Adult Hippocampal Neurogenesis and mRNA Expression are Altered by Perinatal Arsenic Exposure in Mice and Restored by Brief Exposure to Enrichment

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.

Rac1 and Cdc42 Play Important Roles in Arsenic Neurotoxicity in Primary Cultured Rat Cerebellar Astrocytes

“…**P<0.01 for 30 μM NaAsO 2 treatment group, NSC23766 and ZCL278 with 0 μM NaAsO 2 treatment group compared with control. &&P<0.01 for NSC23766 and ZCL278 with 30 μM NaAsO 2 treatment group compared with 30 μM NaAsO 2 treatment group [52]. However, findings from this study did not provide the evidence that Rac1 and Cdc42 GTPases activation by arsenite exposure were related to tumor development.…”

Bisphenol-A Mediated Inhibition of Hippocampal Neurogenesis Attenuated by Curcumin via Canonical Wnt Pathway

“…Altered hippocampal neurogenesis has been associated with a number of neuropsychiatric diseases [58,59], hippocampus-dependent behavioral deficits, and neurodegenerative disorders [60][61][62][63][64]. In the environment, diverse toxic chemicals, such as heavy metals, solvents, pesticides, and EDCs, that can modulate the hippocampal neurogenesis are present [10][11][12][13][14][15]. BPA is one of the toxic environmental and industrial EDCs, targets several tissues and organs, and causes hepatoxicity, immunotoxicity, genotoxicity, neurotoxicity, and mutagenic and carcinogenic effects [65].…”

“…Several environmental toxicants including heavy metals, solvents, pesticides, and endocrine-disrupting chemicals (EDCs) modulate the normal neurodevelopmental processes both during fetal and adult stages and cause cognitive dysfunction [10][11][12][13][14][15]. Bisphenol A (BPA), is an endocrinedisrupting synthetic xenoestrogen, widely distributed in the environment, and used for the production of number of polycarbonate plastics and epoxy resin-containing consumer products [16,17].…”

Fluoxetine treatment ameliorates depression induced by perinatal arsenic exposure via a neurogenic mechanism

“…Indeed, we have previously demonstrated that perinatal (pre- and postnatal developmental) arsenic exposure (PAE) alters glucocorticoid signaling within the HPA axis, blunts stress responses, increases stress reactivity (Goggin et al, 2012), and results in depressive-like behavior in adulthood (Martinez et al, 2008; Martinez-Finley et al, 2009). In addition to these aberrations, we have also observed altered hippocampal morphology and deficits in adult hippocampal neurogenesis after PAE (Tyler and Allan, 2013). Yet, the pathophysiology of arsenic-induced depression and the response to antidepressants after arsenic exposure has not been fully explored.…”

“…Animals were maintained in a 22 °C vivarium on a 12-h reverse light/dark cycle with lights off at 08:00 and ad libitum access to water and food. Exposure to arsenic during all three trimesters of brain development was performed as previously described (Tyler and Allan, 2013). Briefly, singly housed female C57BL/6J mice aged 55 days (Jackson Laboratories, Bar Harbor, ME) were acclimated to drinking 50 ppb arsenic-laced water (sodium arsenate, Sigma–Aldrich, St. Louis, MO) for seven to ten days prior to mating.…”