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Methylmercury causes epigenetic suppression of the tyrosine hydroxylase gene in an in vitro neuronal differentiation model

Go, Suzuna    (Corresponding author.  ); Kurita, Hisaka   Matsumoto, Kana   Hatano, Manami   Inden, Masatoshi   Hozumi, Isao  
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    Abstract Methylmercury (MeHg) is the causative substance of Minamata disease, which is associated with various neurological disorders such as sensory disturbance and ataxia. It has been suggested low-level dietary intake of MeHg from MeHg-containing fish during gestation adversely affects the fetus. In our study, we investigated the toxicological effects of MeHg exposure on neuronal differentiation focusing on epigenetics. We used human fetal brain-derived immortalized cells (LUHMES cells) as a human neuronal differentiation model. Cell viability, neuronal, and catecholamine markers in LUHMES cells were assessed after exposure to MeHg (0–1000 nM) for 6 days (from day 2 to day 8 of neuronal differentiation). Cell viability on day 8 was not affected by exposure to 1 nM MeHg for 6 days. mRNA levels of AADC , DBH , TUJ1 , and SYN1 also were unaffected by MeHg exposure. In contrast, levels of TH , the rate-limiting enzyme for dopamine synthesis, were significantly decreased after MeHg exposure. Acetylated histone H3, acetylated histone H3 lysine 9, and tri-methyl histone H3 lysine 9 levels at the TH gene promoter were not altered by MeHg exposure. However, tri-methylation of histone H3 lysine 27 levels, related to transcriptional repression, were significantly increased at the TH gene promotor after MeHg exposure. In summary, MeHg exposure during neuronal differentiation led to epigenetic changes that repressed TH gene expression. This study provides useful insights into the toxicological mechanisms underlying the effects of developmental MeHg exposure during neuronal differentiation. Highlights The low level of methylmercury induces inhibitory epigenetic changes in LUHMES cells. Tyrosine hydroxylase is decreased by methylmercury in neuronal differentiation model. HistoneH3 lysine27 tri-methylation is increased in promoter of tyrosine hydroxylase.


  • 주제어

    Methylmercury .   Epigenetics .   Neuronal development .   Tyrosine hydroxylase .   LUHMES cell.  

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