Methylazoxymethanol

Methylazoxymethanol (MAM) is a potent carcinogen present in the nuts of cycad trees as methylazoxymethanol b-D-glucoside and is commonly used in a synthetic form, methylazoxymethanol acetate (MAM-Ac), to produce experimental neoplasms in fish (Hawkins et al., 1988a) and mammals (Sohn et al., 1991). Methylazoxymethanol and related compounds are not important as environmental pollutants, but 1,1-dimethylhydrazine, a metabolic precursor of MAM, is manufactured as a rocket fuel (NIEHS, 1991). Methylazoxymethanol is metabolized to carbonium ions that alkylate DNA in the same manner as the nitrosamines. Enzymes necessary to metabolize MAM compounds to ultimate carcinogens are species, tissue and age specific, leading to considerable variability in tumour incidence and type between fish of different species and ages.

In an experiment in which seven species of fish were exposed to MAM-Ac when they were 6-10 days old, frequency of hepatic neoplasms ranged from 7 to

67% (Hawkins et al., 1988a). The highest incidence of neoplasms occurred in guppies, with a latent period of about 1 month. In contrast, the lowest incidence occurred in fathead minnows (Pimephales promelas), which had a latent period of 6 months. Medaka, guppy and sheepshead minnow had the most diversity of tumour types; neoplasms were found in six tissues of medaka exposed to MAM-Ac. In addition, a single medaka was found with an exocrine pancreatic carcinoma, but the low incidence of this lesion prevents a conclusive link to MAM-Ac exposure (Hawkins et al., 1991).

In a similar study, western mosquitofish (Gambusia affinis) were exposed to 10 mg l-1 MAM-Ac for 2 hours and developed hepatocellular and cholangio-cellular neoplasms within 25 weeks (Law et al., 1994). By 40 weeks, 52% had hepatic neoplasms, but lesions were found only in the liver.

The types of neoplasms that develop in medaka after MAM-Ac exposure depend on the age of fish exposed. One-year-old fish primarily develop hepatic neoplasms including hepatocellular carcinomas (trabecular and spindle shaped), cholangiomas and cholangiocarcinomas (Harada et al., 1988). Medaka exposed to MAM-Ac when only 6-10 days old develop not only hepatic neoplasms but also rhabdomyosarcoma, fibrosarcoma, nephroblastoma, undifferentiated mesenchymal sarcoma, medulloepithelioma (Hawkins et al., 1988a), leiomyosarcoma and haemagiopericytoma (Fabacher et al., 1991).

Retinal medulloepitheliomas arise from the primitive medullary epithelium and form three cellular patterns in medaka exposed to MAM-Ac (Hawkins et al., 1986). Cells differentiating along the photoreceptor cell pathway form neoplasms that contain photoreceptor cells that are frequently in ductular or rosette patterns. Those with rosette patterns are especially interesting because of their resemblance to human retinoblastomas. Medulloepithelioma cells differentiating toward cells other than photoreceptors form pigmented neoplasms of cuboidal or columnar cells in a glandular pattern. A third type of eye tumour found in medaka exposed to MAM-Ac is invasive teratoid neoplasms that differentiate into striated muscle, mesenchymal tissues and hyalin cartilage.

Guppies exposed to low doses (10 mg l-1 or less) of MAM-Ac for 2 hours develop adenomas or carcinomas of the exocrine pancreas with a frequency of about 9% (Fournie et al., 1987). Interestingly, guppies exposed to higher concentrations of MAM-Ac did not develop pancreatic neoplasms. This inverse dose response could be related to higher mortality of guppies treated with 50-100 mg l-1 MAM-Ac, but an inverse relationship between dose of carcinogen and incidence of pancreatic carcinomas was also found by Thiyagarajah and Grizzle (1986). The exocrine pancreatic neoplasms in guppies fall into three categories: (i) adenomas consisting of large masses of well-differentiated pancreatic cells in a pattern similar to that of normal pancreas and containing zymogen granules; (ii) acinar cell carcinomas that are invasive and vary from well differentiated to poorly differentiated; and (iii) adenocarcinomas of ductal elements containing eosinophilic material. The similarity in appearance and location between the poorly differentiated acinar cells described by Fournie et al. (1987) and the hepatocytes in some forms of hepatocellular carcinomas is probably an impediment to the diagnosis of exocrine pancreatic neoplasms.

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