Pathology of Aging in NOD scid gamma Female Mice

Abstract

In the past decade, NOD.Cg- Prkdc^scid Il2rg^tm1Wjl/SzJ (NSG, NOD scid gamma) mice have become a model of choice in several areas of biomedical research; however, comprehensive data on their spontaneous age-related pathology are not currently available in the literature. The prevalence of spontaneous morbidity affecting aged NSG female breeders enrolled in a parasitology study was documented with classification of neoplastic and non-neoplastic (inflammatory, metabolic, degenerative) lesions. Malignant mammary neoplasms were most commonly diagnosed, often accompanied by pulmonary metastases, while a low frequency of lymphoma and histiocytic sarcoma was documented. The major inflammatory conditions were suppurative pleuropneumonia and bronchopneumonia with abscess formation, from which Pasteurella pneumotropica was commonly isolated, followed by otitis media. Both inflammatory and degenerative lesions of the genital tract were identified, along with neoplasms such as endometrial yolk sac carcinomas and granulosa cell tumors. Novel conditions identified included renal tubular degeneration and necrosis associated with 2 concurrent types of intranuclear inclusions, focal or multifocal hyperostosis of the skull, and neuroendocrine tumors of the mesometrium. The majority of degenerative lesions that affected the genital tract, endocrine, and skeletal systems did not represent the actual underlying cause of death but rather were considered incidental findings. This study indicates that both inflammatory and neoplastic conditions contribute to morbidity and mortality in experimentally manipulated aged female NSG mice.

Keywords: aging; background lesions; female; interleukin-2 receptor gamma chain knockout; mouse; non-obese diabetic; pathology; severe combined immunodeficiency.

Figure 1

Abscesses, lung, mouse. The right cranial lung lobe is obscured by multiple coalescing, variably sized, pale tan to yellow abscesses caused by Pasteurella pneumotropica infection.

Figure 2

Adenosquamous carcinoma, mammary gland, mouse. The neoplasm is composed of microacinar epithelial structures intermingled with cavities lined by stratified squamous epithelium producing keratin. Inset: Scattered keratohyalin and trichohyalin granules are also present. Hematoxylin and eosin (HE).

Figure 3

Parietal yolk sac carcinoma, uterus, mouse. In the endometrium, acini lined by flattened epithelial cells are associated with an abundant extracellular eosinophilic hyaline substance. HE. Inset: This material is immunohistochemically positive for laminin.

Figure 4

Parietal yolk sac carcinoma, uterus, mouse. The hyaline substance is PAS-positive. Periodic acid-Shiff reaction (PAS).

Figure 5

Neuroendocrine carcinoma, mesometrium, mouse. The tumor is arranged in densely cellular packets of cells separated by delicate fibrovascular septa. HE. Inset: The neoplastic cells display strong cytoplasmic expression of chromogranin A, compatible with neuroendocrine differentiation. Immunohistochemistry for chromogranin A.

Figure 6

Precursor T-cell lymphoblastic lymphoma, mesenteric lymph node, mouse. The nodal parenchyma is obscured by dense sheets of intermediate-sized neoplastic lymphoid cells with scant cytoplasm, round nuclei with finely granular chromatin, and several mitotic Figures. HE.

Figure 7

Orthokeratotic hyperkeratosis with intralesional Candida spp., haired skin, mouse. Diffuse superficial accumulation of keratin flakes intermingled with yeasts, septate hyphae and occasional pseudohyphae, compatible with Candida spp. HE. Inset: The aforementioned fungal forms stain positive with periodic acid-Shiff reaction (PAS).

Figure 8

Intranuclear inclusion bodies of unknown etiology, kidney, mouse. Multiple tubular epithelial cells exhibit karyomegaly with large, 15- to 20-µm diameter, amphophilic intranuclear inclusions and margination of chromatin (arrowheads). Scattered small, 3- to 5-µm diameter, round bright eosinophilic intranuclear inclusions are also present (arrow). HE.

Figure 9

Intranuclear inclusion bodies of unknown etiology, renal tubular epithelium, mouse. The nuclei of karyomegalic cells consists of abundant electron-lucent floccular material. The remaining chromatin is peripheralized, and the nuclear membrane is intact. Inset: Rare nuclei display enlarged nucleoli that are expanded by a similar material (arrow). Scale bar: 5 µm. Transmission electron microscopy (TEM).

Figure 10

Proliferative hyperostosis, calvarium, mouse. There is diffuse formation of woven and lamellar bone along the calvarium, with intracranial extension and compression of the brain (arrow). HE. Inset: Despite the compression, the underlying cerebrum appears normal. HE.

Figure 11

Disc protrusion with leukomyelomalacia, spinal cord, mouse. A focal protrusion of the annulus fibrosus is evident at the level of the thoracic segment. HE. Inset: There is evidence of myelin sheath dilation (Wallerian degeneration) of the underlying spinal cord segment. HE.

Figure 12

Multifocal renal atrophy and interstitial fibrosis, kidney, mouse. The cortex and medulla display multifocal interstitial fibrosis, with tubular atrophy and loss, and cystic dilation of the urinary space. HE.