Exposure to a low concentration of methylmercury in neural differentiation downregulates NR4A1 expression with altered epigenetic modifications and inhibits neuronal spike activity in vitro

• Published in: Toxicology letters 2023-02, Vol.374, p.68-76
• Main Authors: Go, Suzuna, Masuda, Haruka, Tsuru, Mizuki, Inden, Masatoshi, Hozumi, Isao, Kurita, Hisaka
• Format: Article
• Language: English
• Subjects: DNA methylation; Epigenetics; Histone modification; Methylmercury; Neuronal spike activity; Nuclear receptor subfamily 4 group A member 1
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2022.12.010

Methylmercury (MeHg) is a well-known developmental neurotoxin. Our previous research showed that the inhibition of neurite extension by exposure to a low level of MeHg (1 nM) was attributed to the decrease of acetylation of histone H3 and the increase of DNA methylation. However, the target molecules responsible for the neurological dysfunctions caused by MeHg exposure have not been identified. This study focused on a nuclear receptor subfamily 4 group A member 1 (NR4A1), which is reported to be related to synaptic plasticity and neurite extension. LUHMES cells, which are derived from human fetal brain, were treated with 0.1 and 1 nM MeHg beginning at two days of differentiation and continued for 6 consecutive days. The present study showed that exposure to a 1 nM MeHg during neural differentiation inhibited neuronal spike activity and neurite extension. Furthermore, MeHg exposure increased DNA methylation, and altered histone modifications for transcriptional repression in the NR4A1 promoter region to decrease the levels of NR4A1 expression. In addition, MeHg exposure inhibited the mobilization of cAMP response element-binding protein (CREB) and CREB binding protein (CBP) in the NR4A1 promoter region. These results suggest that MeHg inhibits the recruitment of the CREB-CBP complex to the NR4A1 promoter region and impairs neuronal functions associated with NR4A1 repression via a decrease in acetylation of histone H3 lysine 14 levels. Conclusively, this study demonstrated that MeHg exposure during neuronal differentiation could induce neurological dysfunctions even at a low concentration in vitro. These dysfunctions could be associated with the transcriptional repression of NR4A1 by the dissociation of CREB and CBP from the NR4A1 promoter region due to the alterations of epigenetic modifications. [Display omitted] •Methylmercury exposure during development inhibited neuronal spike activity.•Methylmercury exposure during neural differentiation reduced NR4A1 expression.•Acetylation of HistoneH3 lysine14 in the promoter region of NR4A1 was decreased.•Methylmercury inhibited CREB-CBP complex binding in the NR4A1 promoter region.