Quantification of cerivastatin toxicity supports organismal performance assays as an effective tool during pharmaceutical safety assessment

被引:14
作者
Gaukler, Shannon M. [1 ,2 ]
Ruff, James S. [1 ]
Galland, Tessa [1 ]
Underwood, Tristan K. [1 ]
Kandaris, Kirstie A. [1 ]
Liu, Nicole M. [1 ]
Morrison, Linda C. [1 ]
Veranth, John M. [3 ]
Potts, Wayne K. [1 ]
机构
[1] Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA
[2] Los Alamos Natl Lab, Environm Stewardship Grp, Mailstop J978, Los Alamos, NM 87545 USA
[3] Univ Utah, Dept Pharmacol & Toxicol, 112 Skaggs Hall, Salt Lake City, UT 84112 USA
来源
EVOLUTIONARY APPLICATIONS | 2016年 / 9卷 / 05期
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
fitness assay; intraspecific competition; pharmaceutical development; reproduction; semi-natural enclosures; toxicity assessment; MAGNIFIES INBREEDING DEPRESSION; COMPETITIVE ABILITY; FITNESS; MICE; POPULATIONS; MECHANISMS; DECLINE; WEIGHT; GENE;
D O I
10.1111/eva.12365
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:685 / 696
页数:12
相关论文
共 51 条
[11]   Toxicogenomics: The challenges and opportunities to identify biomarkers, signatures and thresholds to support mode-of-action [J].
Currie, Richard A. .
MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS, 2012, 746 (02) :97-103
[12]   SEXUAL DIMORPHISM FOR BODY-MASS IN 13 TAXA OF MUROID RODENTS UNDER LABORATORY CONDITIONS [J].
DEWSBURY, DA ;
BAUMGARDNER, DJ ;
EVANS, RL ;
WEBSTER, DG .
JOURNAL OF MAMMALOGY, 1980, 61 (01) :146-149
[13]   Withdrawal of cerivastatin from the world market [J].
Furberg, CD ;
Pitt, B .
CURRENT CONTROLLED TRIALS IN CARDIOVASCULAR MEDICINE, 2001, 2 (05) :205-207
[14]  
Gaukler S., 2016, J PHARM NEG IN PRESS
[15]   Low-dose paroxetine exposure causes lifetime declines in male mouse body weight, reproduction and competitive ability as measured by the novel organismal performance assay [J].
Gaukler, Shannon M. ;
Ruff, James S. ;
Galland, Tessa ;
Kandaris, Kirstie A. ;
Underwood, Tristan K. ;
Liu, Nicole M. ;
Young, Elizabeth L. ;
Morrison, Linda C. ;
Yost, Garold S. ;
Potts, Wayne K. .
NEUROTOXICOLOGY AND TERATOLOGY, 2015, 47 :46-53
[16]   ENERGY ALLOCATION IN MAMMALIAN REPRODUCTION [J].
GITTLEMAN, JL ;
THOMPSON, SD .
AMERICAN ZOOLOGIST, 1988, 28 (03) :863-875
[17]   Experimental infection magnifies inbreeding depression in house mice [J].
Ilmonen, P. ;
Penn, D. J. ;
Damjanovich, K. ;
Clarke, J. ;
Lamborn, D. ;
Morrison, L. ;
Ghotbi, L. ;
Potts, W. K. .
JOURNAL OF EVOLUTIONARY BIOLOGY, 2008, 21 (03) :834-841
[18]  
Keane W., 2004, COMMUNICATION
[19]  
KIMURA M, 1969, GENETICS, V61, P763
[20]  
KRACKOW S, 1993, ETHOLOGY, V95, P76