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

Abstract

Homeobox protein B13 (HOXB13), a transcription factor, is related to methylmercury toxicity; however, the downstream factors involved in enhancing methylmercury toxicity remain unknown. We performed microarray analysis to search for downstream factors whose expression is induced by methylmercury via HOXB13 in human embryonic kidney cells (HEK293), which are useful model cells for analyzing molecular mechanisms. Methylmercury induced the expression of oncostatin M (OSM), a cytokine of the interleukin-6 family, and this was markedly suppressed by HOXB13 knockdown. OSM knockdown also conferred resistance to methylmercury in HEK293 cells, and no added methylmercury resistance was observed when both HOXB13 and OSM were knocked down. Binding of HOXB13 to the OSM gene promoter was increased by methylmercury, indicating the involvement of HOXB13 in the enhancement of its toxicity. Because addition of recombinant OSM to the medium enhanced methylmercury toxicity in OSM-knockdown cells, extracellularly released OSM was believed to enhance methylmercury toxicity via membrane receptors. We discovered tumor necrosis factor receptor (TNF) receptor 3 (TNFR3) to be a potential candidate involved in the enhancement of methylmercury toxicity by OSM. This toxicity mechanism was also confirmed in mouse neuronal stem cells. We report, for the first time, that HOXB13 is involved in enhancement of methylmercury toxicity via OSM-expression induction and that the synthesized OSM causes cell death by binding to TNFR3 extracellularly.

Antioxidant Supplementation Alleviates Mercury-Induced Cytotoxicity and Restores the Implantation-Related Functions of Primary Human Endometrial Cells

“…The effects of Hg have been studied in multiple cell lines and animal models [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]; however, evidence regarding primary cells remains scarce. To address this research gap within the context of female reproduction, the extent of Hg-induced damage on endometrial cells' viability and function using primary cultures of human endometrial cells were investigated in this research.…”

Methylmercury Induces Apoptosis in Mouse C17.2 Neural Stem Cells through the Induction of OSGIN1 Expression by NRF2

“…We first examined OSGIN1 gene expression under conditions of exposure to methylmercury at a concentration that is minimally cytotoxic to C17.2 cells. Further, the concentrations and times of methylmercury exposure were based on the results of previous studies [13,15,16] and preliminary experiments to evaluate methylmercury-induced apoptosis (Figure S1). As a result, exposure to methylmercury at a final concentration of 6 µM increased OSGIN1 mRNA levels, with the maximum peak in particular being observed after 8 h of exposure (Figure 1A).…”

“…We comprehensively searched for intracellular factors involved in methylmercury toxicity using various search tools, and identified tumor necrosis factor α [12], homeobox B13 [13], and other factors involved in enhancing methylmercury toxicity. In contrast, we also reported that chemokine ligand 3 [14], ornithine decarboxylase 1 (ODC1) [15,16], transcription factor 3 [17], and other factors are involved in reducing methylmercury toxicity.…”

Knockdown of deubiquitinating enzyme Usp34 confers resistance to methylmercury in HEK293 cells

“…More than 60 years have passed since the discovery of Minamata disease after a large population was afflicted with the disease after ingestion of large amounts of methylmercury (Al-Ardhi and Al-Ani, 2008;Sheehan et al, 2014), but the mechanisms involved in its toxicity remain unclear. We have previously reported that there are many proteins involved in methylmercury toxicity and that the intracellular levels of some of them are regulated by the ubiquitin-proteasome (UP) system (Hwang et al, 2002;Lee et al, 2020;Toyama et al, 2021Toyama et al, , 2020. Therefore, the UP system might play an important role in determining the sensitivity of cells to methylmercury toxicity.…”