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.
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Abbreviations
- AdoMet:
-
S-Adenosylmethionine
- AMPA:
-
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- As3MT:
-
Arsenic III-methyltransferase
- BBB:
-
Blood–brain barrier
- DG:
-
Dentate gyrus
- EPSP:
-
Excitatory post-synaptic potential
- GSH:
-
Glutathione
- iAs:
-
Inorganic arsenic
- LTP:
-
Long-term potentiation
- NMDA:
-
N-Methyl-d-aspartate
- OPA:
-
o-Phthalaldehyde
- PND:
-
Post-natal day
- PP:
-
Perforant pathway
- PP–DG:
-
Perforant–dentate gyrus pathway
- PPF:
-
Paired-pulse facilitation
- RRP:
-
Relative refractory periods
- TG:
-
Total GSH
- WHO:
-
World Health Organization
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Acknowledgements
We thank Pavel Petrosyan for his technical support and Unidad de Modelos Biológicos, Instituto de Investigaciones Biomédicas, UNAM for supplying the animals. Janikua Nelson-Mora received a scholar fellowship from CONACYT No 384958, and she thanks the Posgrado en Ciencias Biologicas, UNAM for its support. This work received grants from PAPIIT (UNAM) IN 207611, PAPIIT (UNAM) IN 215816 and CONACYT102287 and Red Temática de Salud Ambiental Infantil Conacyt 280296 to María E. Gonsebatt. This study was performed in partial fulfillment of the requirements for the PhD degree in the Posgrado en Ciencias Biológicas at the Universidad Nacional Autónoma de México.
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Nelson-Mora, J., Escobar, M.L., Rodríguez-Durán, L. et al. Gestational exposure to inorganic arsenic (iAs3+) alters glutamate disposition in the mouse hippocampus and ionotropic glutamate receptor expression leading to memory impairment. Arch Toxicol 92, 1037–1048 (2018). https://doi.org/10.1007/s00204-017-2111-x
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DOI: https://doi.org/10.1007/s00204-017-2111-x