Abstract
Both environmental factors and genetic factors are involved in the pathogenesis of autism spectrum disorders (ASDs). Epigenetics, an essential mechanism for gene regulation based on chemical modifications of DNA and histone proteins, is also involved in congenital ASDs. It was recently demonstrated that environmental factors, such as endocrine disrupting chemicals and mental stress in early life, can change epigenetic status and gene expression, and can cause ASDs. Moreover, environmentally induced epigenetic changes are not erased during gametogenesis and are transmitted to subsequent generations, leading to changes in behavior phenotypes. However, epigenetics has a reversible nature since it is based on the addition or removal of chemical residues, and thus the original epigenetic status may be restored. Indeed, several antidepressants and anticonvulsants used for mental disorders including ASDs restore the epigenetic state and gene expression. Therefore, further epigenetic understanding of ASDs is important for the development of new drugs that take advantages of epigenetic reversibility.
Highlights
Autism spectrum disorders (ASDs) are complex, pervasive neurodevelopmental disorders that are characterized by dysfunctions in social interactions and communications and restricted/fixated interests or repetitive behavior that manifest in early childhood [1]
Viral infections with rubella and cytomegalovirus and associated immunological reactions via activation of microglia are thought to be involved in ASDs, which has been demonstrated by pathological studies of post-mortem brains and neuroimaging studies of ASD patients [9,10,11,12,13,14], some epidemiological studies conducted in Denmark and Taiwan did not support the hypothesis that pre- and postnatal infection and immunological reaction are involved in ASD cases with regard to herpes and influenza viral infection and Kawasaki Disease [15,16,17]
Rett syndrome (RTT) is a representative ASD characterized by repetitive and stereotypic hand movements, seizures, gait ataxia and autism [35] and is caused by mutations in the gene that encode methyl-CpG-binding protein 2 (MeCP2), which is associated with chromatin remodeling [36]
Summary
Autism spectrum disorders (ASDs) are complex, pervasive neurodevelopmental disorders that are characterized by dysfunctions in social interactions and communications and restricted/fixated interests or repetitive behavior that manifest in early childhood [1]. Autism susceptibility candidate 2, a nuclear protein involved in cortical neuronal migration and neuritogenesis in the developing brain [30] and whose mutations cause ASDs [31,32], forms a complex with polycomb repressive complex 1 to purge its repressive function and activates expression of neurodevelopmental genes involved in axon guidance in the developing forebrain, such as neruocan [33,34] These results suggest that close interaction between neuronal molecules and epigenetic molecules is important for normal brain development and failure of this interaction is potentially associated with ASDs. In this review, we introduce congenital epigenetic disorders with ASD-like phenotypes and environmental factors that affect epigenetic regulation of neuronal genes, and discuss transgenerational epigenetic inheritance and therapeutic strategies for ASDs taking advantage of use of the epigenetic reversibility
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