Histopathological features of the proper gastric glands in FVB/N-background mice carrying constitutively-active aryl-hydrocarbon receptor

Ai Dantsuka,Yaser Hosny Ali Elewa,Teppei Nakamura,Saori Otsuka-Kanazawa,Osamu Ichii,Annika Hanberg,Yasuhiro Kon

doi:10.1186/s12876-019-1009-x

Abstract

BackgroundAryl-hydrocarbon receptor (AhR) is a multiple ligand-activated transcription factor that has important roles in xenobiotic, physiological, or pathological functions. Transgenic mice systemically expressing constitutively-active AhR (CA-AhR) have been created to mimic activated AhR signaling in vivo. However, their detailed histopathological features are unclear. In the present study, we generated CA-AhR-expressing FVB/N mice (FVB-CA-AhR mice) and clarified their phenotypes in detail.MethodsMale and female FVB-CA-AhR and wild-type mice were histopathologically examined from 6 to 33 weeks of age.ResultsAmong the systemic organs, only the stomachs in FVB-CA-AhR mice showed pathological changes including cystic structures beneath the serosa; in addition, stomach weights increased with age. Histopathologically, cystic structures and alcian blue-positive metaplasia were observed in the mucosa of the proper gastric glands, and these two histometric parameters were positively correlated. Furthermore, proliferating cells shifted from the isthmus to the base of the glands, and parietal cells decreased. Age-related histopathological changes were clearer in females than in males. Importantly, in FVB-CA-AhR mice, intramucosal cysts developed as extramucosal cysts beneath the serosa, penetrating the lamina muscularis mucosae and the muscularis propria. Their incidence reached 100% in 28-week-old male mice and 33-week-old female mice. Extramucosal cysts contained alcian blue-, Griffonia simplicifolia lectin II-, or trefoil factor 2-positive cells, suggesting a stomach origin for the cysts and spasmolytic polypeptide-expressing metaplasia-like lesions.ConclusionsDisease onset occurred earlier in FVB-CA-AhR mice than previously reported in C57BL/6-derived CA-AhR mice. Importantly, the histopathological features were partly similar with gastritis cystica profunda in humans and animals. Excessive activation of AhR signaling aggravated abnormalities in the gastric mucosa and were affected by both genetic- and sex-related factors.

Highlights

Aryl-hydrocarbon receptor (AhR) is a multiple ligand-activated transcription factor that has important roles in xenobiotic, physiological, or pathological functions
Body weights of FVB-constitutivelyactive AhR (CA-AhR) and wild-type mice increased comparably with age, and significant sex-related differences were observed in both FVB-CA-AhR and wild-type mice (Fig. 1a)
Stomachs of FVB-CA-AhR mice showed cystic structures beneath the serosa on the parietal and visceral surfaces (Fig. 1c); these structures were only localized around the lesser curvature

Summary

Introduction

Aryl-hydrocarbon receptor (AhR) is a multiple ligand-activated transcription factor that has important roles in xenobiotic, physiological, or pathological functions. Transgenic mice systemically expressing constitutivelyactive AhR (CA-AhR) have been created to mimic activated AhR signaling in vivo. Aryl-hydrocarbon receptor (AhR) is widely expressed in various animal species and in humans. AhR is a multiple ligand-binding transcription factor and a member of the basic helix-loop-helix/Per-Arnt Sim domain proteins [1, 2]. AhR is constantly expressed in various organs and plays an important role in xenobiotic metabolism [3, 4]. AhR binds to endogenous ligands, including heme-, arachidonic acid-, or tryptophan-derived metabolites, such as 6-formylindolo[3,2-b]carbazole (FICZ) and indoxyl sulfate [6, 7]

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Results

Discussion

Conclusion