecular mechanism of folic acid deficiency impacted development, thereby causing health problems.
The scientists used mice in which a gene called Mtrr was specifically mutated. The gene is key to the normal progression of the folic acid cycle and, when mutated, it results in abnormal folic acid metabolism causing similar effects to dietary folic acid deficiency.
The researchers found that when either the maternal grandmother or the maternal grandfather had this Mtrr mutation, their genetically normal grandchildren were at risk of a wide spectrum of developmental abnormalities.
These developmental abnormalities were also seen in the fourth and fifth generations of mice.
Through another experiment which involved transferring the embryo from the third generation into a normal healthy female mouse, they discovered that these developmental abnormalities were not passed down genetically.
Instead, the serious defects were the result of epigenetic changes which had been inherited.
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.
The researchers hypothesise 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.
The study was published in the journal Cell.
