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 α (eIF2α), 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.

The nervous system is a target of arsenic toxicity. Phosphatase and tensin homologue deleted on chromosome 10/protein kinase B/cAMP-response element binding protein (PTEN/Akt/CREB) signaling pathway has been reported to be involved in maintaining normal function of the nervous system, modulating growth and proliferation of neurocyte, regulating neuron synaptic plasticity, and long-term memory. And many studies have demonstrated that expressions of PTEN, Akt, and CREB protein were influenced by arsenic, but it is not clear whether this signaling pathway is involved in the nervous system impairment of rats induced by chronic arsenite exposure, and we have addressed this in this study. Eighty male Sprague-Dawley (SD) rats were randomly divided into eight groups (n = 10 each), four groups exposed to NaAsO2 (0, 5, 10, and 50 mg/L NaAsO2 in drinking water) for 3 months, the other four groups exposed to NaAsO2 (0, 5, 10, 50 mg/L NaAsO2 in drinking water) for 6 months. Hematoxylin and eosin (HE) staining showed that chronic arsenite exposure induced varying degrees of damage in cerebral neurons. And arsenite exposure increased arsenic amount in serum and brain samples in a dose- and time-dependent manner. Moreover, the protein levels of PTEN and Akt in brain tissue were not significantly changed compared with the control group, but p-Akt, CREB, and p-CREB were all significantly downregulated in arsenite-exposed groups with a dose-dependent pattern. These results suggested that chronic arsenite exposure negatively regulated the PTEN-Akt-CREB signaling pathway, and dysfunction of the signaling pathway might be one of the mechanisms of nervous system impairment induced by chronic arsenite exposure.

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