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COMPARISON OF CHEMICAL-INDUCED CHANGES IN PROLIFERATION AND APOPTOSIS IN HUMAN AND MOUSE NEUROPROGENITOR CELLS.
Culbreth, M., W. R. MUNDY, AND TIM SHAFER. COMPARISON OF CHEMICAL-INDUCED CHANGES IN PROLIFERATION AND APOPTOSIS IN HUMAN AND MOUSE NEUROPROGENITOR CELLS. Presented at 27th International Neurotoxicology Conference, RTP, NC, January 01 - 02, 2011.
There is a need to develop rapid and efficient models for screening chemicals for their potential to cause developmental neurotoxicity
There is a need to develop rapid and efficient models for screening chemicals for their potential to cause developmental neurotoxicity. Use of in vitro neuronal models, including human cells, is one approach that allows for timely, cost-effective toxicity screening. The present study utilizes human (ReN CX) and mouse (mCNS) neuroprogenitor cell lines to develop assays for proliferation and apoptosis, endpoints that are critical for neural development. Experiments were designed to compare the sensitivity of cell lines from different species. Cells were exposed to 11 chemicals (0.001-100JlM) reported in the literature to effect proliferation and/or apoptosis, and 5 chemicals with no reports of effects on either endpoint. High-throughput screening of markers for proliferation (BrdU) and apoptosis (caspase 3 and p53) was used to assess the effect of chemicals in both cell lines. Of the chemicals tested, methylmercury, cadmium, dieldrin, chlorpyrifos oxon, trans-retinoic acid, and trimethyltin decreased proliferation by at least 50% of control in either ReN CX or mCNS cells. None of the chemicals tested induced apoptosis in ReN CX, while methylmercury, cadmium, dieldrin, chlorpyrifos oxon, trimethyltin, and glyphosate all induced at least a doubling in apoptotic markers caspase 3 or p53 in mCNS cells. Cell viability (ATP levels) was also assessed in both cell lines. Cadmium, trans-retinoic acid, and trimethyltin decreased viability by at least 50% of control in ReN CX, while methylmercury and dieldrin decreased viability by at least 50% of control in mCNS. Based on these results, this assay can be used to screen chemicals for effects on proliferation, as well as compare the sensitivity of different cell lines. However, the lack of response in ReN CX for apoptotic markers necessitates further investigation of screening methods for apoptosis. This abstract does not necessarily reflect US EPA policy.
Record Details:Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LABORATORY
INTEGRATED SYSTEMS TOXICOLOGY DIVISION
SYSTEMS BIOLOGY BRANCH