PMID- 16251481 OWN - NLM STAT- MEDLINE DCOM- 20060310 LR - 20121115 IS - 1096-6080 (Print) IS - 1096-0929 (Linking) VI - 89 IP - 2 DP - 2006 Feb TI - Cell cycle inhibition by sodium arsenite in primary embryonic rat midbrain neuroepithelial cells. PG - 475-84 AB - 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 microM) 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 microM. Morphologically, apoptosis was not apparent until 4 microM 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 (> or =0.5 microM). 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. FAU - Sidhu, Jaspreet S AU - Sidhu JS AD - Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98195, USA. FAU - Ponce, Rafael A AU - Ponce RA FAU - Vredevoogd, Melinda A AU - Vredevoogd MA FAU - Yu, Xiaozhong AU - Yu X FAU - Gribble, Elizabeth AU - Gribble E FAU - Hong, Sung-Woo AU - Hong SW FAU - Schneider, Emily AU - Schneider E FAU - Faustman, Elaine M AU - Faustman EM LA - eng GR - P01ES09601/ES/NIEHS NIH HHS/United States GR - P30 ES07033/ES/NIEHS NIH HHS/United States GR - R01-ES10613/ES/NIEHS NIH HHS/United States GR - U10 ES 11387/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20051026 PL - United States TA - Toxicol Sci JT - Toxicological sciences : an official journal of the Society of Toxicology JID - 9805461 RN - 0 (Arsenites) RN - 0 (Environmental Pollutants) RN - 0 (Sodium Compounds) RN - 48OVY2OC72 (sodium arsenite) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Arsenites/*toxicity MH - Cell Cycle/*drug effects MH - Cell Survival/drug effects MH - Cells, Cultured MH - Dose-Response Relationship, Drug MH - Environmental Pollutants/*toxicity MH - Flow Cytometry MH - Mesencephalon/*cytology/embryology MH - Neuroepithelial Cells/*drug effects/pathology MH - Rats MH - Rats, Sprague-Dawley MH - Sodium Compounds/*toxicity MH - Time Factors EDAT- 2005/10/28 09:00 MHDA- 2006/03/11 09:00 CRDT- 2005/10/28 09:00 PHST- 2005/10/28 09:00 [pubmed] PHST- 2006/03/11 09:00 [medline] PHST- 2005/10/28 09:00 [entrez] AID - kfj032 [pii] AID - 10.1093/toxsci/kfj032 [doi] PST - ppublish SO - Toxicol Sci. 2006 Feb;89(2):475-84. doi: 10.1093/toxsci/kfj032. Epub 2005 Oct 26.