Cadmium Induces Apoptosis in Pancreatic β-Cells through a Mitochondria-Dependent Pathway: The Role of Oxidative Stress-Mediated c-Jun N-Terminal Kinase Activation

Abstract

Cadmium (Cd), one of well-known highly toxic environmental and industrial pollutants, causes a number of adverse health effects and diseases in humans. The growing epidemiological studies have suggested a possible link between Cd exposure and diabetes mellitus (DM). However, the toxicological effects and underlying mechanisms of Cd-induced pancreatic β-cell injury are still unknown. In this study, we found that Cd significantly decreased cell viability, and increased sub-G1 hypodiploid cells and annexin V-Cy3 binding in pancreatic β-cell-derived RIN-m5F cells. Cd also increased intracellular reactive oxygen species (ROS) generation and malondialdehyde (MDA) production and induced mitochondrial dysfunction (the loss of mitochondrial membrane potential (MMP) and the increase of cytosolic cytochrome c release), the decreased Bcl-2 expression, increased p53 expression, poly (ADP-ribose) polymerase (PARP) cleavage, and caspase cascades, which accompanied with intracellular Cd accumulation. Pretreatment with the antioxidant N-acetylcysteine (NAC) effectively reversed these Cd-induced events. Furthermore, exposure to Cd induced the phosphorylations of c-jun N-terminal kinases (JNK), extracellular signal-regulated kinases (ERK)1/2, and p38-mitogen-activated protein kinase (MAPK), which was prevented by NAC. Additionally, the specific JNK inhibitor SP600125 or JNK-specific small interference RNA (si-RNA) transfection suppressed Cd-induced β-cell apoptosis and related signals, but not ERK1/2 and p38-MAPK inhibitors (PD98059 and SB203580) did not. However, the JNK inhibitor or JNK-specific si-RNA did not suppress ROS generation in Cd-treated cells. These results indicate that Cd induces pancreatic β-cell death via an oxidative stress downstream-mediated JNK activation-triggered mitochondria-regulated apoptotic pathway.

Effect of Curcuma Longa Supplementation on Lipid Peroxidation, Serum Amylase, Lipase Activites in Mice Exposed to Cadmium.

“…Similar results were observed by (Chang et al, 2013) and they observed that cadmium also increased intracellular reactive oxygen species (ROS) generation and malondialdehyde (MDA) production and induced mitochondrial dysfunction in pancreatic β-cells.…”

Protective Effect of Montelukast against Cadmium Induced Pituitary Gland Toxicity

“…This finding appeared from both microscopic examinations of immunohistologically stained sections and AI calculation. The apoptotic effect of Cd was reported by different authors on pituitary gland [32,33] and other tissues [34][35][36].…”

Blood cadmium in Chinese adults and its relationships with diabetes and obesity

“…A deterioration of β cell function may happen once a certain toxic cadmium level is exceeded. It has also been found that cadmium may induce hyperglycemia, alter lipid metabolism (Trevino et al 2015) and induce apoptosis in pancreatic β cells (Chang et al 2013). One previous study observed a reduction of serum insulin level in cadmium exposure rats (Edwards and Prozialeck 2009).…”