N6-methyladenine levels in DNA increase throughout embryonic development, are enriched in the eukaryotic brain, and are a target for neurodevelopmental toxicity.

DNA methylation is one of the most important epigenetic modifications and is closely related with several biological processes such regulation of gene transcription and the development of non-malignant diseases. The prevailing dogma states that DNA methylation in eukaryotes occurs essentially through 5-methylcytosine but recently adenine methylation, through 6-methyl adenine (6mA), was also found to be present in eukaryotes. In mouse embryonic stem cells it was shown to be associated with the repression and silencing of genes, particularly in the X-chromosome, known to play an important role in cell fate determination.

Here, we have demonstrated that 6mA is a ubiquitous eukaryotic epigenetic modification that is put in place during epigenetically sensitive periods such as embryogenesis and foetal development. In somatic cells there are clear tissue specificity in 6mA levels, with, the highest 6mA levels being observed in the brain. In zebrafish, during the first 120h of embryo development, from a single pluripotent cell to an almost fully formed individual, 6mA levels steadily increase. An identical pattern was observed over embryonic days 7-21 in the mouse. Furthermore, exposure to a neurotoxic environmental pollutant  during the same early life period led to a decrease in the levels of this modification.

Our identification of the periods during which 6mA epigenetic marks are put in place and how they dynamically change in response to an early environmental stress, may shed a light on our understanding of the mammalian epigenetic modifications, and, as outlined in the developmental origins of health and disease, mechanistically contribute how a deviation from normal development can trigger disease phenotypes later in life.