It is generally agreed that sunlight exposure is one of the etiologic agents in malignant melanoma of fairskinned individuals. However, the wavelengths responsible for tumorigenesis are not known, although DNA is assumed to be the target because individuals defective in the repair of UV damage to DNA are several thousandfold more prone to the disease than the average population. Heavily pigmented backcross hybrids of the genus Xiphophorus (platyfish and swordtails) are very sensitive to melanoma induction by single exposures to UV. We irradiated groups of five 6-day-old fish with narrow wavelength bands at 302, 313, 365, 405, and 436 nm and scored the irradiated animals for melanomas 4 months later. We used several exposures at each wavelength to obtain estimates of the sensitivity for melanoma induction as a function of exposure and wavelength. The action spectrum (sensitivity per incident photon as a function of wavelength) for melanoma induction shows appreciable sensitivity at 365, 405, and probably 436 nm, suggesting that wavelengths not absorbed directly in DNA are effective in induction. We interpret the results as indicating that light energy absorbed in melanin is effective in inducing melanomas in this animal model and that, in natural sunlight, 90-95% of melanoma induction may be attributed to wavelengths > 320 nm-the UV-A and visible spectral regions.The incidence of malignant melanoma has been increasing for several years at a rate of -5% per year among fair-skinned individuals in North America and Europe, probably due to changes in lifestyle. The disease has a complex etiology. Although sunlight exposure is implicated, melanoma is not associated with chronic exposure nor is it located primarily on highly exposed areas of the body (1, 2). Because individuals with the DNA repair-deficient disease xeroderma pigmentosum are several thousandfold more susceptible than unaffected individuals (3), sunlight damages to DNA are thought to be initiating carcinogenic events. However, the wavelengths effective in melanoma induction are not known. The wavelengths in sunlight between 280 and 320 nm (UV-B) are more strongly absorbed by DNA than are the longer UV-A wavelengths. On the other hand, the melanin in melanocytes absorbs UV at all wavelengths and energy absorbed by this pigment might affect DNA by energy or free-radical transfer to DNA (4). Useful animal models for determining melanoma induction as a function of wavelength-the action spectrumare the hybrid offspring from intra-and interspecific crosses between pigmented and nonpigmented fishes of the genus Xiphophorus (5

Sunlight exposure is strongly indicated as one of the important etiologic agents in human cutaneous malignant melanoma. However, because of the absence of good animal models, it has not been possible to estimate the wavelengths or wavelength regions involved. We have developed a useful animal model from crosses and backcrosses of platyfish (Xiphophorus maculatus) and swordtails (Xiphophorus heUeri).Two strains of these fish are susceptible to invasive melanoma induction by exposure to filtered radiation from sunlamps in the wavelength ranges A > 290 nm and A > 304 nm. Multiple exposures on 5-20 consecutive days beginning on day 5 after birth or a single exposure of =200 J/(m2 day) of A > 304 nm result in a tumor prevalence of 20% to 40% at 4 months of age compared with a background rate of 12% in one strain and 2% in another. Exposure of the fish to visible light after UV exposure reduces the prevalence to background. The melanomas are similar in many respects to mammalian melanomas, as judged by light and electron microscopy. The genetics of the crosses determined by others and the high sensitivity of the hybrids to melanoma induction indicate that the UV radiation probably inactivates the one tumor repressor gene (or a small number of tumor repressor genes) in the hybrid fish. The small size of the animals and their high susceptibility to melanoma induction make them ideal for action spectroscopy.Agents that cause a decrease in stratospheric ozone would cause an increase in UV-B (A = 280-320 nm) intensities at the earth's surface without appreciably changing the longer UV or visible intensities of light. Melanoma among the white population of the United States and Europe is increasing dramatically as a function of time, probably as a result of changing lifestyles (1). The relation between latitude and melanoma mortality suggests that there is a correlation between the average solar radiation and mortality from malignant melanoma. However, it is not known which parts of the solar spectrum can plausibly be related to the increasing mortality because, although sunlight exposure seems to be an essential component in melanoma incidence, it is not the only one. Body areas most exposed to light are not the primary locations of melanomas as they are for basal and squamous cell carcinomas. There is good evidence that UV-B is tumorigenic in animals (2) and can cause neoplastic transformation in vitro (3). Four types of experiment indicate that light energy absorbed in DNA can cause cellular damage leading to tumors: (i) the tumorigenicity of fish cells as a result of UV-irradiation in vitro can be photoreactivated (4)-a process that monomerizes UV-induced cyclobutane pyrimidine dimers in DNA; (ii) the wavelengths effective in neoplastic transformation in vitro are those absorbed by DNA (5); (iii) transformation in vitro by UV is photoreactivable (6); and (iv) xeroderma pigmentosum individuals are defective in the ability to repair UV damages in their DNA and are extraordinarily sensitive to cancer induction, inc...

ABSTRACr The Amazon molly, Poecilia formosa, is a small fish that grows in clones. Hence, cells from one animal may be transplanted to another without danger of rejection. Cells from thyroid and adjacent tissue were irradiated with UV light in vitro and injected into the abdominal cavity of isogeneic recipients. At appropriate UV doses and numbers of cells injected, all recipients showed exuberant thyroid proliferation. We give arguments and data indicating that the proliferation is a tumor, not a goitrogenic response. If the UV irradiation is followed, but not preceded, by photoreactivating illumination, the yield of thyroid growths is markedly decreased. Because other investigtions have shown that photoreactivation monomerizes UV-induced cyclobutylpyimiine dimers in DNA and does not affect other photoproducts, our data indicate that pyrimidine dimers in DNA can give rise to tumors. A number of physical and chemical environmental agents damage DNA in vivo. Many of these agents are carcinogenic (1-3),-and various mutagen test systems show that there is an excellent correlation between carcinogenicity and DNA damage as measured by mutagenesis (4). Nevertheless, because treatment of DNA with carcinogens results in the formation of many products, it has not been possible to identify particular molecular changes in DNA as initiating carcinogenic events. To make such an identification, one needs an experimental trick that will change the relative proportions of the various products and permit observation of how tumor induction depends on these proportions. UV radiation makes many types of photoproducts in DNA. One of these-cyclobutylpyrimidine dimers (pyrimidine dimers)-has been shown to have lethal and mutagenic effects in microorganisms by virtue of the fact that such dimers can be monomerized by photoreactivating (PR) enzyme plus light of wavelength >320 nm (5, 6). Because, to the best of our knowledge, enzymic photoreactivation works only on pyrimidine dimers and not on other products, our finding of a PR effect strongly implicates pyrimidine dimers as the important initial DNA damage in tumor induction.There is excellent evidence that most human skin cancer arises from solar UV radiation (7) and it is a good inference that DNA is the target molecule (8 (12), cooked spinach (6), marine fish meal (6), high-protein baby cereal (4), wheat germ (2), and iodized salt (1).Cell Isolation and Injections. Donor animals (2-3 months old, 2 cm long) were placed on ice for 5 min and then given 3-min washes in each of 2.6% sodium hypochlorite, cold 95% ethanol, and sterile fish Ringer's solution. Scales were removed and tissue was excised from along the ventral aorta. The excised region contained thyroid, muscle, and cardiac tissue (from the thyroid gland, urohyal, and heart, respectively). Tissues were pooled and homogenized in fish Ringer's solution without Ca2+ or Mg2+ and containing isoniazid (0.7 mg/ml), streptomycin (1 ,sg/ml), and penicillin (1000 units/ml). Homogenization yielded primarily small clumps of two to five ...

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