In Vitro Assay To Replace Animals in Genetic Toxicity Studies

This test requires injection of the drug compound into a live mouse. The new assay is based on adult red cell precursors taken from mouse bone marrow and grown in tissue culture. These precursor cells are suitable for this purpose, as they normally lose their nucleus during the last stage of red cell formation, and DNA-damaged precursors generate red blood cells containing an easily detected "micronucleus” consisting of fragments of nuclear DNA.

The in vitro assay allowed the precursor cells to proliferate and differentiate in the normal way, dividing four or five times before losing their nucleus and becoming immature red blood cells. Results obtained from the assay and published in the May 14, 2007, online edition of the Proceedings of the [U.S.] National Academy of Sciences revealed that adult bone marrow cultures responded to erythropoietin, the principal hormone that stimulates erythropoiesis, with physiologic erythropoietic proliferation, differentiation, and enucleation. The in-vitro erythropoietic system clearly signaled exposure to genotoxicants through erythroid MN formation. Responses to genotoxicants during erythroid differentiation varied with exposure time, demonstrating that this system could used to study the effect of DNA damage at specific developmental stages.

"This is a much cheaper assay that is at least as predictive as previous assays,” said senior author Dr. Linda Griffith, professor of biological engineering at MIT, "and drug developers can afford to use it a lot earlier in the drug development process.”


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