Considerations in the Design and Conduct of Subchronic and Chronic Dermal Exposure Studies with Chemicals
David W. Hobson in 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
Inbred Laboratory Mice as Animal Models and Biomedical Tools: General Concepts
John P. Sundberg in Handbook of Mouse Mutations with Skin and Hair Abnormalities, 2020
In 1907, Clarence Cook Little began working on mouse genetics and eventually established the dilute brown non-agouti (DBA) as the first inbred strain, a feat considered impossible at the time.11 Many inbred strains have subsequently been established.12,13,14 Little founded the Jackson Laboratory as a nonprofit research institution in 1929, just prior to the Great Stock Market Crash. To keep the laboratory viable during the Depression, scientists began to sell the inbred strains, which was the start of the production and distribution facility. The Jackson Laboratory maintains the world’s largest collection of genetically defined inbred and mutant laboratory mice, providing approximately 20% of the mice used in research in the U.S. and 98% of the variety of genetically defined strains.
Subchronic Dermal Exposure Studies with Industrial Chemicals
Rhoda G. M. Wang, James B. Knaak, Howard I. Maibach in Health Risk Assessment, 2017
The nature and severity of a chemical’s toxicity response is not only a function of the sensitivity of the animal species used in the study; it also may be related to the strain used within a given species. In selecting an appropriate animal strain, genetics is usually an important consideration (i.e., whether the animals are inbred, hybrid, or outbred). 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 low genetic stability marked by genetic drift and this can produce considerable variation in response. Inbred strains, on the other hand, will reduce variation, but they are single genotypes and may not be representative of the species. Fl hybrids are a uniform genotype, but they have a level of heterozygosity more closely resembling the outbred animals and are often chosen for use in toxicity studies.3 Examples of strains from species often used in subchronic dermal toxicity studies incude mice (B6C3F1, CD-1, C3H), rats (F344, Osborne-Mendel), guinea pigs (Hartley), and rabbits (New Zealand White).
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.
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.
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.