期刊
EVOLUTIONARY APPLICATIONS
卷 9, 期 5, 页码 685-696出版社
WILEY
DOI: 10.1111/eva.12365
关键词
fitness assay; intraspecific competition; pharmaceutical development; reproduction; semi-natural enclosures; toxicity assessment
资金
- University of Utah's Technology Commercialization Program
- National Science Foundation [DEB 09-18969]
- National Institutes of Health [R01-GM109500]
- National Science Foundation GK-12 Educational Outreach Fellowship [DGE 08-41233]
A major problem in pharmaceutical development is that adverse effects remain undetected during preclinical and clinical trials, but are later revealed after market release when prescribed to many patients. We have developed a fitness assay known as the organismal performance assay (OPA), which evaluates individual performance by utilizing outbred wild mice (Mus musculus) that are assigned to an exposed or control group, which compete against each other for resources within semi-natural enclosures. Performance measurements included reproductive success, survival, and male competitive ability. Our aim was to utilize cerivastatin (Baycol (R), Bayer), a pharmaceutical with known adverse effects, as a positive control to assess OPAs as a potential tool for evaluating the safety of compounds during preclinical trials. Mice were exposed to cerivastatin (similar to 4.5 mg/kg/day) into early adulthood. Exposure ceased and animals were released into semi-natural enclosures. Within enclosures, cerivastatin- exposed females had 25% fewer offspring and cerivastatin- exposed males had 10% less body mass, occupied 63% fewer territories, sired 41% fewer offspring, and experienced a threefold increase in mortality when compared to controls. OPAs detected several cerivastatin-induced adverse effects indicating that fitness assays, commonly used in ecology and evolutionary biology, could be useful as an additional tool in safety testing during pharmaceutical development.
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