Early Neurotoxic Effects of Inorganic Arsenic Modulate Cortical GSH Levels Associated With the Activation of the Nrf2 and NFκB Pathways, Expression of Amino Acid Transporters and NMDA Receptors and the Production of Hydrogen Sulfide

• Published in: Frontiers in cellular neuroscience Vol. 14; p. 17
• Main Authors: Silva-Adaya, Daniela, Ramos-Chávez, Lucio Antonio, Petrosyan, Pavel, González-Alfonso, Wendy Leslie, Pérez-Acosta, Alegna, Gonsebatt, Maria E
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 25.02.2020; Frontiers Media S.A
• Subjects: Amino acids; Arsenic; Arsenite; Brain; Cellular Neuroscience; Central nervous system; Cerebellum; Cerebral cortex; CNS cysteine/glutamate transporters; Drinking water; Excitatory amino acid transporters; Glutamic acid receptors (ionotropic); GSH; H2S; Heavy metals; Hippocampus; Hydrogen sulfide; Immunoglobulins; Laboratory animals; Memory; N-Methyl-D-aspartic acid receptors; Neostriatum; Neurodegeneration; Neurotoxicity; NF-κB protein; NFκB; Nrf2; Sodium arsenite; United States > US; H2S; NFκB; arsenic; Nrf2; GSH; CNS cysteine/glutamate transporters
• DOI: 10.3389/fncel.2020.00017
• ISSN: 1662-5102

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 H S in the cortex and increased levels of GSH in the cortex and cerebellum at 24 h. In the cortex, the -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.