Associate Professor Ken Tachibana reveals how prenatal exposure to ambient fine particles disrupts DNA methylation and subsequent gene expression in fetal development
Human and animal epidemiological studies indicate that nutrition and environmental stimuli during prenatal and postnatal mammalian development influence developmental pathways and thus induce permanent changes in metabolism and susceptibility to chronic disease. Nutritional intake during pregnancy was the first factor identified that affects fetal development. Since then, numerous studies have shown that environmental factors are also closely associated with reproductive and child health. These phenomena have led to the hypothesis of “developmental origins of health and disease (DOHaD)”. Epigenetic mechanisms probably play an important role in this hypothesis.
Regulation and development of epigenetic genes
DNA methylation is a critical mechanism in the epigenetic regulation of genes. In mammals, methylation occurs almost exclusively on the cytosine residue of the CpG dinucleotide. CpG islets are regions of GC rich DNA that possess relatively high densities of CpG dinucleotide. They are present in many genes and positioned mainly around the site of the start of transcription of these genes. Their methylation status is closely associated with gene transcription activity, and hypermethylation results in transcriptional silence.
During the developmental period, the DNA methylation pattern derived from germ cells disappears when the fertilized egg develops into a blastocyst. The de novo methylation pattern is then reestablished around the implantation stage. The overall level of DNA methylation also changes in the early postnatal stages. These DNA methylation processes that occur during development are associated with long-lasting phenotypic changes. Additionally, tissue-specific DNA methylation patterns are built during this period of development, and this differential DNA methylation would be crucial for every organ to function properly. Aberrant DNA methylation is associated with various diseases and disorders. In fact, previous studies have indicated that deregulation of DNA methylation contributes to immunodeficiency, instability of the centromeric region, facial abnormalities syndrome, etc.
The developing embryo / fetus could be very vulnerable to environmental stimuli, even those having no toxic effect on the adult. The majority of environmental factors do not seem to modify the nucleotide sequence of DNA, i.e. these environmental factors do not induce genetic mutations. However, environmental factors can affect epigenetic changes, which include DNA methylation. In fact, previous reports have suggested that prenatal exposure to environmental factors, such as chemicals, metals, or particles, disrupts the DNA methylation pattern and subsequently induces various abnormal phenotypes in the offspring.
Exposure to ambient fine particles and aberrant DNA methylation in the brain
Numerous studies have shown that exposure to ambient fine particles (PM), one of the main environmental pollutants, is linked 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 particulate matter in urban environments. Several studies have indicated that exposure to EDs can affect the central nervous system. Our previous report also showed that prenatal ED exposure affects the brain of offspring with respect to neurotransmitter levels and spontaneous locomotor activity. We have further shown that prenatal ED exposure disrupts the state of DNA methylation at the genome level in the brains of offspring mice. To understand molecular events influenced by ED exposure, differentially methylated genes have been bioinformatically categorized using genetic ontology (GO) terms which are a computational representation of current scientific knowledge about gene functions. . This bioinformatic interpretation indicated that the differentially methylated genes of DNA were enriched in GO terms related to neuronal differentiation and neurogenesis. These results suggest that aberrant DNA methylation induced by prenatal ED exposure affects neuronal development. Since the established DNA methylation pattern is generally maintained by cell division, it is expected 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 disease, Huntington’s disease and Parkinson’s disease. Additionally, degeneration of cortical neurons was also observed in dogs that inhaled air pollutants containing PM. It would appear that the altered DNA methylation induced by prenatal exposure to EDs is also associated with the subsequent pathogenesis of neurodegenerative disorders.
Exposure to nanoscale particles and aberrant DNA methylation
It is increasingly evident that prenatal exposure to environmental factors can promote deregulation of DNA methylation and subsequent alteration of gene expression. This evidence indicates that the social environment in early life could be critical for building the DNA methylation pattern and may be associated with a long-term health effect. Concerns have been expressed about the adverse health effects, not only on ambient fine particles, but also on the nanoparticles (NP) produced. As the production and use of NPs continues to expand, the potential risk of toxicity to humans and the environment from NPs increases. Several studies indicate that NP exposure 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. development. To avoid the harmful effects on the health of newborns caused by prenatal exposure to NP, 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, courtesy of Nova Science Publishers, Inc. should also be noted.
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