Adrenal Gland Background Findings in CD-1 (Crl:CD-1(ICR)BR) Mice from 104-week Carcinogenicity Studies

Petterino, Claudio; Naylor, Stuart W.; Mukaratirwa, Samson; Bradley, Alys

doi:10.1177/0192623315587921

Cited by 13 publications

(5 citation statements)

References 33 publications

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“…Up to 70% of the irradiated animals presented the change, whereas the background incidence is usually below 10%. 38 This needs to be considered when evaluating the toxicity of the GTMP.…”

Section: Discussionmentioning

confidence: 99%

Conditioning Regimens in Long-Term Pre-Clinical Studies to Support Development of Ex Vivo Gene Therapy: Review of Nonproliferative and Proliferative Changes

et al. 2021

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Hematopoietic stem cell gene therapy has become a successful therapeutic strategy for some inherited genetic disorders. Pre-clinical toxicity studies performed to support the human clinical trials using viral-mediated gene transfer and autologous hematopoietic stem and progenitor cell (HSPC) transplantation are complex and the use of mouse models of human diseases makes interpretation of the results challenging. In addition, they rely on the use of conditioning agents that must induce enough myeloablation to allow engraftment of transduced and transplanted HSPC. Busulfan and total body irradiation (TBI) are the most commonly used conditioning regimens in the mouse. Lenticular degeneration and atrophy of reproductive organs are expected histopathological changes. Proliferative and nonproliferative lesions can be observed with different incidence and distribution across strains and mouse models of diseases. The occurrence of these lesions can interfere with the interpretation of pre-clinical toxicity and tumorigenicity studies performed to support the human clinical studies. As such, it is important to be aware of the background incidence of lesions induced by different conditioning regimens. We review the histopathology results from seven long-term studies, five using TBI and two using busulfan.

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“…Up to 70% of the irradiated animals presented the change, whereas the background incidence is usually below 10%. 38 This needs to be considered when evaluating the toxicity of the GTMP.…”

Section: Discussionmentioning

confidence: 99%

Conditioning Regimens in Long-Term Pre-Clinical Studies to Support Development of Ex Vivo Gene Therapy: Review of Nonproliferative and Proliferative Changes

et al. 2021

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“…They can also contribute, albeit at low frequency, to adrenal cortex replenishment in the adult (6,9,18,19,33), and can be mobilized upon gonadectomy, giving rise to adrenal neoplasia (34,35), presenting characteristics of adrenogonadal cells such as GATA4, LHR, and PDGFRα expression (19). Interestingly, aging mouse adrenals also present subcapsular accumulation of spindle-shaped cells (36,37). Although lineage tracing has shown that gonadectomy-induced lesions arise in part from WT1/GLI1-positive cells, the origin of spindle-shaped cells in the aging adrenal cortex is not as clear, even though GLI1-positive cells may contribute to their appearance (19).…”

Section: Discussionmentioning

confidence: 99%

Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex

Mathieu

Drelon

Rodriguez

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Adrenal cortex steroids are essential for body homeostasis, and adrenal insufficiency is a life-threatening condition. Adrenal endocrine activity is maintained through recruitment of subcapsular progenitor cells that follow a unidirectional differentiation path from zona glomerulosa to zona fasciculata (zF). Here, we show that this unidirectionality is ensured by the histone methyltransferase EZH2. Indeed, we demonstrate that EZH2 maintains adrenal steroidogenic cell differentiation by preventing expression of GATA4 and WT1 that cause abnormal dedifferentiation to a progenitor-like state in Ezh2 KO adrenals. EZH2 further ensures normal cortical differentiation by programming cells for optimal response to adrenocorticotrophic hormone (ACTH)/PKA signaling. This is achieved by repression of phosphodiesterases PDE1B, 3A, and 7A and of PRKAR1B. Consequently, EZH2 ablation results in blunted zF differentiation and primary glucocorticoid insufficiency. These data demonstrate an all-encompassing role for EZH2 in programming steroidogenic cells for optimal response to differentiation signals and in maintaining their differentiated state.

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“…Aging female mice of A, C57BL/6, BALB/c DBA/2, 6 CD-1 (Crl:CD 1(ICR)BR), 49 and FVB 36 strains have a higher incidence of adrenal subcapsular fusiform cell hyperplasia compared to males, although these changes were minimally present in female NSG mice.…”

Section: Discussionmentioning

confidence: 99%

Pathology of Aging in NOD scid gamma Female Mice

et al. 2017

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In the past decade, NOD.Cg-Prkdcscid Il2rgtm1Wjl/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.

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Adrenal Gland Background Findings in CD-1 (Crl:CD-1(ICR)BR) Mice from 104-week Carcinogenicity Studies

Cited by 13 publications

References 33 publications

Conditioning Regimens in Long-Term Pre-Clinical Studies to Support Development of Ex Vivo Gene Therapy: Review of Nonproliferative and Proliferative Changes

Conditioning Regimens in Long-Term Pre-Clinical Studies to Support Development of Ex Vivo Gene Therapy: Review of Nonproliferative and Proliferative Changes

Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex

Pathology of Aging in NOD scid gamma Female Mice

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