Right Ventricular Epicardial Fibrosis in Mice With Sternal Segment Dislocation

Abstract

We report coincident sternal segment dislocation and focally extensive right ventricular epicardial fibrosis observed during routine histopathology evaluation of C57BL/6N mice as part of a high throughput phenotyping screen conducted between 4 and 16 weeks of age. This retrospective case series study was conducted to determine whether cardiac fibrosis was a pathological consequence of sternal segment dislocation. We identified sternal segment dislocation in 51 of the total 1103 mice (4.6%) analyzed at 16 weeks of age. Males were more frequently affected. In all cases but 2, the dislocation occurred at the fourth intersternebral joint. In 42 of the 51 cases (82.4%), the dislocation was encased by regenerative cartilaginous callus that protruded internally into the thoracic cavity (intrathoracic callus) and/or externally to the outer aspect of the sternum (extrathoracic callus). Displacement of dislocated ends of the sternum into the thoracic cavity was present in 19 of 51 cases (36.5%). Coincident minimal or mild right ventricular epicardial and subepicardial fibrosis was observed in 22 of the 51 cases (43%) but was not observed in any of the mice in the absence of sternal segment dislocation. Our data suggest that right ventricular fibrosis was likely caused by direct injury of the right ventricle by the dislocated ends of the sternum and/or by intrathoracic callus that develops post dislocation. Potential pathogenesis for the sternal and cardiac lesions and their implication for the interpretation of phenotypes in mouse models of cardiopulmonary and skeletal disease are discussed.

The occurrence of tarsal injuries in male mice of C57BL/6N substrains in multiple international mouse facilities

“…Conversely, there are reports of sporadic, low-level defects in inbred lines which are likely due to oligogenic or polygenic effects and exhibit variable penetrance thus only observed or measured in a proportion of the population of an inbred colony [3]. These include complex behaviours such as aggression [4], hyperactivity [5], morphological anomalies such as sternal segment dislocation [6] and developmental defects such as hydrocephalus (https://www.jax. org/news-and-insights/2003/july/hydrocephalus-in-laboratory-mice).…”

Reactive mesothelial hyperplasia mimicking mesothelioma in an African green monkey (<i>Chlorocebus aethiops</i>)

“…Besides humans, mesothelial hyperplasia is reported in monkeys (Sato et al, 2012;Winn et al, 2018), dogs (Milne et al, 2018), cats (Weiss and Scott, 1981), rabbits (Dalton and Chun, 1966), horses (Hoon-Hanks et al, 2016), cattle (Gold-smith and Adaska, 2020), rats (Slater et al, 1991), and mice (Adissu et al, 2015).…”

“…However, the finding of homozygous deletion of p16 by fluorescence in situ hybridization (FISH) or the loss of BRCA1 associated protein 1 (BAP1) by immunohistochemistry is found only in mesotheliomas (Husain et al, 2018). Using gene-expression-based tests for BAP1 and p16 analysis might become a reliable tool to distinguish benign from malignant mesothelial proliferations (Ali et al, 2020).…”

The Vital Role of Pathology in Improving Reproducibility and Translational Relevance of Aging Studies in Rodents

“…With physiological phenotyping, findings may not fully contribute to determining the cause of morbidity or death without histopathological confirmation, and indeed important phenotypes may be entirely missed. 2,3,16 For example, a recent study by Adissu et al 2 on a random selection of mutants from the International Mouse Phenotyping Consortium (IMPC) primary phenotyping pipeline found that histopathology added correlating morphological data in 63% of cases for which the primary physiological screen detected a phenotype, and 14% presented significant histopathology findings that were not predicted by the standard primary physiological screen. On the other hand, if pathology findings do not discover the cause of illness, other phenotype data may aid in the determination of the cause of morbidity and mortality.…”