Inorganic mercury causes pancreatic beta-cell death via the oxidative stress-induced apoptotic and necrotic pathways

Toxicol Appl Pharmacol. 2010 Mar 15;243(3):323-31. doi: 10.1016/j.taap.2009.11.024. Epub 2009 Dec 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Adenosine Triphosphate / metabolism
  • Animals
  • Antioxidants / pharmacology
  • Apoptosis / drug effects*
  • Blotting, Western
  • Cell Death / drug effects
  • Cell Line
  • Cell Separation
  • Cricetinae
  • DNA / biosynthesis
  • DNA / genetics
  • Flow Cytometry
  • Insulin / metabolism
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • L-Lactate Dehydrogenase / metabolism
  • Mercuric Chloride / toxicity*
  • Mice
  • Mitochondrial Membranes / drug effects
  • Necrosis
  • Oxidative Stress / drug effects*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects

Substances

  • Antioxidants
  • Insulin
  • Reactive Oxygen Species
  • Mercuric Chloride
  • Adenosine Triphosphate
  • DNA
  • L-Lactate Dehydrogenase
  • Acetylcysteine