title: Methylmercury upregulates RE-1 silencing transcription factor (REST) in SH-SY5Y cells and mouse cerebellum.
abstract: Methylmercury (MeHg) is a highly neurotoxic compound that, in adequate doses, can cause damage to the brain, including developmental defects and in severe cases cell death. The RE-1-silencing transcription factor (REST) has been found to be involved in the neurotoxic effects of environmental pollutants such as polychlorinated biphenyls (PCBs). In this study, we investigated the effects of MeHg treatment on REST expression and its role in MeHg-induced neurotoxicity in neuroblastoma SH-SY5Y cells. We found that MeHg exposure caused a dose- and time- dependent apoptotic cell death, as evidenced by the appearance of apoptotic hallmarks including caspase-3 processing and annexin V uptake. Moreover, MeHg increased REST gene and gene product expression. MeHg-induced apoptotic cell death was completely abolished by REST knockdown. Interestingly, MeHg (1μM/24h) increased the expression of REST Corepressor (Co-REST) and its binding with REST whereas the other REST cofactor mammalian SIN3 homolog A transcription regulator (mSin3A) was not modified. In addition, we demonstrated that the acetylation of histone protein H4 was reduced after MeHg treatment and was critical for MeHg-induced apoptosis. Accordingly, the pan-histone deacetylase inhibitor trichostatin-A (TSA) prevented MeHg-induced histone protein H4 deacetylation, thereby reverting MeHg-induced neurotoxic effect. Male mice subcutaneously injected with 10mg/kg of MeHg for 10 days showed an increase in REST expression in the granule cell layer of the cerebellum together with a decrease in histone H4 acetylation. Collectively, we demonstrated that methylmercury exposure can cause neurotoxicity by activating REST gene expression and H4 deacetylation.
authors.affiliation: IRCSS SDN, Naples 80131, Italy.
authors.forename: Natascia
authors.initials: N
authors.lastname: Guida
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy.
authors.forename: Giusy
authors.initials: G
authors.lastname: Laudati
authors.affiliation: IRCSS SDN, Naples 80131, Italy.
authors.forename: Serenella
authors.initials: S
authors.lastname: Anzilotti
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Sirabella
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Cuomo
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Brancaccio
authors.affiliation: Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II" Napoli, 80131, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Santopaolo
authors.affiliation: Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli, 80131, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Galgani
authors.affiliation: Department of Preventive Medical Sciences, University Federico II, Via Pansini 5, 80131 Naples, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Montuori
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Di Renzo
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy; Division of Pharmacology, Department of Science and Technology, University of Sannio, 82100 Benevento, Italy.
authors.forename: Lorella M T
authors.initials: LM
authors.lastname: Canzoniero
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, "Federico II" University of Naples, Naples 80131, Italy; Division of Pharmacology, Department of Science and Technology, University of Sannio, 82100 Benevento, Italy. Electronic address: cformisa@unisannio.it.
authors.forename: Luigi
authors.initials: L
authors.lastname: Formisano
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D056970:Co-Repressor Proteins / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D008297:Male; D008767:Methylmercury Compounds / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D012097:Repressor Proteins / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D056970:Co-Repressor Proteins; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D008767:Methylmercury Compounds; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C004925:methylmercuric chloride
keywords: Acetylation; Cerebellum; Methylmercury; REST