N6-Methyladenine in Eukaryotic DNA: Tissue Distribution, Early Embryo Development, and Neuronal Toxicity

Abstract

DNA methylation is one of the most important epigenetic modifications and is closely related with several biological processes such as 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 (5mC) but recently adenine methylation was also found to be present in eukaryotes. In mouse embryonic stem cells, 6-methyladenine (6mA) was 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 fetal 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 120 h 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 may led to a decrease in the levels of this modification in female rats. The identification of the periods during which 6mA epigenetic marks are put in place increases our understanding of this mammalian epigenetic modification, and raises the possibility that it may be associated with developmental processes.

Brominated flame retardants, a cornelian dilemma

“…Hexabromocyclododecane disrupts the thyroid system in humans and other animals, and is a substance of concern for foetuses, new-borns exposed by breastfeeding, and children exposed via food and dust ingestion (Chain et al 2021; ECHA 2019 ; Kim and Oh 2014 ). Pre-clinical early-life models confirm the toxicity of hexabromocyclododecane for the developing brain (Fernandes et al 2021 ; Maurice et al 2015 ). Epidemiological data suggest that in utero exposure to hexabromocyclododecane induces modifications in motor skills, attention span and metabolism (Roze et al 2009 ).…”

DNA N6-Methyladenine Modification in Eukaryotic Genome

“…(Wu et al, 2016). In contrast, the level of 6 mA showed a linear increase in the embryonic states of mice and zebrafish (Fernandes et al, 2021). However, another group of researchers could not detect 6 mA in mouse ESCs or other tissues, which aroused extensive discussion (Schiffers et al, 2017).…”

“…However, another study showed that the level of 6 mA presented a linear increase in the embryonic states of mice and zebrafish (Fernandes et al, 2021). In mice, 6 mA is most abundant in the lungs, spleen, and brain, especially in the prefrontal cortex (PFC); therefore, it may play an important role in regulating the development of the nervous system and may be associated with certain neurological disorders (Fernandes et al, 2021). 6 mA was also detected in mouse ESCs.…”

Head-to-Head Study of Developmental Neurotoxicity and Resultant Phenotype in Rats: α-Hexabromocyclododecane versus Valproic Acid, a Recognized Model of Reference for Autism Spectrum Disorders

“…α-HBCDD exposure impacts various biological systems such as the thyroid axis [17], the immune system [18] and the liver [19]. These tissues are all highly vulnerable during the perinatal period, and exposure to α-HBCDD will result in long-term consequences, even at low doses [20]. The potential human toxicity of α-HBCDD has been widely established and has resulted in its recent classification as a "Substance of Very High Concern" in Annex XIV of the REACH European Regulation.…”