Calcium Signaling Involvement in Cadmium-Induced Astrocyte Cytotoxicity and Cell Death Through Activation of MAPK and PI3K/Akt Signaling Pathways

Abstract

Cadmium (Cd), a highly ubiquitous toxic heavy metal, can contaminate the environment, including agricultural soil, water and air, via industrial runoff and other sources of pollution. Cd accumulated in the body via direct exposure or through the food chain results in neurodegeneration and many other diseases. Previous studies on its toxicity in the central nervous system (CNS) focused mainly on neurons. To obtain a more comprehensive understanding of Cd toxicity for the CNS, we investigated how astrocytes respond to acute and chronic Cd exposure and its toxic molecular mechanisms. When primary cultures of cerebral cortical astrocytes incubated with 1-300 μM CdCl2, morphological changes, LDH release and cell death were observed in a time and dose-dependent manner. Further studies demonstrated that acute and chronic Cd treatment phosphorylated JNK, p38 and Akt to different degrees, while ERK1/2 was only phosphorylated under low doses of Cd (10 μM) exposure. Inhibition of JNK and PI3K/Akt, but not of p38, could partially protect astrocyte from cytotoxicity in chronic and acute Cd exposure. Moreover, Cd also induced a strong calcium signal, while BAPTA, a specific intracellular calcium (Ca(2+)) chelator, prevented Cd-induced intracellular increase of calcium levels in astrocytes; inhibited the Cd-induced activation of ERK1/2, JNK, p38 and Akt; and also significantly reduced astrocyte cell death. All of these results suggested that the Cd-Ca(2+)-MAPK and PI3K/Akt signaling pathways were involved in Cd-induced toxicity in astrocytes. This toxicity involvement indicates that these pathways may be exploited as a target for the prevention of Cd-induced neurodegenerative diseases.

Modelling cadmium‐induced cardiotoxicity using human pluripotent stem cell‐derived cardiomyocytes

“…We first sought to determine whether cadmium can induce morphological changes and cell death in H9‐CMs. Previous studies have investigated cadmium‐induced cytotoxicity in different cell types within a range of 0‐300 μmol/L . Therefore, cells were exposed to escalating concentrations of cadmium chloride (CdCl 2 ) from 0.1 to 100 μmol/L for 24 hours, and significantly morphological changes appeared in cells treated with 30 and 100 μmol/L CdCl 2 (Videos ).…”

“…To relate changes in gene expression to functional consequences, we next investigated MAPK signalling pathway, which was associated with cadmium‐induced apoptosis of several cell types in previous studies and was dramatically up‐regulated in CdCl 2 ‐treated H9‐CMs …”

Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases

“…In a study using hippocampal slides of CA1 neurons, cadmium was shown to affect synaptic transmission and short-term neural plasticity [150]. In another cell study using PC12 and SH-SY5Y cells, cadmium induced cell apoptosis [151,152]. Animal models have shown cadmium to affect different aspects of brain health.…”

Cadmium induces actin cytoskeleton alterations and dysfunction in Neuro‐2a cells

“…Among the various Cd‐related diseases, the nephrotoxicity has been widely studied and well‐illustrated . However, in recent years, the neurotoxicity of Cd has been reported, which attract a growing number of attention . After being absorbed into the bloodstream, Cd can destroy the structural integrity of the blood‐brain barrier, allowing Cd to enter and accumulate in the brain .…”