Gestational exposure to inorganic arsenic (iAs3+) alters glutamate disposition in the mouse hippocampus and ionotropic glutamate receptor expression leading to memory impairment

Abstract

Early life exposure to environmental pollutants and toxic chemicals has been linked to learning and behavioral alterations in children. iAs exposure is associated with different types neurological disorders such as memory and learning impairment. iAs is methylated in the brain by the arsenic III-methyltransferase in a process that requires glutathione (GSH). The xCT-antiporter cell membrane transporter participates in the influx of cystine for GSH synthesis in exchange for glutamate in a 1:1 ratio. In CD-1 mice gestationally exposed to 20 ppm of sodium arsenite in drinking water, we have previously observed up-regulation of xCT in the male mouse hippocampus which caused glutamatergic synapse alterations affecting learning and memory processes. Here, we used the same gestational iAs exposure model to investigate whether the up-regulation of xCT and down-regulation of GLT-1 transporters were associated with higher levels of extracellular glutamate and changes in the expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor, responsible for excitatory fast synaptic transmission. The induction of LTP in the perforant-dentate gyrus pathway (PP-DG) of the hippocampus was also studied, as well as learning and memory formation using the water maze test. Changes in GSH levels were also tested in the hippocampus of animals exposed to iAs. Results showed increased GSH synthesis (p < 0.05), associated with significantly higher extracellular glutamate levels in iAs exposed mice. Exposure was also significantly associated with AMPA subunits down-regulation, deficient LTP induction, and lower excitability of the PP-DG pathway. In addition, animals showed deficient learning and memory in the Morris Water Maze test.

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

“…The AMPA receptor subunits GLUA1 and 2 were also tested, but we did not observe changes (data not shown). A similar observation was made by Nelson-Mora et al (2018) when AMPA modulation was reported at the hippocampus but not in the cortex of mice gestationally exposed to iAs.…”

“…Thus, we used lower doses to compare the early effects on GSH and amino acid transporters with those observed after a prolonged exposure. Similar to what has been observed in mice exposed during gestation, the augmentation of GSH levels in the brain was directly related to the expression of amino acid transporters involved in the import of cystine/cysteine for GSH synthesis, such as xCT in astrocytes and EAAC1 in neurons ( Figures 1A-D, 2A,B; Ramos-Chávez et al, 2015;Nelson-Mora et al, 2018). However, the upregulation of EACC1 was FIGURE 5 | Inorganic arsenic (iAs) effects on the messenger RNA (mRNA) levels of ikkbα (A) and nfe2l2 (B) in the cortex of mice treated with 0, 5, or 14 mg/kg NaAsO 2 .…”

“…These effects were reversed when the animals received the membranepermeable L-cys precursor N-acetylcysteine (Aoyama et al, 2006). We have observed that gestational exposure to iAs through drinking water induced the upregulation of xCT, which was associated with increased levels of GSH in the cortex and hippocampus (Ramos-Chávez et al, 2015;Nelson-Mora et al, 2018). In addition, the overexpression of xCT leads to increased extracellular glutamate and to the downregulation of both N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) ionotropic glutamate receptors, with significant negative effects on learning and memory (Ramos-Chávez et al, 2015;Nelson-Mora et al, 2018).…”

“…Chronic exposure to iAs was associated with increased extracellular glutamate and the negative modulation of the expression and activity of the NMDAR subunits NR2A and NR2B (Luo et al, 2009(Luo et al, , 2012Ramos-Chávez et al, 2015;Nelson-Mora et al, 2018). In the cortex, NMDAR acts as a detector for activity-dependent plasticity and associative learning (Hasan et al, 2013).…”

Adsorption of Aqueous As (III) in Presence of Coexisting Ions by a Green Fe-Modified W Zeolite

“…Exposure to arsenic (As) through drinking water has been reported to be associated with diverse diseases, for instance adverse pregnancy outcomes and many types of cancer [1][2][3]. There is strong evidence that chronic inorganic arsenic ingestion increases the risk to developing cardiovascular diseases, diabetes mellitus and damaged cognitive function in early childhood [4,5]. Diabetes has been investigated in arsenic-exposed Mexican populations by Del Razo et al who found that the prevalence of diabetes was associated with arsenic in drinking water and with the concentration of dimethylarsenite in urine, linking the risk of diabetes to the production of one of the most toxic metabolites of inorganic arsenic [6].…”