NTP Research Report on Baseline Characteristics of Diversity Outbred (J:DO) Mice Relevant to Toxicology Studies

Harrill, Alison H.; Borghoff, Susan J.; Zorrilla, Leah M.; Blystone, Chad R.; Kissling, Grace E.; Malarkey, Dave; Shockley, Keith R.; Travlos, Greg; DeVito, Michael J.

doi:10.22427/ntp-rr-6

Cited by 7 publications

(2 citation statements)

References 23 publications

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“…The genetic diversity of the stock can’t be maintained by traditional husbandry used in individual laboratories; the complex breeding scheme requires them to be acquired from The Jackson Laboratory. In general, J:DO mice were developed to promote genetic analysis of complex traits 50, 51 and because it is sometimes desirable to perform studies in animals that, which like most humans, are not inbred 52, 53 . Our study shows that if overt retinal disease occurs in J:DO mice, it is likely rare (< 1 in 47 mice), but that there is broad range of variability in many retinal features which could be studied using quantitative genetic approaches.…”

Section: Discussionmentioning

confidence: 99%

Biological Correlations and Confounding Variables for Quantification of Retinal Ganglion Cells Based on Optical Coherence Tomography using Diversity Outbred Mice

Hedberg-Buenz

Meyer

Heide

et al. 2020

Preprint

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PurposeDespite popularity of optical coherence tomography (OCT) in glaucoma studies, it’s unclear how well OCT-derived metrics compare to traditional measures of retinal ganglion cell (RGC) abundance. Here, Diversity Outbred (J:DO) mice are used to directly compare ganglion cell complex (GCC)-thickness measured by OCT to metrics of retinal anatomy measured ex vivo with retinal wholemounts or optic nerve cross sections.MethodsJ:DO mice (n = 48) underwent OCT and fundoscopic exams, with GCC-thickness measured using automated segmentation. Following euthanasia, RGC axons were quantified from para-phenylenediamine-stained optic nerve cross sections and RGC somas from BRN3A-immunolabeled retinal wholemounts with total cellularity assessed by TO-PRO or hematoxylin nuclear staining.ResultsJ:DO tissues lacked overt disease. GCC-thickness (62.4 ± 3.7 µm), RGC abundance (3,097 ± 515 BRN3A+ nuclei/mm2; 45,533 ± 9,077 axons), and total inner retinal cell abundance (6,952 ± 810 nuclei/mm2) varied broadly. GCC-thickness correlated significantly to RGC somal density (r = 0.46) and axon number (r = 0.49), whereas total inner retinal cellularity did not. Retinal area (20.3 ± 2.4 mm2) and optic nerve (0.09 ± 0.02 mm2) cross-sectional area varied widely. Sex did not significantly influence any of these metrics. In bilateral comparisons, GCC-thickness (r = 0.89), inner retinal cellularity (r = 0.47), and RGC axon abundance (r = 0.72) all correlated significantly.ConclusionsAmongst outbred mice with widely variable phenotypes, OCT-derived measurements of GCC thickness correlate significantly to RGC abundance and axon number. The extensive phenotypic variability exhibited by J:DO mice make them a powerful resource for studies of retinal anatomy using quantitative genetics.

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Section: Discussionmentioning

confidence: 99%

Biological Correlations and Confounding Variables for Quantification of Retinal Ganglion Cells Based on Optical Coherence Tomography using Diversity Outbred Mice

Hedberg-Buenz

Meyer

Heide

et al. 2020

Preprint

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“…Among zileuton-treated DO mice, there were extreme responders with greater serum levels of ALT, AST, and ALP compared with other DO mice in the same group (Figure 1). There was a single outlier animal in the vehicle control group that displayed a high ALT value outside of the established DO reference range ( Figure 1A) (Harrill et al, 2018). Although there were individuals in the zileuton-exposed group that experienced a large increase in total bilirubin, there was overall not a significant treatment-related effect in the zileuton group within this short-term dosing paradigm (data not shown; p ¼ .50).…”

Section: Liver Histopathology and Clinical Chemistrymentioning

confidence: 87%

Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice

You

Lyn‐Cook

Gatti

et al. 2020

Toxicological Sciences

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Zileuton is an orally active inhibitor of leukotriene synthesis for maintenance treatment of asthma, for which clinical usage has been associated with idiosyncratic liver injury. Mechanistic understanding of zileuton toxicity is hampered by the rarity of the cases and lack of an animal model. A promising model for mechanistic study of rare liver injury is the Diversity Outbred (J:DO) mouse population, with genetic variation similar to that found in humans. In this study, female DO mice were administered zileuton or vehicle daily for 7 days (i.g.). Serum liver enzymes were elevated in the zileuton group, with marked interindividual variability in response. Zileuton exposure-induced findings in susceptible DO mice included microvesicular fatty change, hepatocellular mitosis, and hepatocellular necrosis. Inducible nitric oxide synthase and nitrotyrosine abundance were increased in livers of animals with necrosis and those with fatty change, implicating nitrosative stress as a possible injury mechanism. Conversely, DO mice lacking adverse liver pathology following zileuton exposure experienced decreased hepatic concentrations of resistin and increased concentrations of insulin and leptin, providing potential clues into mechanisms of toxicity resistance. Transcriptome pathway analysis highlighted mitochondrial dysfunction and altered fatty acid oxidation as key molecular perturbations associated with zileuton exposure, and suggested that interindividual differences in cytochrome P450 metabolism, glutathione-mediated detoxification, and farnesoid X receptor signaling may contribute to zileuton-induced liver injury (ZILI). Taken together, DO mice provided a platform for investigating mechanisms of toxicity and resistance in context of ZILI which may lead to targeted therapeutic interventions.

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An interaction of inorganic arsenic exposure with body weight and composition on type 2 diabetes indicators in Diversity Outbred mice

et al. 2022

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NTP Research Report on Baseline Characteristics of Diversity Outbred (J:DO) Mice Relevant to Toxicology Studies

Cited by 7 publications

References 23 publications

Biological Correlations and Confounding Variables for Quantification of Retinal Ganglion Cells Based on Optical Coherence Tomography using Diversity Outbred Mice

Biological Correlations and Confounding Variables for Quantification of Retinal Ganglion Cells Based on Optical Coherence Tomography using Diversity Outbred Mice

Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice

An interaction of inorganic arsenic exposure with body weight and composition on type 2 diabetes indicators in Diversity Outbred mice

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