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Considerations in the Design and Conduct of Subchronic and Chronic Dermal Exposure Studies with Chemicals
Published in David W. Hobson, Dermal and Ocular Toxicology, 2020
The nature and severity of a toxic response is not only a function of the sensitivity of the animal species used in the study, but also may be related to the strain used within a given species. In selecting an appropriate animal strain, genetics (i.e., whether the animals are inbred, hybrid, or outbred) is usually an important consideration. Many laboratories have experience with outbred strains because they are more readily available and these strains are commonly more disease resistant than inbred animals. However, randomly bred strains are subject to genetic drift and this can produce considerable variation in response. On the other hand, inbred strains are single genotypes and may not be representative of the species. F1 hybrids are a uniform genotype, but they have a level of heterozygosity more closely resembling the outbred animals.1,3
The Jackson Laboratory Mouse Mutant Resource
Published in John P. Sundberg, Handbook of Mouse Mutations with Skin and Hair Abnormalities, 2020
The mouse has long been the mammal of choice for studying the role of genes in development and in normal biological functions and for providing experimental models of human inherited diseases. Because mice have close metabolic and internal anatomical similarities with human beings, mutant genes in mice frequently produce syndromes similar to human inherited conditions. Their short life span permits the study of the course of a disease. Their small size and relative ease of maintenance makes mice economical. Mouse mutations can be maintained on controlled genetic backgrounds, so that mutant and control mice only differ by the mutated gene being studied. The short generation time and availability of inbred strains makes it possible to study the effect of modifying genes by placing mutations on different genetic backgrounds. Finally, the mouse genome is the best genetically mapped of any experimental mammal, and many genetic homologies exist between mice and humans. This linkage conservation provides additional evidence for identity between potential mouse models and human diseases. To date, comparative mapping studies have identified nearly 950 homologous mouse and human genes in over 60 conserved autosomal segments and the X-chromosome (GBASE, 1993).2
Cytokine Regulation of the Mouse SAA Gene Family
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Jean D. Sipe, Hanna Rokita, Frederick C. de Beer
Inbred strains of mice have been powerful tools in the analysis of serum amyloid A (SAA) synthesis and catabolism in normal host defense and in dysfunctions such as amyloidosis.1-40 Six inbred strains (C57BL, C3H, BALB/c, DBA/2, CBA, and A) constituted about 70% of the strains used in 1600 wide-ranging research studies reviewed by Festing;41 with the possible exception of DBA/2, these strains are also most frequently employed to study SAA.
A diversity outbred F1 mouse model identifies host-intrinsic genetic regulators of response to immune checkpoint inhibitors
Published in OncoImmunology, 2022
Justin B. Hackett, James E. Glassbrook, Maria C. Muñiz, Madeline Bross, Abigail Fielder, Gregory Dyson, Nasrin Movahhedin, Jennifer McCasland, Claire McCarthy-Leo, Heather M. Gibson
Despite the reduced number of test subjects needed for GWAS studies in DO mice versus humans, DO mouse studies may still require large numbers of animals depending on the phenotype chosen for analysis. Minor allele frequency in the DO/CC mouse populations is a factor that reduces the required “n” because the minor allele frequency is close to 0.125 compared to the large number of near zero minor allele frequencies in humans.59 Ideal candidate phenotypes will have low variation within a particular inbred model, with variation between different inbred strains. Importantly, not all phenotypes will have a genetic influence.60,61 The effect size of the variation in phenotype is also an important consideration when determining sample size. Additionally, while genetics may regulate a specific phenotype in mice, the genetic component itself may not translate to humans. However, identified genes and their related pathways may still impact the same biological processes, and thus modulation of these targets may still have clinical value.
From leptin to lasers: the past and present of mouse models of obesity
Published in Expert Opinion on Drug Discovery, 2021
Joshua R. Barton, Adam E. Snook, Scott A. Waldman
The scientific rigor of obesity research arrived with the advent of animal models for obesity. Inbred mouse strains, first developed in the early 20th century, were gaining acceptance as models of human physiology [13]. These inbred strains were bred specifically to reduce genetic variability of previous outbred strains and provide reproducible, translatable data. Two specific mutations in inbred mouse strains: the ‘obese’ (ob/ob) and ‘diabetic’ (db/db) mouse mutations, were instrumental in legitimizing obesity research and the molecular basis for metabolic regulation. After decades of research, we now know that ob/ob mice model deficiency in the hormone leptin, while db/db mice model deficiency in the leptin receptor. The discovery of the leptin system changed the zeitgeist for obesity therapy from quackery and happenstance to testable hypotheses, as evidenced by increases in anti-obesity publications (Figure 1). This article will review some landmark discoveries in the leptin system that form the basis for obesity research, as well as the modern mouse models of obesity research influenced by leptin.
Drug development for noise-induced hearing loss
Published in Expert Opinion on Drug Discovery, 2020
Isabel Varela-Nieto, Silvia Murillo-Cuesta, Miryam Calvino, Rafael Cediel, Luis Lassaletta
Guinea pigs (Cavia porcellus) show auditory traits similar to those in chinchilla, with a human-like hearing frequency range (50 Hz-50 kHz) [42] and best hearing at 8–16 kHz [58]. The effects of noise on guinea pig cochlea were well characterized in the late 1950s and since then, there have been relevant findings in this species such as the protective effect of strial melanin [59], the description of noise-induced cochlear synaptopathy [60] and synaptic ribbon recovery after noise [61]. Guinea pigs have also been used in preclinical research to study neuromodulators (NMDA and AMPA receptor blockers), MAPK-JNK and caspase inhibitors, anti-inflammatory molecules (glucocorticoids), antioxidants (D-methionine, N-acetyl cysteine and glutathione, among others) and trophic factors (BDNF, NT-3 and GDNF) [58]. The main disadvantages of chinchilla, as well as guinea pig models are the lack of inbred strains for genetic studies and molecular biology tools.