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New toxicity test could cut animal testing

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19.03.2004

To test whether chemicals are toxic to humans, researchers need to use liver cells that have been freshly harvested from mice or other mammals. A new collection of stable cell lines, described in BMC Biotechnology this week, could reduce the numbers of animals needed in such experiments.

The MMH-GH cell lines are derived from the liver cells of transgenic mice. These cells have been engineered to secrete human growth hormone when they are exposed to toxic compounds. The cells also continuously produce an activated version of the growth factor receptor, c-MET, which enables them to survive for longer than normal liver cells and to retain features of differentiated liver cells when they are grown in culture.

The researchers who created the cell lines come from Istituto Tecnologie Biomediche-National Research Council in Milan and Università La Sapienza in Rome. They write: “We believe that the MMH-GH cell lines provide a cheap, reproducible, rapid, reliable and ethically acceptable tool,” for assessing the toxicity of chemicals.

To test their system the researchers added toxic arsenic and cadmium compounds to the cells and then looked for human growth hormone in the culture media. They found that even at low doses these compounds caused the cells to secrete the hormone – and were therefore deemed to be toxic. These low concentrations of the chemicals would not have been picked up by current toxicity-testing methods, which brand a chemical as ‘toxic’ only if it kills liver cells.

As the MMH-GH cell lines can survive for longer than cultured primary liver cells, the cell type most commonly used in toxicity testing, adopting this new technique would reduce the number of animals used in such experiments. Currently researchers must repeatedly derive fresh primary cells from animals or humans, which is time consuming, costly, and ethically undesirable.

The researchers believe that experiments using the transgenic cell lines will also be more informative than those using cultured liver cancer cell lines, the current alternative to cultured primary cells. Over time, liver cells in culture are known to alter their patterns of gene expression and no longer behave like liver cells in vivo. For example they often lose the ability to produce drug-activating and modifying enzymes. Cultured MMH-GH cell lines do not suffer from this problem, retaining features of liver cells inside the mouse. Moreover, if important changes do occur in these cells, fresh cell lines can be derived from the transgenic animals.

The MMH-GH cell lines have a further advantage over current toxicity testing methods, according to the researchers. As they are derived from clonal cell populations assays using these cells should also be easier to standardise than current tests, which use heterogeneous primary cell cultures.

As there is considerable discomfort about the use of animals in research, researchers have tried to develop methods that reduce our reliance on animal experiments. Although lower organisms, such as yeast, can be used to carry out toxicological studies, assays using mammalian liver cells retain an important role. This is because mammalian cells will treat chemicals differently to cells from lower organisms. For example, a compound that seems benign in preliminary experiments could be broken down in mammalian cells to produce a toxic product.

Gemma Bradley | Source: BioMed Central
Further information: www.biomedcentral.com/1472-6750/4/5/abstract
www.biomedcentral.com/bmcbiotechnol

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