Risk assessment of chemical-induced autism: epigenetic mutation analysis of SHANK3

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K12277
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 64010:Environmental load and risk assessment-related
• Research Institution: University of Miyazaki
• Principal Investigator: ARAI YOSHIKAZU 宮崎大学, 農学部, 助教 (90614769)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: エピジェネティクス / 環境化学物質 / 自閉症 / DNAメチル化 / ヒトiPS細胞 / SHANK3

Outline of Final Research Achievements

Autism is an inherited neurological disorder that has been increasing in children in recent years. However, genetic mutations alone cannot explain the disease onset, and there is concern about interactions with environmental factor(s). In this study, we focused on chemicals present in the maternal environment during pregnancy as environmental factors and examined their effects on neuronal differentiation. Human iPS cells with a heterozygous mutation in SHANK3, one of the genes responsible for autism, showed decreased ability to differentiate into neurons. Furthermore, combined exposure to five chemicals (DEP, cotinine, S-421, Hg, and Se) at maternal serum concentrations caused a further reduction in the differentiation potential of neurons derived from SHANK3 heterozygous deficient iPS cells. This suggests that environmental factors may further promote abnormal neuronal differentiation through interactions with genetic mutations.

Free Research Field

エピジェネティクス

Academic Significance and Societal Importance of the Research Achievements

自閉症を含めた神経疾患は、遺伝子変異による遺伝的要因と、化学物質などの環境要因との相互作用で発症すると考えられている。しかし、これらの相互作用に着目した研究は依然として少ないのが現状である。本研究では、自閉症の原因遺伝子の1つであるSHANK3のヘテロ欠損ヒトiPS細胞を樹立し、環境要因として胎児期に晒される危険性のある有害な化学物質に着目した。解析の結果、遺伝的要因と環境要因の相互作用は神経細胞分化に影響し、さらなる神経分化異常を引き起こすことが示された。本研究は遺伝的要因と環境要因との相互作用を検証した新たな取り組みであり、自閉症を含めた神経疾患の発症機序の解明に繋がることが期待できる。