Cortical Astrocytes Acutely Exposed to the Monomethylarsonous Acid (MMA^III) Show Increased Pro-inflammatory Cytokines...

Long-term exposure to inorganic arsenic (iAs) through drinking water has been associated with cognitive impairment in children and adults; however, the related pathogenic mechanisms have not been completely described. Increased or chronic inflammation in the brain is linked to impaired cognition and neurodegeneration; iAs induces strong inflammatory responses in several cells, but this effect has been poorly evaluated in central nervous system (CNS) cells. Because astrocytes are the most abundant cells in the CNS and play a critical role in brain homeostasis, including regulation of the inflammatory response, any functional impairment in them can be deleterious for the brain. We propose that iAs could induce cognitive impairment through inflammatory response activation in astrocytes. In the present work, rat cortical astrocytes were acutely exposed in vitro to the monomethylated metabolite of iAs (MMA^III), which accumulates in glial cells without compromising cell viability. MMA^III LD₅₀ in astrocytes was 10.52 μM, however, exposure to sub-toxic MMA^III concentrations (50-1000 nM) significantly increased IL-1β, IL-6, TNF-α, COX-2, and MIF-1 gene expression. These effects were consistent with amyloid precursor protein (APP) and β-secretase (BACE-1) increased gene expression, mainly for those MMA^III concentrations that also induced TNF-α over-expression. Other effects of MMA^III on cortical astrocytes included increased proliferative and metabolic activity. All tested MMA^III concentrations led to an inhibition of intracellular lactate dehydrogenase (LDH) activity. Results suggest that MMA^III induces important metabolic and functional changes in astrocytes that may affect brain homeostasis and that inflammation may play a major role in cognitive impairment-related pathogenicity in As-exposed populations.