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ToxSci Advance Access published online on October 26, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfj032
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© The Author 2005. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received August 31, 2005
Accepted October 24, 2005

Neurotoxicology

Cell Cycle Inhibition by Sodium Arsenite in Primary Embryonic Rat Midbrain Neuroepithelial Cells

Jaspreet S. Sidhu 1, Rafael A. Ponce 2, Melinda A. Vredevoogd 1, Xiaozhong Yu 1, Elizabeth Gribble 1, Sung-Woo Hong 1, Emily Schneider 1, and Elaine M. Faustman 3*

1 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195
2 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195; Center for Ecogenetics and Environmental Health and Institute for Risk Analysis and Risk Communication, Seattle, Washington 98105
3 Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98195; Center for Ecogenetics and Environmental Health and Institute for Risk Analysis and Risk Communication, Seattle, Washington 98105; Center on Human Development and Disability, Seattle, Washington 98195

* To whom correspondence should be addressed.
Elaine M. Faustman, E-mail: faustman{at}u.washington.edu


  Abstract

Arsenite (As3+) exposure during development has been associated with neural tube defects and other structural malformations, and with behavioral alterations including altered locomotor activity and operant learning. The molecular mechanisms underlying these effects are uncertain. Because arsenic can cross the placenta and accumulate in the developing neuroepithelium, we examined cell cycling effects of sodium arsenite (As3+ 0, 0.5, 1, 2 and 4 µM) on embryonic primary rat midbrain (GD12) neuroepithelial cells over 48 h. There was a concentration- and time-dependent As3+-induced reduction in cell viability assessed by neutral red dye uptake assay but minimal apoptosis at concentrations below 4 µM. Morphologically, apoptosis was not apparent until 4 µM at 24 h, which was demonstrated by a marginal but statistically significant increase in cleaved caspase-3/7 activity. Cell cycling effects over several rounds of replication were determined by continuous BrdU labeling and bivariate flow cytometric Hoechst-Propidium Iodide analysis. We observed a time- and concentration-dependent inhibition of cell cycle progression as early as 12 h after exposure (≥ 0.5 µM). In addition, data demonstrated a concentration-dependent increase in cytostasis within all cell cycle phases, a decreased proportion of cells able to reach the second cell cycle, and a reduced cell cycle entry from G1. The proportion of affected cells and the severity of the cell cycle perturbation, which ranged from a decreased transition probability to complete cytostasis in all cell cycle phases, were also found to be concentration-dependent. Together, these data support a role for perturbed cell cycle progression in As3+ mediated neurodevelopmental toxicity.

Keywords: sodium arsenite; cell cycle; embryonic neuroepithelial cells; development; neurotoxicity.
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