Molecular targets and early response biomarkers for the prediction of developmental toxicity in vitro

被引:4
作者
Stigson, Michael
Kultima, Kim
Jergil, Mans
Scholz, Birger
Alm, Henrik
Gustafson, Anne-Lee
Dencker, Lennart
机构
[1] Uppsala Univ, BMC, Div Toxicol, Dept Pharmaceut Biosci, SE-75124 Uppsala, Sweden
[2] AstraZeneca R&D, Safety Assessment, Sodertalje, Sweden
来源
ATLA-ALTERNATIVES TO LABORATORY ANIMALS | 2007年 / 35卷 / 03期
基金
英国医学研究理事会;
关键词
embryo; microarray; neural tube defect; P19 mouse embryocarcinoma cells; valproic acid;
D O I
10.1177/026119290703500313
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
There is an urgent need for new in vitro methods to predict the potential developmental toxicity of candidate drugs in the early lead indentification and optimisation process. This would lead to a reduction in the total number of animals required in full-scale developmental toxicology studies, and would improve the efficiency of drug development. However, suitable in vitro systems permitting robust high-throughput screening for this purpose, for the most part, remain to be designed. An understanding of the mechanisms involved in developmental toxicity may be essential for the validation of in vitro tests. Early response biomarkers - even a single one - could contribute to reducing assay time and facilitating automation. The use of toxicogenomics approaches to study in vitro and in vivo models in parallel may be a powerful tool indefining such mechanisms of action and the molecular targets of toxicity, and also for use in finding possible biomarkers of early response. Using valproic acid as a model substance, the use of DNA microarrays to identify teratogen-responsive genes in cell models is discussed. It is concluded that gene expression in P19 mouse embryocarcinoma cells represents a ptoentially suitable assay system, which could be readily used in a tiered testing system for developmental toxicity testing.
引用
收藏
页码:335 / 342
页数:8
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