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PROLIFERATION AS A KEY EVENT IN DEVELOPMENTAL TOXICITY: "CHEMICAL SCREENING IN HUMAN NEURAL STEM CELLS USING HIGH CONTENT IMAGING
Citation:
Culbreth, M., T. M. FREUDENRICH, TIM SHAFER, AND W. R. MUNDY. PROLIFERATION AS A KEY EVENT IN DEVELOPMENTAL TOXICITY: "CHEMICAL SCREENING IN HUMAN NEURAL STEM CELLS USING HIGH CONTENT IMAGING. Presented at Society of Toxicology (SOT) Annual Meeting, San Francisco, CA, March 11 - 15, 2012.
Impact/Purpose:
These results demonstrate the ability to screen rapidly chemicals for effects on cell proliferation, a key event in development. Effects of this chemical set will be examined in other model systems (embryonic stem cells, zebrafish) to identify common pathways leading to developmental toxicity.
Description:
New toxicity testing approaches will rely on in vitro assays to assess chemical effects at the cellular and molecular level. Cell proliferation is imperative to normal development, and chemical disruption of this process can be detrimental to the organism. As part of an effort to elucidate toxicity pathways, we screened 38 known developmental toxicants for effects on proliferation of neural stem cells. Human neuroprogenitor (ReN CX) cells were grown in 96 well plates and exposed to chemicals (0.001 to 100 uM) for 24 h. BrdU, which incorporates into replicating DNA, was added to the cells 20 h post exposure. Proliferating (BrdU positive) cells were quantified using immunocytochemistry and automated image analysis; cell viability was assessed in duplicate plates. The concentration which caused a 30% decrease from control (E30) and the lowest statistically effective concentration (LEC) were compared across endpoints and chemicals. Of the 38 developmental toxicants tested, 16 induced at least a 30% decrease in proliferation, and in 14 cases this effect was also statistically significant. Thirteen out of the 16 chemicals affecting proliferation were known developmental neurotoxicants. For the chemicals that decreased proliferation, 6 did so at concentrations that did not affect cell viability. Seven chemicals with no reports of developmental toxicity (negative controls) were also tested, and did not affect proliferation or cell viability. These results demonstrate the ability to screen rapidly chemicals for effects on cell proliferation, a key event in development. Effects of this chemical set will be examined in other model systems (embryonic stem cells, zebrafish) to identify common pathways leading to developmental toxicity. This abstract does not necessarily reflect US. EPA policy.