Sustained cadmium exposure and hyperglycemia additively drives mitochondrial dysfunction in hepatic cells:...

Effects of chronic heavy metal stress on hepatocellular pathophysiology remains ill-understood. Human livers are a long-term accumulative site for many toxic heavy metals (e.g., cadmium and arsenic) whose health effects are unknown. In the current study, we studied the effects of chronic, low-dose exposures of cadmium (CLEC) modulated by normoglycemic (5.6 mM) and diabetes relevant hyperglycemic (15 mM) exposures, focusing on hepatocellular mitochondrial function. Hepatocellular cell lines were exposed to CLEC and glucose for 24 weeks, mimicking a chronic heavy metal exposure paradigm of normal and type II diabetic individuals. CLEC exposures significantly affect the long-term health of mitochondria, including decreased mitochondrial mass, increased superoxide production, and loss of mitochondrial membrane potential (MMP) in a CLEC and glucose-dependent manner. Furthermore, CLEC induced significant chronic oxidative stress revealed by the Seahorse MitoStress assay. In particular, CLEC cells show altered levels of basal and non-mitochondrial respiration, causing dysregulation in mitochondrial oxygen consumption rates (OCRs) of the cells. Lastly, we identify significant impacts of CLEC and glucose exposures on mitochondrial dynamics (fission/fusion), which show enhanced mitochondrial fragmentation and turnover rates. We also identified novel cell compensatory mechanisms that may mask the true extent of chronic Cd exposure induced damage in liver cells. New approach methodologies (NAMs) such as the current toxicology study, establish the insidious, long-term damaging effects of chronic heavy metal pollutant exposures on human hepatocellular function.