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.
Highlights
Arsenic is a naturally occurring essential trace element found in soil deposits and water
Cells that were only labeled with BrdU or Ki67 or more than three nuclei away from the subgranular zone of the dentate gyrus were not counted as proliferating progenitor cells
The results presented here demonstrate that our developmental arsenic exposure model, which represents a low and environmentally relevant concentration previously considered safe, significantly impacts adult neurogenesis, the number of differentiated neural progenitor cell (NPC) in the SGZ
Summary
Arsenic is a naturally occurring essential trace element found in soil deposits and water. Based on our previously published behavioral data and research supporting the link between learning and memory and adult neurogenesis, we hypothesized that our environmentally relevant perinatal arsenic exposure model induces deficits in proliferation and differentiation of neural progenitor cells in the dentate gyrus of exposed animals. This deficit may be responsible for the behavioral outcomes we observe in these animals [8,13]. It is possible that impaired hippocampal adult neurogenesis is a candidate mechanism by which developmental arsenic exposure induces deficits in learning and memory seen in adulthood
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