Chemical modulation of endoplasmic reticulum stress-mediated apoptosis by MeHg exposure <i>in vivo</i>

<p> Methylmercury (MeHg) causes severe CNS disorders such as Minamata disease. However, the molecular mechanisms underlying MeHg-induced neurotoxicity remain unclear. We previously reported that MeHg induces endoplasmic reticulum (ER) stress and activates the unfolded protein response (UPR). Here, to identify the negative role of ER stress in MeHg toxicity, we investigated the signaling alternations of ER stress-mediated apoptosis pathway by MeHg exposure in vivo and tested the effects of 4-phenylbutyric acid (4-PBA), a chemical chaperone, against MeHg toxicity. </p><p> Mice carrying an ER stress activation indicator (ERAI), whose expression is induced under ER stress, were exposed to MeHg via drinking water. We performed immunofluorescence and TUNEL staining of the brain sections and observed ER stress/UPR activation and apoptosis, respectively. </p><p> Simultaneously with an increase of ERAI-positive cells, the phosphorylation of IRE1α and PERK was enhanced by MeHg exposure. These increases in ER-stress indicators were followed by an increase in CHOP-positive cells, a key driver of ER stress-mediated apoptosis. By contrast, the administration of 4-PBA significantly suppressed ERAI-positive cells as well as p-IRE1α and p-PERK-positive cells. Most importantly, 4-PBA also significantly suppressed CHOP-positive cells and TUNEL-positive cells. </p><p> The ER stress-mediated apoptosis pathway may play a critical role in neuronal cell death by MeHg exposure in vivo. Chemical chaperones such as 4-PBA may be a potential therapeutic approach for MeHg poisoning.</p>