High Background Incidence of Spontaneous Subcapsular Adrenal Gland Hyperplasia of Tg.rasH2 Mice Used in 26-week Carcinogenicity Studies

Abstract

The Tg.rasH2 model was accepted by regulatory agencies worldwide for 26-week carcinogenicity assays as an alternative to the standard 2-year assays in conventional mice in 2003. Several references documenting spontaneous nonneoplastic findings and incidences of spontaneous tumors in the Tg.rasH2 mice have been published. The purpose of this publication is to add adrenal gland subcapsular hyperplasia to the database pertaining to spontaneous lesions noted in Tg.rasH2 mice, review physiology related to this finding, and discuss its significance. The incidence of spontaneous subcapsular adrenal gland hyperplasia was determined in control Tg.rasH2 mice from nine 26-week carcinogenicity studies carried out within the last 5 years at two contract research organizations. Incidence of this finding ranged from 56% to 79% in males and 88% to 100% in females, with an incidence average of 62% in males and 93% in females. Adrenal gland subcapsular hyperplasia is a common finding in male and female Tg.rasH2 mice that did not progress to neoplasia in Tg.rasH2 mice. In general, it tends to be more frequent and severe in females in comparison to males.

Androgen Receptor Is Dispensable for X-Zone Regression in the Female Adrenal but Regulates Post-Partum Corticosterone Levels and Protects Cortex Integrity

“…Normal development and cellular turnover of the adrenal cortex is tightly linked to the balance between proliferation, differentiation and cell death ( 29 ), due to the presence of spindle cells in the outer cortex, we would expect to see perturbed cellular turnover. It has been shown that spindle cells in the adrenal cortex proliferate from the sub-capsular region, and can extend into the ZF ( 30 ). Proliferation marker, PCNA ( 31 ) and apoptosis marker, CLEAVED CASPASE 3 ( 32 ), were analyzed to determine whether the spindle cells present in Ad-ARKO adrenals is a result of perturbed cellular turnover.…”

Gardenia blue is not carcinogenic in the rasH2 mouse

“…In the present 26-weeks carcinogenicity study in transgenic rasH2 mice, no microscopic finding was noted that could be attributed to the dietary administration of gardenia blue. The range of neoplastic and non-neoplastic lesions reported in this study are well-documented and are all considered spontaneous/background findings, either specific to the transgenic rasH2 mice 34,[36][37][38]46,47,49,50 or common to inbred strains of mice. 51,52 Additionally, incidences of neoplastic lesions observed in the control group in this study were consistent with historical control data published in the literature.…”

“…Non-neoplastic lesions comprising a range of background lesions either occurred with similar incidences in control and treated animals or sporadically across all groups. Lesions such as skeletal muscle myopathy, 35 subcapsular cortical hyperplasia of the adrenal glands, 36 and epithelial hyperplasia in the thymus are typical of the transgenic rasH2 mice, whereas lesions such as chronic progressive nephropathy (CPN), cardiomyopathy, and mononuclear cell infiltrates in the lacrimal and salivary glands are common background findings in inbred mice. Neoplastic lesions observed in the stomach and thymus of animals in the positive control group confirmed the efficacy of MNU.…”