title: Inorganic mercury causes pancreatic beta-cell death via the oxidative stress-induced apoptotic and necrotic pathways.
abstract: Mercury is a well-known highly toxic metal. In this study, we characterize and investigate the cytotoxicity and its possible mechanisms of inorganic mercury in pancreatic beta-cells. Mercury chloride (HgCl2) dose-dependently decreased the function of insulin secretion and cell viability in pancreatic beta-cell-derived HIT-T15 cells and isolated mouse pancreatic islets. HgCl2 significantly increased ROS formation in HIT-T15 cells. Antioxidant N-acetylcysteine effectively reversed HgCl2-induced insulin secretion dysfunction in HIT-T15 cells and isolated mouse pancreatic islets. Moreover, HgCl2 increased sub-G1 hypodiploids and annexin-V binding in HIT-T15 cells, indicating that HgCl2 possessed ability in apoptosis induction. HgCl2 also displayed several features of mitochondria-dependent apoptotic signals including disruption of the mitochondrial membrane potential, increase of mitochondrial cytochrome c release and activations of poly (ADP-ribose) polymerase (PARP) and caspase 3. Exposure of HIT-T15 cells to HgCl2 could significantly increase both apoptotic and necrotic cell populations by acridine orange/ethidium bromide dual staining. Meanwhile, HgCl2 could also trigger the depletion of intracellular ATP levels and increase the LDH release from HIT-T15 cells. These HgCl2-induced cell death-related signals could be significantly reversed by N-acetylcysteine. The intracellular mercury levels were markedly elevated in HgCl2-treated HIT-T15 cells. Taken together, these results suggest that HgCl2-induced oxidative stress causes pancreatic beta-cell dysfunction and cytotoxicity involved the co-existence of apoptotic and necrotic cell death.
authors.affiliation: Department of Physiology and Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Ya Wen
authors.initials: YW
authors.lastname: Chen
authors.forename: Chun Fa
authors.initials: CF
authors.lastname: Huang
authors.forename: Ching Yao
authors.initials: CY
authors.lastname: Yang
authors.forename: Cheng Chieh
authors.initials: CC
authors.lastname: Yen
authors.forename: Keh Sung
authors.initials: KS
authors.lastname: Tsai
authors.forename: Shing Hwa
authors.initials: SH
authors.lastname: Liu
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002469:Cell Separation; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D005434:Flow Cytometry; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008627:Mercuric Chloride / Q000633:toxicity*; D051379:Mice; D051336:Mitochondrial Membranes / Q000187:drug effects; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000975:Antioxidants; D007328:Insulin; D017382:Reactive Oxygen Species; D008627:Mercuric Chloride; D000255:Adenosine Triphosphate; D004247:DNA; D007770:L-Lactate Dehydrogenase; D000111:Acetylcysteine