Methylmercury induces the expression of TNF-α selectively in the brain of mice

Abstract

Methylmercury selectively damages the central nervous system (CNS). The tumor necrosis factor (TNF) superfamily includes representative cytokines that participate in the inflammatory response as well as cell survival, and apoptosis. In this study, we found that administration of methylmercury selectively induced TNF-α expression in the brain of mice. Although the accumulated mercury concentration in the liver and kidneys was greater than in the brain, TNF-α expression was induced to a greater extent in brain. Thus, it is possible that there may exist a selective mechanism by which methylmercury induces TNF-α expression in the brain. We also found that TNF-α expression was induced by methylmercury in C17.2 cells (mouse neural stem cells) and NF-κB may participate as a transcription factor in that induction. Further, we showed that the addition of TNF-α antagonist (WP9QY) reduced the toxicity of methylmercury to C17.2 cells. In contrast, the addition of recombinant TNF-α to the culture medium decreased the cell viability. We suggest that TNF-α may play a part in the selective damage of the CNS by methylmercury. Furthermore, our results indicate that the higher TNF-α expression induced by methylmercury maybe the cause of cell death, as TNF-α binds to its receptor after being released extracellularly.

The Nuclear Protein HOXB13 Enhances Methylmercury Toxicity by Inducing Oncostatin M and Promoting Its Binding to TNFR3 in Cultured Cells

“…Recent studies using mouse brain spheroid cultures have reported methylmercury-induced IL-6 in astrocytes to have a protective effect on the neurotoxicity caused by methylmercury [14]. However, our in vivo study using mice showed methylmercury induces the expression of tumor necrosis factor receptor (TNF)-α, IL-1β, and IL-19, but not IL-6, in the brain [15,16]. Therefore, the downstream factor that is induced by methylmercury via HOXB13 and is involved in methylmercury toxicity remains unknown.…”

“…The extracellularly released OSM is known to bind as a ligand to the OSM receptor (OSMR) or LIF receptor (LIFR) on the cell membrane [20,21]; however, knockdown of OSMR or/and LIFR did not affect methylmercury sensitivity ( Figure 5A,B). We have previously shown that addition of WP9QY, a peptide that mimics the ligand-binding site of the TNF receptor (TNFR), to the medium suppresses methylmercury toxicity [15]. Therefore, the effects of WP9QY on the enhancement of methylmercury toxicity via HOXB13 were examined.…”

“…Although methylmercury is an environmental pollutant that causes severe neuronal damage, the role of HOXB13, OSM, and TNFR3 in methylmercury toxicity to neuronal cells is still unknown. To date, we have used mouse neural stem cells, C17.2, as a model cell line to clarify the involvement of various inflammatory cytokines in methylmercury toxicity [15,[25][26][27][28]. When C17.2 cells were treated with methylmercury, OSM expression was induced in a time-dependent and dose-dependent manner ( Figure 7A), and this induction was suppressed by HOXB13 knockdown (Figure 7B,C).…”

Identification of transcription factors activated by methylmercury in mouse brain

“…We previously performed expression variation analysis of gene clusters in the brain tissue of mice that were administered methylmercury, and identified chemokines (CCL3 and CCL4) , secretoglobin (SCGB3A1) and tumor necrosis factor α (TNFα) (Iwai-Shimada et al, 2016) as genes whose expression were increased specifically in the brain in response to methylmercury. This suggests that there is a transcription mechanism that is activated by methylmercury specifically in the brain.…”

Evaluation of Protective Effect of Tageteserecta Against Mercuric Chloride Induced Nephrotoxicity

“…Inorganic mercury present in the environment is a well established toxicant to human health. On absorption through the alimentary tract, mercury binds with the thio proteins, which plays an important role in the further metabolism of this metal [1][2][3][4][5][6] . Historically, plants have been used as folk medicine against various types of diseases.…”