Associate Professor Ken Tachibana, discloses how prenatal ambient fine particle exposure disrupts DNA methylation and subsequent gene expression in the foetal development stage
Human epidemiologic and animal studies indicate that nutrition and environmental stimuli during prenatal and postnatal mammalian development influence developmental pathways and thereby induce permanent changes in metabolism and susceptibility to chronic disease. Nutritional intake during pregnancy was the first factor identified that affects foetal development. Since then, many studies have shown that environmental factors are also closely associated with reproductive and child health. These phenomena led to the proposal of the “developmental origins of health and diseases (DOHaD)” hypothesis. Epigenetic mechanisms likely play an important role in this hypothesis.
Epigenetic gene regulation and development
DNA methylation is a critical mechanism of epigenetic gene regulation. In mammals, methylation almost exclusively occurs on the cytosine residue of CpG dinucleotide. CpG islands are GC-rich DNA regions that possess relatively high densities of CpG dinucleotide. They are found in many genes and positioned mainly around the transcription start site of those genes. Their methylation status is closely associated with gene transcription activity and hypermethylation results in transcriptional silencing.
In the developmental period, the DNA methylation pattern derived from germ cells disappears when the fertilised egg develops into a blastocyst. The de novo methylation pattern is then re-established at around the stage of implantation. The global DNA methylation level also changes in the early postnatal stages. These DNA methylation processes that occur during development are associated with long-lasting phenotypic changes. In addition, tissue-specific DNA methylation patterns are constructed during this developmental period, and this differential DNA methylation would be crucial for each organ to function properly. Aberrant DNA methylation is associated with various diseases and disorders. In fact, previous studies have indicated that dysregulation of DNA methylation contributes to immunodeficiency, centromeric region instability, facial anomalies syndrome and so on.
The developmental embryo/foetus could be highly vulnerable to environmental stimuli, even those having no toxic effect on the adult. The majority of environmental factors do not appear to change the nucleotide sequence of DNA, that is, these environmental factors do not induce genetic mutations. However, environmental factors can affect the epigenetic modifications, which include DNA methylation. In fact, previous reports suggested that prenatal exposure to environmental factors, such as chemicals, metals, or particulate matter, disrupts the DNA methylation pattern and subsequently induces various abnormal phenotypes in the offspring.
Fine ambient particulate matter exposure and aberrant DNA methylation in the brain
Many studies have shown that exposure to fine ambient particulate matter (PM), one of the major environmental pollutants, is related to brain dysfunction in addition to respiratory and cardiovascular disorders. Diesel exhaust (DE) is one of the main types of air pollution and is a major source of fine ambient PM in urban environments. Several studies have indicated that DE exposure may affect the central nervous system. Our previous report also showed that prenatal DE exposure affects the brain of offspring with regard to neurotransmitter levels and spontaneous locomotor activity. We further showed that prenatal DE exposure disrupts the genome-wide DNA methylation state in the brain of offspring mice. To understand the molecular events influenced by DE exposure, differentially methylated genes were bioinformatically categorised using Gene Ontology (GO) terms that is a computational representation of current scientific knowledge about the functions of genes. This bioinformatic interpretation indicated that differentially DNA methylated genes were enriched in the GO terms related to neuronal differentiation and neurogenesis. These results suggested that aberrant DNA methylation induced by prenatal DE exposure affects neuronal development. Given that the established DNA methylation pattern is generally maintained through cell division, it is predicted that altered DNA methylation would be partially maintained after development. Several reports suggest a relationship between aberrant DNA methylation and neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s disease. In addition, cortical neuron degeneration has also been observed in canines that inhaled air pollutants containing PM. It would seem that altered DNA methylation induced by prenatal DE exposure would also be associated with the later pathogenesis of neurodegenerative disorder.
Nano-sized particulate matter exposure and aberrant DNA methylation
There is growing evidence that prenatal exposure to environmental factors can promote dysregulation of DNA methylation and subsequent alteration of gene expression. This evidence indicates that the early life social environment could be critical for the construction of the DNA methylation pattern and may be associated with a long-term effect on health. There are raised concerns about adverse health effects not only on ambient fine particles but also on engineered nanoparticle (NP). As the production and use of NPs continues to expand, the potential risk of toxicity to humans and the environment caused by NPs increases. Several studies indicate that exposure to NPs induces not only genomic mutations but also epigenetic changes, which include altered DNA methylation. Although several reports show the ability of NPs to affect the DNA methylation pattern in adults, it remains unclear whether prenatal exposure to NPs affects the construction of precise DNA methylation patterns in the developmental stage. To avoid the adverse health effects to new-borns caused by prenatal exposure to NPs, it is important to clarify the molecular mechanisms of these effects.
Reprinted from: DNA Methylation: Patterns, Functions and Roles in Disease; Tachibana K and Takeda K, Disruption of DNA methylation patterns caused by exposure to environmental factors during the developmental period, pp. 1-28, copyright (2016). The statement, with permission from Nova Science Publishers, Inc. should also be noted.
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