ToxSci Advance Access originally published online on October 26, 2005
Toxicological Sciences 2006 89(2):475-484; doi:10.1093/toxsci/kfj032
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Cell Cycle Inhibition by Sodium Arsenite in Primary Embryonic Rat Midbrain Neuroepithelial Cells
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* Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195; Center for Ecogenetics and Environmental Health and Institute for Risk Analysis and Risk Communication, Seattle, Washington 98105; and Center on Human Development and Disability, Seattle, Washington 98195
Received August 31, 2005; accepted October 24, 2005
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 (gestational day [GD] 12) 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 5-bromo-2'-deoxyuridine (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 gap 1 phase (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.
Key Words: sodium arsenite; cell cycle; embryonic neuroepithelial cells; development; neurotoxicity.
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