Abstract
Exposure to toxic metals and metalloids is an important cause of preventable diseases worldwide. Inorganic arsenic (iAs) affects several organs and tissues, causing neurobehavioral alterations in the central nervous system (CNS) that might lead to neurodegeneration. In this work, we wanted to explore the time- and dose-related changes on glutathione (GSH) levels in several regions of the CNS, such as the cortex, striatum, hippocampus, and cerebellum, to identify the initial cellular changes associated to GSH depletion due to iAs exposure. Mice received a single intraperitoneal injection containing 5 or 14 mg/kg sodium arsenite. Animals were killed at 2, 6, and 24 h. Significant depletion of GSH levels was observed in the cortex at 2 and 6 h, while on the striatum, hippocampus, or cerebellum regions, no significant changes were observed. GSH depletion in the cortex was associated with the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NFκB) pathways, which led to the upregulation of xCT, excitatory amino acid carrier 1 (EAAC1), glutamate/aspartate transporter (GLAST), and glial glutamate transporter 1 (GLT-1), and the activation of the transsulfuration pathways, which led to the overproduction of H2S in the cortex and increased levels of GSH in the cortex and cerebellum at 24 h. In the cortex, the N-methyl-D-aspartate (NMDA) receptor subunits NR2A and NR2B were also altered at 24 h. These early effects were not homogeneous among different brain regions and indicate early neurotoxic alterations in the cortex and cerebellum.
Highlights
Improvements in the quality of life of humans is reflected in the increase in our life span; environmental pollution continues to be the largest cause of disease and premature death worldwide (Landrigan et al, 2018)
GSH Levels in the Cortex, Striatum, and Cerebellum Are Affected by inorganic arsenic (iAs)
Significantly decreased levels of GSH were observed in the brain cortex region at 2 and 6 h for both doses of iAs and at 24 h in the animals treated with the highest dose (Figures 1A–C), while animals treated with 5 mg/kg showed upregulated GSH synthesis at 24 h (Figure 1C) in both the cortex, striatum, and cerebellum, suggesting that GSH was actively synthesized in these regions at that time
Summary
Improvements in the quality of life of humans is reflected in the increase in our life span; environmental pollution continues to be the largest cause of disease and premature death worldwide (Landrigan et al, 2018). In children exposed to iAs concentrations ranging from 5 to 50 ppb in drinking water, neurobehavioral alterations such as impaired cognitive functions, verbal abilities, and long-term memory, and decreased motor skills have been reported (Calderón et al, 2001; Parvez et al, 2011). It is not clear when the initial effects are observed in the central nervous system (CNS; Garza-Lombó et al, 2019)
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