Inorganic mercury causes pancreatic beta-cell death via the oxidative stress-induced apoptotic and necrotic pathways.
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.
Chen
Ya Wen
YW
Department of Physiology and Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.
Huang
Chun Fa
CF
Yang
Ching Yao
CY
Yen
Cheng Chieh
CC
Tsai
Keh Sung
KS
Liu
Shing Hwa
SH
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
D000975:Antioxidants; D007328:Insulin; D017382:Reactive Oxygen Species; D008627:Mercuric Chloride; D000255:Adenosine Triphosphate; D004247:DNA; D007770:L-Lactate Dehydrogenase; D000111:Acetylcysteine