Cadmium (Cd) is accumulated in human astrocytes and induces the production of interleukin (IL)-6 and IL-8. Astrocytes are one of the major sources of chemokine CC motif ligand 2 (CCL2; known as monocyte chemoattractant protein-1 [MCP-1]), in the brain. Elevated CCL2 levels are associated with cognitive impairment as well as the migration and invasion of glioblastoma cells. The present study hypothesized that non-toxic concentrations of Cd (as cadmium chloride [CdCl 2 ]) could up-regulate CCL2 production in U-87 MG human glio-blastoma cells. The results showed that after exposure of the U-87 MG cells to CdCl 2 at 1 and 10 mM, there was an up-regulation of CCL2 mRNA expression after 3 h of exposure and increased CCL2 secretion after 6 and 24 h. The study also found that inhibition of MAPK pathways, including ERK1/ 2, p38, and JNK by U0126, SB203580 and SP600125, respectively, reduced Cd-induced CCL2 secretion by the cells. Moreover, when cells were pretreated with Ro 32-0432 (an inhibitor of calcium-dependent PKC) and LY294002 (a PI3K inhibitor), this also resulted in a down-regulation of any Cd-induced CCL2 expression. Taken together, the results of this study allow for the conclusion to be made that CCL2 up-regulation in U-87 MG cells induced by Cd is mediated, in part, by an activation of MAPK, PI3K/Akt, and PKC pathways.

Nickel, a heavy metal found in electronic wastes and fume from electronic cigarettes, induces neuronal cell death and is associated with neurocognitive impairment. Astrocytes are the first line of defense against nickel after entering the brain; however, the effects of nickel on astrocytes remain unknown. Herein, we investigated the effect of nickel exposure on cell survival and proliferation and the underlying mechanisms in U-87 MG human astrocytoma cells and primary human astrocytes. Intracellular nickel levels were elevated in U-87 MG cells in a dose- and time-dependent manner after exposure to nickel chloride. The median toxic concentrations of nickel in astrocytoma cells and primary human astrocytes were 600.60 and >1000 µM at 48 h post-exposure, respectively. Nickel exposure triggered apoptosis in concomitant with the decreased expression of anti-apoptotic B-cell lymphoma protein (Bcl-2) and increased caspase-3/7 activity. Nickel induced reactive oxygen species formation. Additionally, nickel suppressed astrocyte proliferation in a dose- and time-dependent manner by delaying G2 to M phase transition through the upregulation of cyclin B1 and p27 protein expression. These results indicate that nickel-induced cytotoxicity of astrocytes is mediated by the activation of apoptotic pathway and disruption of cell cycle regulation.

Background: Nowadays heavy metal toxicity remains one of world public health concern. In addition to systemic toxicity, heavy metals are toxic to the central nervous system (CNS). Manganese induced Parkinson's like symptoms. Cadmium is associated with Alzheimer's disease and learning disability. Excessive copper is linked with Alzheimer's disease, Parkinson's disease and Wilson's disease. Intrathecal injection of magnesium also leads to neurodegeneration. Astrocytes are major glial cells in the CNS. In addition to their neuronal supportive roles, astrocytes also play an important role in neuroinflammation by releasing various cytokines and chemokines. Manganese and cadmium induced interleukin-6 and interleukin-8 release from astrocytes. C-C motif ligand 2 (CCL2), also known as monocyte chemoattractant protein 1 (MCP1), is a major chemokine released by astrocytes. CCL2 plays a role in the pathogenesis of Alzheimer's disease, HIVassociated dementia, multiple sclerosis, and ischemic brain injury. This study aims to compare the effects of several heavy metals including cadmium, copper, magnesium, manganese and nickel on CCL2 release from astrocytes. Method: U-87 MG cells were exposed to heavy metals at 10 µM for 24 hours and CCL2 levels in supernatant were measured by ELISAs. Results: CCL2 levels of cells treated with cadmium chloride and manganese chloride were 550% and 140% compared to mock-treated cells. Copper sulfate, magnesium chloride and nickel chloride at 10 µM have no effect on CCL2 expression. Cadmium chloride at 1 µM also induced CCL2 release by 3 folds. Because cadmium chloride at does higher than 10 µM was toxic to human astrocytes, the maximum test dose for cadmium is 10 µM. Manganese chloride at 100 µM also increased CCL2 release similar to 10 µM. Conclusion: Cadmium has the highest stimulative effect on CCL2 release. The increased CCL2 levels could explain the association of cadmium and dementia. The reduction of CCL2 levels could be beneficial to reduce CNS toxicity by cadmium and manganese.