Communication Regarding Metabonomic Identification of Two Distinct Phenotypes in Sprague-Dawley (Crl:CD(SD)) Rats

Robosky, Lora C.; Wells, Dale F.; Egnash, Laura A.; Manning, Matthew L.; Reily, Michael D.; Robertson, Donald G.

doi:10.1093/toxsci/kfj134

Cited by 11 publications

(8 citation statements)

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“…Although it would be interesting to further explore the differences between the HIP and the CA rats, especially with respect to how their differences might affect drug metabolism, the CA rats are no longer available. The CA rats, as recently reported, have now reverted to the HIP phenotype .…”

Section: Discussionsupporting

confidence: 73%

Metabonomic Evaluation of Schaedler Altered Microflora Rats

Rohde

Wells

Robosky

et al. 2007

Chem. Res. Toxicol.

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Previously, we identified two distinct metabonomic phenotypes in Sprague-Dawley rats sourced from two different rooms (colonies) in the Charles River, Raleigh facility [Robosky, L. C., Wells, D. F., Egnash, L. A., Manning, M. L., Reily, M. D., and Robertson, D. G. (2005) Metabonomic identification of two distinct phenotypes in Sprague-Dawley (Crl:CD(SD)) rats. Toxicol. Sci. 87,[277][278][279][280][281][282][283][284]. On the basis of literature reports and cohabitation experiments, we concluded that the differing phenotypes were due to different gut flora populations. One hypothesis explaining this phenomenon was attributed to the practice of initiating new colonies with rats derived from foundation colonies that had limited gut floral populations, the Charles River altered Schaedler flora (CRASF) rats. We hypothesized that the lack of differentiation of CRASF rats to the full complement of microflora was responsible for the altered phenotype characterized by increased urinary chlorogenic acid metabolites and decreased hippurate (CA rats) as opposed to the prevalent phenotype characterized by the inverse ratio of these metabolites (HIP rats). Upon receipt, it was confirmed that the CRASF rats exhibited a metabonomic profile similar to CA rats that remained constant while animals were housed individually in a dedicated animal room. However, exposure of CRASF rats to HIP rats, or their bedding, led to a relatively rapid but variable rate of reversion to the historic HIP type metabolic profile. On the basis of the results, we conclude that CRASF rats have a unique metabolic profile due to their limited gut flora constitution. If rigorous isolation procedures are not employed, the CRASF phenotype will eventually differentiate into the more typical HIP phenotype with a time course that may be quite variable. Given the marked metabolic heterogeneity between the phenotypes, this work highlights the importance of monitoring rat metabolic profiles.

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Section: Discussionsupporting

confidence: 73%

Metabonomic Evaluation of Schaedler Altered Microflora Rats

Rohde

Wells

Robosky

et al. 2007

Chem. Res. Toxicol.

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“…We were not looking for this; it was just an anecdotal finding in several of the studies that we were conducting at the time. We monitored this phenotypic difference for over a year, during which time the phenotype was stable, although it eventually disappeared (13). We suspected that the difference was due to unusual gut microflora and later confirmed that the origin of the phenotypic difference was most likely due to husbandry practices where rat colonies, which were originated with limited gut flora, were prevented from acquiring normal gut bacterial speciation due to meticulous hygiene practices (14).…”

Section: Examplementioning

confidence: 86%

The Muddle of Models: What You Donʼt Know Can Hurt You

Robertson

2008

Chem. Res. Toxicol.

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Prior to clinical trials, animal models remain the primary tools by which the pharmaceutical industry demonstrates the efficacy and safety of candidate therapeutic agents. Despite this reliance, much remains unknown about the models that we use and the factors that affect how they perform. This ignorance can lead to inappropriate assumptions, questionable procedures, and incorrect conclusions from data generated in these models. This perspective provides a narrative of several such instances and provides recommendations as to how we might address our knowledge gap by better characterization of our models, better understanding of our practices, and better control of our studies.

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“…A 1 H NMR metabolomics study revealed the existence of at least two different phenotypes according to their colony of origin. Differences in the metabolite profiles of urine have been correlated with changes in the microbiome, likely due to animal housing. ,, These modifications may affect the responses of these rats in several pharmacological models, thereby also affecting the validity and reproducibility of the results generated with the models. This study highlighted the following crucial problem of this “controlled” in vivo animal model: many parameters are completely ignored or underestimated, could be responsible for error in the results and/or interpretation, and could alter the drug discovery process.…”

Section: Metabolomics and Drug Discoverymentioning

confidence: 99%

“…A 1 H-NMR metabolomics study revealed the existence of at least two different phenotypes according to their colony of origin. Differences in the metabolite profiles of urine have been correlated with changes in the microbiome, likely due to animal housing 22,130,131. These modifications may affect the responses of these rats in several pharmacological models, thereby also affecting the validity and reproducibility of the results generated with the models.…”

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confidence: 99%

Metabolomics as a Challenging Approach for Medicinal Chemistry and Personalized Medicine

et al. 2016

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"Omics" sciences have been developed to provide a holistic point of view of biology and to better understand the complexity of an organism as a whole. These systems biology approaches can be examined at different levels, starting from the most fundamental, i.e., the genome, and finishing with the most functional, i.e., the metabolome. Similar to how genomics is applied to the exploration of DNA, metabolomics is the qualitative and quantitative study of metabolites. This emerging field is clearly linked to genomics, transcriptomics, and proteomics. In addition, metabolomics provides a unique and direct vision of the functional outcome of an organism's activities that are required for it to survive, grow, and respond to internal and external stimuli or stress, e.g., pathologies and drugs. The links between metabolic changes, patient phenotype, physiological and/or pathological status, and treatment are now well established and have opened a new area for the application of metabolomics in the drug discovery process and in personalized medicine.

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Communication Regarding Metabonomic Identification of Two Distinct Phenotypes in Sprague-Dawley (Crl:CD(SD)) Rats

Cited by 11 publications

References 1 publication

Metabonomic Evaluation of Schaedler Altered Microflora Rats

Metabonomic Evaluation of Schaedler Altered Microflora Rats

The Muddle of Models: What You Donʼt Know Can Hurt You

Metabolomics as a Challenging Approach for Medicinal Chemistry and Personalized Medicine

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