Hexavalent Chromium Induces Apoptosis and Autophagy in Human Neurons and Astrocytes via MAPK Pathway Activation

Abstract

Hexavalent chromium (Cr[VI]), one of the major heavy metals in fine particulate matter (PM<inf>2.5</inf>), has been linked to increased risks of neurological impairment and brain cancer. However, the direct effect of Cr(VI) on brain cells remains unclear. In this study, we investigated the cell type–specific cytotoxicity of Cr(VI) at environmentally relevant concentrations to cultured human neurons and astrocytes. Our findings showed that higher concentrations of Cr(VI) were required to induce cell death in human astrocytes (IC<inf>50</inf> of 32.05 µM at 24 h) than in the human neurons (IC<inf>50</inf> of 24.55 µM at 24 h). The neurotoxicity effects associated with elevated intracellular chromium levels included DNA damage (decreased poly[ADP–ribose] polymerase expression), mitochondria-mediated apoptosis (increased caspase 3/7 activation), and autophagy (increased light chain 3 [LC3]–II to LC3–I levels accompanied by decreased p62 expression). Activation of the MAPK signalling pathway triggered Cr(VI) –induced brain death. Furthermore, Cr(VI) exposure induced S–phase accumulation in U-87 MG cells by altering cell cycle–related protein expression, specifically by upregulating CDK inhibitors (p21, p27, and p53) and downregulating cyclin B, cyclin D, and CDK4. Together, these findings demonstrate that the mechanisms underlying Cr(VI)-induced neurotoxicity were similar between the two cell types and further highlight the importance of increased awareness of chromium pollution and its impact on human health.