Methylmercury induces caspase-dependent apoptosis and autophagy in human neural stem cells

Abstract

Methylmercury (MeHg) is a well-known human neurotoxic agent whose exposure sources are mainly environmental and aquatic-derived food. MeHg is reported to induce central nervous system disability. However, the exact mechanism of MeHg-induced neurotoxicity is still unknown. In this study, to investigate which cell death signaling pathway is related with MeHg-induced cytotoxicity, the effects of MeHg on apoptosis and autophagy were evaluated in HB1.F3 human neural stem cells (NSCs). Human NSCs were treated with 1 μM of MeHg for 48 hr and the effect of MeHg on cell signaling pathway was elucidated. MeHg inhibited Akt1/mTOR signaling that led to induction of caspase-dependent apoptosis and autophagy in the NSCs. Furthermore, retinoic acid (RA)-induced neuronal differentiation was inhibited by MeHg. Taken together, these results suggest that MeHg inhibits the differentiation of human NSCs by induction of caspase-dependent apoptosis and autophagy.

Hydroxytyrosol, a dietary phenolic compound forestalls the toxic effects of methylmercury-induced toxicity in IMR-32 human neuroblastoma cells

“…In our study, only MeHg showed cytotoxic and growth‐inhibitory effects on IMR‐32 cells in a time‐ and concentration‐dependent manner, which has also been demonstrated in previous studies using various in vitro models (Chang et al, ; Petroni et al, ). The cells exposed to HT did not show any alteration in cell viability, which is supported by a previous report (Zhu et al, ) wherein human retinal pigment epithelial cells were used as an in vitro model to study the protective efficacy of HT against oxidative stress.…”

Role of autophagy in methylmercury-induced neurotoxicity in rat primary astrocytes

“…The fact that autophagy in neonatal rat primary astrocytes is activated by MeHg is thus not surprising. Induction of both autophagy and apoptosis by MeHg has been described in human neural stem cells via the AKT-mTOR pathway and caspase-dependent apoptosis (Chang et al 2013). In addition, inorganic mercury has been shown to induce autophagy in rat hepatocytes treated in vitro (Chatterjee et al 2012, 2013).…”

Sensitivity of neural stem cell survival, differentiation and neurite outgrowth within 3D hydrogels to environmental heavy metals

“…Similarly, 1 μM CH 3 Hg was shown to inhibit retinoic acid induced neural differentiation within human NSCs over a 48 h culture period, via induction of caspase-dependent apoptosis (Chang et al, 2013). Single doses of CH 3 Hg (2.5 or 5 nM) drastically inhibited neuronal differentiation of primary embryonic rat cortical NSCs (bFGF omission, 120 h culture) (Tamm et al, 2006), compared to controls under similar conditions.…”

“…On the other hand, methylmercury induced caspase-dependent apoptosis and autophagy in human NSCs within 48 h exposure at 1 μM dosage, via inhibition of Akt1/mTOR signaling (Chang et al, 2013). Although cadmium, methylmercury or lead did not activate caspase 3 or p53 (indicators of apoptosis) in human fetal cortex neuroprogenitor cells, exposure to cadmium or methylmercury doubled apoptotic cells within embryonic mouse cortical NSCs (Culbreth et al, 2012).…”

“…A few recent studies investigated the toxic effects of cadmium, mercury or lead on NSC and neural progenitor cell (NPC) viability, proliferation, migration, and differentiation into various neural and glial lineages (Bose et al, 2012; Buzanska et al, 2009; Cedrola et al, 2003; Chang et al, 2013; Gulisano et al, 2009; Guo et al, 2013; Huang and Schneider, 2004; Kermani et al, 2008; Moors et al, 2009; Tamm et al, 2006; Watanabe et al, 2013; Xu et al, 2010). Some of these reports also identified the mechanisms and signaling pathways underlying the metal ion induced toxicity, leading to apoptosis and cell death.…”