N-Methyl-N'-Nitro-N-Nitrosoguanidine-Induced Neoplasms in Medaka (Oryzias latipes)*¹

Abstract

To test the sensitivity of the small fish species Oryzias latipes to the direct-acting carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), medaka were exposed at 15 days of age to 30 mg/L for 1 hr and followed for up to 16 mo. One hundred neoplasms were diagnosed in 84 of 213 exposed fish, with approximately equal percentages in males and females. Many neoplasms (62%) were of mesenchymal origin and were categorized as blood vascular neoplasms (hemangioma and hemangiosarcoma), invasive sarcomas, and scale-associated neoplasms. Invasive sarcomas included rhabdomyosarcoma, fascial sarcoma, hemangiopericytoma, and undifferentiated sarcoma. A scale-associated neoplasm, termed lepidocytoma, was an unusual neoplasm of scale anlage. Thyroid follicular neoplasms, with a 100% incidence in males, and pancreatic acinar carcinoma were the most common epithelial tumors. Neoplasms of the gills, swim bladder, and olfactory epithelium were also seen as well as teratoma with mixed epithelial and mesenchymal components. The study showed a broad range of neoplasms induced by MNNG in medaka, with a tissue distribution that might support direct action on exposed tissues.

Reactivity of Tissue-Specific Antigens in N-Methyl-N'-Nitro-N-Nitrosoguanidine-Induced Neoplasms and Normal Tissues from Medaka (Oryzias latipes)*1

“…6a, b). The cellular density, stromal compartment, and deposition of scale varied between tumors (7). All of the neoplasms were negative for actin, vimentin, neurofilament proteins, and S-100 protein.…”

“…Medaka (Oryzias latipes) were housed and maintained in accordance to established standards as previously described (3,7) (Fig. 6a, b).…”

“…Other antigens, including oncogenes and tumor suppressor genes (16,17), actin (6), and neuron-specific enolase and S-100 (33), have also been detected in fish neoplasms. In the present study, the exposure of medaka to the carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) resulted in the development of predominately mesenchymal neoplasms, including an unusual scale-associated neoplasm (7). This paper describes the expression of keratin, vimentin, neurofilament protein, actin, and S-100 protein in normal medaka tissues and the neoplasms induced by MNNG.…”

Use of the Japanese Medaka (Oryzias latipes) and Guppy (Poecilia reticulata) in Carcinogenesis Testing Under National Toxicology Program Protocols

“…It appears that compounds that are carcinogenic in small fish species usually express their effects in the liver or gall bladder and that was the case in these studies. However, experimental studies with a wide range of compounds indicate several other organ systems are susceptible to carcinogen-induced neoplasia (2). As with rodent tests, every compound is not amenable to the same type of testing approach.…”

Review Article: Experimental Chemical Carcinogenesis in Fish

“…Sex reversal and hermaphroditism was also in rainbow trout exposed to MNNG (88), although the hormonal mechanism was not determined. However, MNNG may function as a hormonal carcinogen with both anti-androgen and mixed glucocorticosteroid effects (106), and testicular and ovarian neoplasms have been induced in medaka exposed to MNNG (36,94). These studies illustrate the hormonal sensitivity of fish species, with both the gonad and liver as indicator organs.…”