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Front Neurosci. 2016 Mar 31;10:137. doi: 10.3389/fnins.2016.00137. eCollection 2016.

Prenatal Exposure to Arsenic Impairs Behavioral Flexibility and


Cortical Structure in Mice.
Aung KH1, Kyi-Tha-Thu C2, Sano K3, Nakamura K4, Tanoue A4, Nohara K3, Kakeyama M5, Tohyama
C6, Tsukahara S2, Maekawa F3.
Author information
Abstract
Exposure to arsenic from well water in developing countries is suspected to cause
developmental neurotoxicity. Although, it has been demonstrated that exposure to sodium
arsenite (NaAsO2) suppresses neurite outgrowth of cortical neurons in vitro, it is largely
unknown how developmental exposure to NaAsO2 impairs higher brain function and affects
cortical histology. Here, we investigated the effect of prenatal NaAsO2 exposure on the
behavior of mice in adulthood, and evaluated histological changes in the prelimbic cortex
(PrL), which is a part of the medial prefrontal cortex that is critically involved in cognition.
Drinking water with or without NaAsO2 (85 ppm) was provided to pregnant C3H mice from
gestational days 8 to 18, and offspring of both sexes were subjected to cognitive behavioral
analyses at 60 weeks of age. The brains of female offspring were subsequently harvested
and used for morphometrical analyses. We found that both male and female mice
prenatally exposed to NaAsO2 displayed an impaired adaptation to repetitive reversal
tasks. In morphometrical analyses of Nissl- or Golgi-stained tissue sections, we found that
NaAsO2 exposure was associated with a significant increase in the number of pyramidal
neurons in layers V and VI of the PrL, but not other layers of the PrL. More strikingly,
prenatal NaAsO2 exposure was associated with a significant decrease in neurite length but
not dendrite spine density in all layers of the PrL. Taken together, our results indicate that
prenatal exposure to NaAsO2 leads to behavioral inflexibility in adulthood and cortical
disarrangement in the PrL might contribute to this behavioral impairment.

PLoS One. 2013 Sep 3;8(9):e73720. doi: 10.1371/journal.pone.0073720. eCollection 2013.

Adult hippocampal neurogenesis and mRNA


expression are altered by perinatal arsenic exposure
in mice and restored by brief exposure to
enrichment.
Tyler CR1, Allan AM.
Author information
Abstract
Arsenic is a common and pervasive environmental contaminant found in drinking water in
varying concentrations depending on region. Exposure to arsenic induces behavioral and
cognitive deficits in both human populations and in rodent models. The Environmental
Protection Agency (EPA) standard for the allotment of arsenic in drinking water is in the
parts-per-billion range, yet our lab has shown that 50 ppb arsenic exposure during
development can have far-reaching consequences into adulthood, including deficits in
learning and memory, which have been linked to altered adult neurogenesis. Given that the
morphological impact of developmental arsenic exposure on the hippocampus is unknown,
we sought to evaluate proliferation and differentiation of adult neural progenitor cells in the
dentate gyrus after 50 ppb arsenic exposure throughout the perinatal period of
development in mice (equivalent to all three trimesters in humans) using a BrdU pulse-
chase assay. Proliferation of the neural progenitor population was decreased by 13% in
arsenic-exposed mice, but was not significant. However, the number of differentiated cells
was significantly decreased by 41% in arsenic-exposed mice compared to controls. Brief,
daily exposure to environmental enrichment significantly increased proliferation and
differentiation in both control and arsenic-exposed animals. Expression levels of 31% of
neurogenesis-related genes including those involved in Alzheimer's disease, apoptosis,
axonogenesis, growth, Notch signaling, and transcription factors were altered after arsenic
exposure and restored after enrichment. Using a concentration previously considered safe
by the EPA, perinatal arsenic exposure altered hippocampal morphology and gene
expression, but did not inhibit the cellular neurogenic response to enrichment. It is possible
that behavioral deficits observed during adulthood in animals exposed to arsenic during
development derive from the lack of differentiated neural progenitor cells necessary for
hippocampal-dependent learning. This study is the first to determine the impact of arsenic
exposure during development on adult hippocampal neurogenesis and related gene
expression.

Front Mol Neurosci. 2017 Sep 7;10:286. doi: 10.3389/fnmol.2017.00286. eCollection 2017.

Sodium Arsenite-Induced Learning and Memory


Impairment Is Associated with Endoplasmic
Reticulum Stress-Mediated Apoptosis in Rat
Hippocampus.
Sun H1, Yang Y1, Shao H1, Sun W 1, Gu M1, Wang H1, Jiang L1, Qu L1, Sun D1, Gao Y1,2.
Author information
Abstract
Chronic arsenic exposure has been associated to cognitive deficits. However, mechanisms
remain unknown. The present study investigated the neurotoxic effects of sodium arsenite
in drinking water over different dosages and time periods. Based on results from the Morris
water maze (MWM) and morphological analysis, an exposure to sodium arsenite could
induce neuronal damage in the hippocampus, reduce learning ability, and accelerate
memory impairment. Sodium arsenite significantly increased homocysteine levels in serum
and brain. Moreover, sodium arsenite triggered unfolded protein response (UPR), leading
to the phosphorylation of RNA-regulated protein kinase-like ER kinase (PERK) and
eukaryotic translation initiation factor 2 subunit (eIF2), and the induction of activating
transcription factor 4 (ATF4). Arsenite exposure also stimulated the expression of the
endoplasmic reticulum (ER) stress markers, glucose-regulated protein 78 (GRP78), C/EBP
homologous protein (CHOP) and the cleavage of caspase-12. Furthermore, exposure to
arsenite enhanced apoptosis as demonstrated by expression of caspase-3 and TUNEL
assay in the hippocampus. The results suggest that exposure to arsenite can significantly
decrease learning ability and accelerate memory impairment. Potential mechanisms are
related to enhancement of homocysteine and ER stress-induced apoptosis in the
hippocampus.