European Society of Toxicologic Pathology (ESTP)
    European Society of Toxicologic Pathology
Guess What! - ESTP Case 26

Case Background Information

This fish was a retired broodstock of the zebrafish transparent line absolute (ednrb1ab140; mitfab692) mutant line. Gross lesions were not observed at necropsy on this fish. This fish was 1 year old, which is young to retire broodstock, but both males and females of this line seem to "burn out young" in terms of breeding. Most broodstock of other wild-type and mutant lines are still productive at 1.5 year of age. Here is a link regarding the mutant genes in this zebrafish line.
zebrafish.org/fish/lineAll.php?t=Anything&sverb=containing&c=absolute&searchMenuQuick=Go

Click on the images below for a larger view.
Case 20, Fig. 1
Fig. 1: Ovary, normal 2.5x
Case 20, Fig. 1
Fig. 2: Atrophic areas of lamellae 2.5x
Case 20, Fig. 1
Fig. 3: Atrophic areas of lamellae 5x
Case 20, Fig. 1
Fig. 4: Atrophic areas of lamellae 10x
Case 20, Fig. 1
Fig. 5: Atrophic areas of lamellae 20x
Case 20, Fig. 1
Fig. 6: Atrophic areas of lamellae 40x

Genotype (Background) Allele [previous names] Affected Gene(s) [previous names]
ednrb1ab140; mitfab692 b140
b692
ednrba [ednrb1, ednrb1a, ros, rose, rse, absolute]
mitfa [Mitf2, Mitf-related gene, nac, nacre, z3A.1, absolute]

Morphologic Description

This ovary has regions with ovigerous lamellae showing normal developing and vitellogenic follicles. However, multifocal segments of the ovigerous lamellae are completely atrophic, with no residual follicular structures. The atrophic segments of lamellae are composed of clusters of macrophages with amorphous eosinophilic material in their cytoplasm. Occasional macrophages filled with yellow-brown lipofuscin-like material are present among the eosinophilic macrophage clusters.

Contributors Comments and Morphologic Diagnoses

Eight contributor posts with comments and/or morphologic diagnoses were submitted. These ranged from a diagnosis of lamellar atrophy with possible residual Leydig cells, possible intersex, ovarian atresia with egg debris, multifocal atrophy/atresia of oocytes, oocyte atresia with interstitial hyperplasia, mesothelial hyperplasia, macrophage aggregates, granulomatous inflammation, increased amount of yolk granules, increased atretic follicles.

I did not observe mesothelial hyperplasia, vacuolated interstitial cells, Sertoli cells, or evidence of intersex. The macrophages present appear to have scavenged previtellogenic atretic oocytes. This pattern differs from the more disorganized granulomatous inflammation occurring in egg-associated inflammation in zebrafish or chronic granulomatous inflammation occurring with piscine mycobacteriosis.

Case Discussion

Zebrafish has become a leading model species for basic biomedical research because of its small size, continuous breeding, short generation time, ease of cloning, fully sequenced genome, and abundance of mutant lines for study of models for human disease. In recent years, several zebrafish mutant lines which are transparent throughout life allow unprecedented in vivo studies of developmental processes, tumor progression, and host-pathogen interactions. Several of the genes mutated in these transparent mutant lines have been associated with ovarian abnormalities when mutated in humans and mice. For example, ovarian hypoplasia and atrophy have occurred in humans and mice with oculocutaneous albinism, vitiligo, Waardenburg syndrome, KIT mutations. Neurogenic neural crest tissue plays an essential role in ovarian development and homeostasis. Thus, mutations in the genes regulating pigment production by neural crest cells can have significant effects on ovarian morphology and function.

Proposed Diagnosis
Severe multifocal locally extensive atrophy of ovigerous lamellae

References

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  • Kissel H, Timokhina I, Hardy MP, Rothschild G, Tajima Y, Soares V, Angeles M, Whitlow SR, Manova K, Besmer P (2000) Point mutation in kit receptor tyrosine kinase reveals essential roles for kit signaling in spermatogenesis and oogenesis without affecting other kit responses. EMBO J 19(6): 1312-1326.
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