The Effects of AD Libitum (AL) Overfeeding and Moderate Dietary Restriction (DR) on the Incidence of Spontaneous Corneal Dystrophy in Control Sprague-Dawley (SD) Rats

Hubert, Marie-Françoise; Laroque, Ph.; Durand-Cavagna, G.; Delort, P; Keenan, Kevin P.

doi:10.1007/978-1-4615-5937-5_8

Cited by 2 publications

(5 citation statements)

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“…No ophthalmoscopic or histological differences were seen between the AL-fed and 2 moderate DR-fed groups over the course of this study. However, the group 4 (50% DR) rats of both sexes had the lowest incidence and least severe lesions of corneal dystrophy (multifocal linear or pinpoint areas of mineralization in the corneal basement membrane) that correlated with the significantly lower clinical incidence of corneal opacities observed ophthalmoscopically, and were consistent with our previous studies (Hubert et al, 1997). In addition, the marked DR-fed group 4 animals also had the highest incidence of retinal atrophy, which was seen ophthalmologically as retinal hyperreflexia.…”

Section: Pituitarysupporting

confidence: 91%

“…Therefore, targeting the metabolic syndrome as a whole rather than specifically dissecting each one of its subcomponents should be considered as a key objective in the development of models to test treatments and management programs of this important human syndrome. In this regard, the Charles River outbred SD rat appears to represent an excellent polygenic model that is only now beginning to be thoroughly phenotyped and understood from the perspective of an animal model of diabesity (Gumprecht et al, 1993;Klinger et al, 1996;Keenan et al, 1997Keenan et al, , 1994aKeenan et al, , 1994bKeenan et al, , 1995Keenan et al, , 1996Keenan et al, , 1999Keenan et al, , 2000aKeenan et al, , 2000bHubert et al, 1997Hubert et al, , 2000Laroque et al, 1997;Levin et al, 1997Levin et al, , 2000Hoe et al, 1998;Vermorel et al, 1998;Molon-Noblot et al, 2001Kemi et al, 2000). While not all of the phenotypic and genetic characteristics of this stock have yet been well defined, the results of this study and previous work indicate that when ALfed this animal clearly has a well-developed set of phenotypic characteristics that would be best described as diabesity.…”

Section: Discussionmentioning

confidence: 99%

“…This results in a better experimental toxicity model by reducing the “noise” of background diseases while allowing an increased duration of exposure to test substances for the evaluation of the potential carcinogenicity and toxicity in long-term studies. The adverse effects of ad libitum (AL)-overfeeding on the early development of many spontaneous tumors and degenerative diseases of this SD outbred stock (Gumprecht et al, 1993; Keenan et al, 1994a, 1994b, 1995a, 1995b, 1996, 1999, 2000a, 2000b; Dixit et al, 1996; Keenan et al, 1997; Hubert et al, 1997; Laroque et al, 1997; Hoe et al, 1998; Vermorel et al, 1998; Hubert et al, 2000; Kemi et al, 2000; Molon-Noblot et al, 2003) and other aged rat strains (McCay et al, 1935; Burek, 1978; Tucker, 1979; Ross et al, 1983; Kritchevsky et al, 1984; Maeda et al, 1985; Berry, 1986; Masoro et al, 1989; Laganiere and Yu, 1989a, 1989b; Yu et al, 1989; Mietes, 1990; Chapin et al, 1993; Grasl-Kraupp et al, 1994; Merry and Holehan, 1994; Sonntag and Yu 1994; Roe et al, 1995; Masoro et al, 1996; Masoro and Austad, 1996; McShane and Wise, 1996; Seki et al, 1997; Kritchevsky, 1999; Sonntag, 1999; Duffy et al, 2001; Haseman et al, 2003; Wan et al, 2003) have been reported. However, the role of AL-overfeeding in the pathogenesis of dietary-induced obesity (DIO) and the metabolic syndrome (syndrome X) associated with adult-onset diabetes, or “diabesity” (Levin et al, 1997; Leiter, 2002; Reifsnyder and Leiter, 2002; Axen et al, 2003) in SD rats has not been fully investigated or exploited as a model of the polygenic diabesity syndrome which is common in heterozygous human populations worldwide (Klinger et al, 1996; Weindruch and Sohal, 1997; Brunner et al, 2001; Eckel et al, 2002;…”

Section: Introductionmentioning

confidence: 99%

“…This results in a better experimental toxicity model by reducing the "noise" of background diseases while allowing an increased duration of exposure to test substances for the evaluation of the potential carcinogenicity and toxicity in long-term studies. The adverse effects of ad libitum (AL)-overfeeding on the early development of many spontaneous tumors and degenerative diseases of this SD outbred stock (Gumprecht et al, 1993;Keenan et al, 1994aKeenan et al, , 1994bKeenan et al, , 1995aKeenan et al, , 1995bKeenan et al, , 1996Keenan et al, , 1999Keenan et al, , 2000aKeenan et al, , 2000bDixit et al, 1996;Keenan et al, 1997;Hubert et al, 1997;Laroque et al, 1997;Hoe et al, 1998;Vermorel et al, 1998;Hubert et al, 2000;Kemi et al, 2000;Molon-Noblot et al, 2003) and other aged rat strains (McCay et al, 1935;Burek, 1978;Tucker, 1979;Ross et al, 1983;Kritchevsky et al, 1984;Maeda et al, 1985;Berry, 1986;Masoro et al, 1989;Yu, 1989a, 1989b;Yu et al, 1989;Mietes, 1990;Grasl-Kraupp et al, 1994;Merry and Holehan, 1994;Sonntag and Yu 1994;Roe et al, 1995;Masoro et al, 1996;Masoro and Austad, 1996;McShane and Wise, 1996;Seki et al, 1997;…”

Section: Introductionmentioning

confidence: 99%

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Diabesity: A Polygenic Model of Dietary-Induced Obesity from Ad Libitum Overfeeding of Sprague–Dawley Rats and Its Modulation by Moderate and Marked Dietary Restriction

et al. 2005

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This study compared the effects of ad libitum (AL) overfeeding and moderate or marked dietary restriction (DR) on the pathogenesis of a metabolic syndrome of diabesity comprised of age-related degenerative diseases and obesity in a outbred stock of Sprague-Dawley (SD) rats [Crl:CD (SD) IGS BR]. SD rats were fed Purina Certified Rodent Diet AL (group 1), DR at 72-79% of AL (group 2), DR at 68-72% of AL (group 3) or DR at 47-48% of AL (group 4) for 106 weeks. Interim necropsies were performed at 13, 26, and 53 weeks, after a 7-day 5-bromo-2-deoxyuridine (BrdU)-filled minipump implantation. Body weights, organ weights, carcass analysis, in-life data including estrous cyclicity, and histopathology were determined. At 6-7 weeks of age SD rats had 6% body fat. AL-feeding resulted in hypertriglyceridemia, hypercholesterolemia, and dietary-induced obesity (DIO) by study week 14, with 25% body fat that progressed to 36-42% body fat by 106 weeks. As early as 14 weeks, key biomarkers developed for spontaneous nephropathy, cardiomyopathy, and degenerative changes in multiple organ systems. Early endocrine disruption was indicated by changes in metabolic and endocrine profiles and the early development and progression of lesions in the pituitary, pancreatic islets, adrenals, thyroids, parathyroids, liver, kidneys, and other tissues. Reproductive senescence was seen by 9 months with declines in estrous cyclicity and pathological changes in the reproductive organs of both sexes fed AL or moderate DR, but not marked DR. The diabesity syndrome in AL-fed, DIO SD rats was readily modulated or prevented by moderate to marked DR. Moderate DR of balanced diets resulted in a better toxicology model by significantly improving survival, controlling adult body weight and obesity, reducing the onset, severity, and morbidity of age-related renal, endocrine, metabolic, and cardiac diseases. Moderate DR feeding reduces study-to-study variability, increases treatment exposure time, and increases the ability to distinguish true treatment effects from spontaneous aging. The structural and metabolic differences between the phenotypes of DIO and DR SD rats indicated changes of polygenic expression over time in this outbred stock. AL-overfeeding of SD rats produces a needed model of DIO and diabesity that needs further study of its patterns of polygenic expression and phenotype.

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Section: Pituitarysupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Diabesity: A Polygenic Model of Dietary-Induced Obesity from Ad Libitum Overfeeding of Sprague–Dawley Rats and Its Modulation by Moderate and Marked Dietary Restriction

et al. 2005

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“…Although several drugs induce retinal atrophy, a spontaneous liner hyper reflectivity of fundus is frequently observed in albino rats (Fig. 4) (Hubert et al, 1994). Diffused hyper reflectivity of fundus due to light-induced damage is often occurred in albino rats (Fig.…”

Section: Ophthalmological Examinations In Nonclinical Toxicity Studiesmentioning

confidence: 99%

General considerations in ocular toxicity risk assessment from the toxicologists’ viewpoints

et al. 2015

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-Humans commonly obtain approximately 80% of external information from vision. Since loss of vision markedly decreases quality of life, risk assessments for visual toxicity of new drugs are extremely important. However, the ICH S4 guideline for nonclinical toxicity study of new drugs only indicates a brief instruction for ophthalmologic examinations, and submitted data for drug approval according only to this guideline are not always considered sufficient in light of ocular toxicity risk assessments. The eye is an assembly of many specialized sub-organs which have specific functions, and its integral maintenance of homeostasis plays an important role of visual function. When only a part of integrity of functions is lost, overall function of the eye might be commonly disturbed. Therefore, understanding of anatomy and physiology of these sub-organs may help know mechanisms of observed ocular changes. In ophthalmologic examinations in nonclinical toxicity studies, it is vital to understand the principles and features of each examination. Comparisons of findings between pre and post drug treatment as well as considerations of species differences, strain differences, age differences, and location/degree of abnormalities are essential. In addition, many kinds of spontaneous ocular findings are well known in experimental animals. To differentiate treatment-related changes from spontaneous findings, mastering basic skills for ophthalmologic examinations and taking advantage of collection of background data are necessary. For ocular toxicity risk assessments, while an evaluation of "sight-threatening" effects is most critical matter, "quality of vision" related findings also should be considered. To extrapolate animal data to human, clinical significances of ocular toxicity findings should be evaluated based on considerations for "species differences", "safety margins", "reversibility", and "risk-benefit balance". In addition, a detailed recording of features of lesions is also important for an appropriate judgment of clinical significance of ocular findings. For preparation of histopathological specimens, careful sampling of organs and suitable selection of fixatives are important. To accurately orient ocular lesions in the specimen for histopathological examinations, securing close communications prior to necropsy among ophthalmologists, gross necropsy pathologists and histopathology technicians should be effective and helpful. It is impossible to detect all ocular changes in histopathological examinations; that is, there is a limitation in histopathological examinations. Therefore, for ocular toxicity risk assessments, comprehensive evaluation with pathological findings as well as other results of various examinations in toxicity studies should be considered. In conclusion, for ocular toxicity risk assessments, integrated judgments from all examination data in nonclinical toxicity studies are required. To achieve appropriate risk assessments which can be extrapolated to human, close communications and sharing...

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The Effects of AD Libitum (AL) Overfeeding and Moderate Dietary Restriction (DR) on the Incidence of Spontaneous Corneal Dystrophy in Control Sprague-Dawley (SD) Rats

Cited by 2 publications

References 4 publications

Diabesity: A Polygenic Model of Dietary-Induced Obesity from Ad Libitum Overfeeding of Sprague–Dawley Rats and Its Modulation by Moderate and Marked Dietary Restriction

Diabesity: A Polygenic Model of Dietary-Induced Obesity from Ad Libitum Overfeeding of Sprague–Dawley Rats and Its Modulation by Moderate and Marked Dietary Restriction

General considerations in ocular toxicity risk assessment from the toxicologists’ viewpoints

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