Controversy continues both as to which wavelengths of sunlight cause melanoma and the mechanisms by which these different wavelengths act. Direct absorption of UVB by DNA is central in albino animal models, but melanin-pigmented models have shown major contributions by wavelengths longer than UVB that are thought to be mediated by photosensitized oxidant production. The only model for which the action spectrum of melanoma causation is known is a genetically melanoma-susceptible specific cross of Xiphophorus fish. We used electron paramagnetic resonance to quantitatively detect the UV induction of reactive melanin radicals in situ in the melanin-containing cells in the skin of this model and derived the action spectrum for melanin-photosensitized oxidant production (Phi(ox)). This action spectrum was identical to that for melanoma induction (Phi(mel)). These results confirm the hypothesis that melanin-photosensitized radical production is the major causative step of melanoma in this model and demonstrate that the wavelengths and mechanisms of melanoma causation in different models are dependent on the presence of melanin. This approach should be applicable to humans, thus providing an accurate surrogate for Phi(mel) for prevention studies.

Four groups of 30 dorsally shaved opossums (Monodelphis domestica) were exposed to graded doses of ultraviolet radiation A (UVA) (320-400 nm) three times per week for 90 weeks. Animals were monitored for the appearance of focal melanocytic hyperplasia (FMH) and nonmelanoma skin tumors (NMST) during the course of the exposures and for an additional 20 weeks following termination of exposures. FMH is the putative precursor for melanoma in the opossum. The lowest dose of UVA (2.5 x 10(3) J/m2) used in this study was selected based on the action spectrum for the induction of melanoma in a fish model. The prediction was that 2.5 x 10(3) J/m2 would induce FMH in the opossum if the action spectra for the induction of FMH in the opossum and melanoma in the fish were the same. The highest UVA dose was 2.5 x 10(5) J/m2. Only the highest dose of UVA gave a statistically significant induction of FMH and NMST in the opossum. As in previous studies, the FMH appeared earlier than the NMST during the course of exposures and the final prevalence of FMH was lower than the final prevalence of NMST. Overall, the results of this study indicate that the efficacy of UVA to induce FMH in the opossum is not as great as would be predicted from the action spectrum for melanoma induction in a fish model.

Chronic ultraviolet radiation (UVR) exposure to the eyes of Monodelphis domestica causes corneal opacification, neovascularization, and fibrosarcoma induction. By immunohistochemistry and Western blotting, we have shown that one to four exposures of the eyes of this opossum to UVR enhances basic fibroblast growth factor (bFGF) expression by the corneal epithelium. Treatment with photoreactivating light, which selectively removes UVR‐induced pyrimidine dimers, suppresses bFGF induction, indicating that UVR induction of bFGF is ultimately due to DNA damage. Furthermore, UVR‐induced corneal tumors derived from corneal keratocytes express bFGF mRNA and protein, as determined by immunohistochemistry and in situ hybridization. Taken together, these findings suggest that bFGF acts in both an autocrine and a paracrine manner to stimulate corneal fibroplasia, neovascularization, and tumor development. Environ. Mol. Mutagen. 38:175–179, 2001 © 2001 Wiley‐Liss, Inc.

The gray, short-tailed opossum, Monodelphis domestica, has been used for photobiologic studies since 1984. The presence of a light-activated DNA repair pathway in the tissues of Monodelphis has been used to identify pyrimidine dimers in DNA as initiating events for a number of ultraviolet radiation (UVR)-induced pathologies of the skin and cornea. Furthermore, Monodelphis, unlike common laboratory rodents, is susceptible to the induction of melanoma by UVR alone.

T cell-mediated immune function, here measured as the contact hypersensitivity reaction, is readily suppressed by moderate exposure of mice to ultraviolet B (UVB) or solar-simulated radiation (SSUV), or by topical application of cis-urocanic acid. The effect of ultraviolet A (UVA) radiation on immune function has been unclear. Here we have demonstrated that when UVA radiation from a fluorescent tube source was rigorously filtered to remove contaminating UVB radiation, it was immunologically innocuous at physiologically relevant doses. Furthermore, we have found that mice exposed to UVA radiation, either immediately after, or up to 24 h before, immunosuppressive treatment with either UVB radiation, SSUV or cis-urocanic acid, became refractory to the immunosuppression and retained more normal contact hypersensitivity. A greater UVA exposure reversed the immunosuppression more effectively. The results suggest that there are immunologically significant interactions between UV wavebands, and that UVA exposure may induce a relatively long-lived immunoprotective photoproduct, as yet unidentified, that can inhibit the activity of epidermal cis-urocanic acid and thus provide protection from photoimmunosuppression.

The use of chemical and physical sunscreening agents has increased dramatically during the last two to three decades as an effective means of preventing sunbum. The use of high sunprotection factor sunscreens has also been widely promoted for the prevention of skin cancer, including melanoma. Whereas sunscreens are undoubtedly effective in preventing sunbum, their efficacy in preventing skin cancer, especially melanoma, is currently under considerable debate. Sunscreens have been shown to prevent the induction of DNA damage that presumably results from the direct effects of ultraviolet radiation (UVR) on DNA. DNA damage has been identified as an initiator of skin cancer formation. However, both laboratory and epidemiological studies indicate that sunscreens may not block the initiation or promotion of melanoma formation. These studies suggest that the action spectrum for erythema induction is different than the action spectrum for the induction of melanoma. Indeed, recent reports on the wavelength dependency for the induction of melanoma in a fish model indicate that the efficacy of ultraviolet A wavelengths (320-400 nm) to induce melanoma is orders of magnitude higher than would be predicted from the induction of erythema in man or nonmelanoma skin tumors in mice. Other strategies for the chemoprevention of skin cancer have also been reported. Low levels and degree of unsaturation of dietary fats protect against UVR-induced skin cancer in mice humens. Compounds with antioxidant activity, including green tea extracts (polyphenols), have been reported to inhibit UVR-induced skin carcinogenesis.

The suppression of contact hypersensitivity by UVB (280-320 nm) radiation can be prevented by photoreactivating light (PRL; 320-400 nm) in the opossum Monodelphis domestica, implicating epidermal DNA lesions as the immunosuppressive impairment. However, contact hypersensitivity can also be suppressed in the opossum with exogenous cis-urocanic acid, a molecule which is produced in UVB-irradiated epidermis and is a second potential mediator of photo-immunosuppression apparently independent of UVB-induced DNA damage. Here we demonstrate that irradiation of opossums with PRL either before or following treatment with exogenous cis-urocanic acid, significantly reduced the degree of immunosuppression. This suggests that, in addition to its capacity to initiate post-UVB-exposure epidermal DNA repair, the PRL waveband can induce an immunoprotective product, as yet unidentified, in opossum epidermis.

The repair of UV radiation-induced pyrimidine dimers has been measured in lens epithelial DNA of the marsupial Monodelphis domestica using a pyrimidine dimer-specific endonuclease from Micrococcus luteus. Approximately 40% of the initially induced dimers were repaired during 90 min exposures to photoreactivating light. This capacity of the lens epithelium to photorepair pyrimidine dimers may provide a means with which to determine whether pyrimidine dimers in lens epithelial DNA are involved in UV radiation-induced pathologic changes of the lens.

S-100 immunoreactivity was determined 1) in foci of melanocytic hyperplasia, 2) in naturally occurring, ultraviolet radiation-induced, and 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced primary melanomas, and 3) in metastatic melanoma lesions in the South American opossum Monodelphis domestica. Preneoplastic lesions of melanocytic hyperplasia contained scattered cells with S-100-positive nuclei. All primary melanomas, with the exception of a single DMBA-induced tumor, contained cells with S-100-positive nuclei. The pattern of S-100 reactivity in tumors varied from large foci of S-100-positive cells to scattered individual S-100-positive cells. Lymph node metastases were S-100 positive, but metastatic masses in internal organs were usually S-100 negative. Although S-100 reactivity did not distinguish preneoplastic lesions from tumors or benign melanomas from malignant melanomas, identification of metastatic tumor cells clearly demonstrated malignancy.

Two groups of 30 dorsally shaved opossums (Monodelphis domestica) were exposed three times per week for 81 weeks to 250 J/m2 of UV radiation from FS40 sunlamps (approximately 150 J/m2 of UV radiation B; UV-B), or to 2.5 x 10(4) J/m2 of UV radiation A (UV-A) from filtered F40BLB fluorescent lamps (black lights). Animals were monitored for the appearance of nonmelanoma skin tumors (NMSTs) and melanocytic hyperplasia (MH). After 81 weeks of exposures, the prevalence of NMSTs was 71% and 4% for animals exposed to UV-B and UV-A, respectively. The difference between the treatment groups was statistically significant (P < 0.001). However, the prevalence of MH in the treatment groups, 31% for UV-B-exposed animals and 22% for UV-A-exposed animals, was not significantly different (P > 0.05). Thus, a dose of UV-A that was relatively ineffective in producing NMSTs, compared to UV-B, was as effective as UV-B in the induction of MH. If, as shown previously, MH is the precursor lesion for melanoma in this model, these results suggest that the action spectra for the induction of melanoma and NMSTs in the opossum are different.

Chronic exposure to ultraviolet radiation (UVR) induces corneal sarcomas in the South American opossum Monodelphis domestica. Cell lines are readily established from these tumors. Northern blotting of mRNA from six such cell lines revealed high expression of the H-ras oncogene. H-ras cDNA from an eye tumor cell line was cloned and characterized; the germline sequence of codons 12, 13, and 61 was confirmed by examination of H-ras sequences amplified from liver DNA by the polymerase chain reaction. The Monodelphis H-ras coding sequence is 84-89% identical to that of other vertebrates at the nucleotide level, and the predicted 189-amino-acid sequence differs by 2-12 amino acids from that of other vertebrates. Analysis of 12 primary invasive corneal sarcomas induced by chronic UVR exposure revealed no evidence of H-ras gene amplification or rearrangement. One tumor was heterozygous for an activating point mutation in codon 61 of the H-ras gene; the tumor was also homozygous for a point mutation at an adjacent site in codon 62. These results provide additional evidence for the functional importance and consequent evolutionary conservation of the ras oncogenes.

The effect of exposure to chronic ultraviolet (UV) radiation on life span was examined in Monodelphis domestica, which is capable of photoreactivation repair of UV-radiation-induced pyrimidine dimers. Shaved Monodelphis were exposed to 500 J/m2 UV radiation, 500 J/m2 UV radiation then 90 min of photoreactivating light (PRL), or 90 min of PRL three times weekly for 104 weeks. Opossums were weighed weekly; samples for serum chemistry and hematology testing were obtained periodically. Complete postmortem examinations revealed a primary cause of death for each opossum. Meaningful differences among the groups in weight gain, serum chemistry values or hematology values were not seen. Significant life-shortening due to UV-radiation exposure was found for females but not males. Photoreactivation prolonged life only in the females exposed to UV radiation. Exposure to UV radiation was not associated with accelerated development of degenerative disease. Significant treatment-related mortality occurred in both male and female opossums exposed to UV radiation. Photoreactivation reduced the relative risk of skin tumors but not eye tumors in Monodelphis exposed to UV radiation. Eye and skin tumors were less likely to be a cause of death in UV-radiation-exposed opossums subsequently exposed to PRL than in opossums exposed to UV radiation alone. Females exposed only to UV radiation had an increased risk of skin tumor development relative to males.

A single specific epidermal photoreceptor for the immunosuppressive action of UV radiation has not been defined, although separate evidence is accruing in favour of each of two candidates, trans-urocanic acid and DNA. In Monodelphis domestica, specific photoreactivation repair of UV radiation-induced pyrimidine dimers has been shown to abrogate the suppression of contact hypersensitivity (CHS), thus suggesting that DNA is the target for this impairment. However, the both haired and hairless mice, immunosuppressive effects of UV radiation have been reproduced by the exogenous administration of the UV photoproduct of urocanic acid, cis-urocanic acid. We show here that the epidermis of M. domestica contains urocanic acid, that UV irradiation of the shaved dorsal skin has resulted in an increase in epidermal cis-urocanic acid and that the topical application of a cis-urocanic acid-containing lotion significantly depressed the capacity of Monodelphis to respond to contact sensitisers, in a manner analogous to these responses in the hairless mouse. Therefore in Monodelphis, suppression of CHS by UV irradiation appears to involve both urocanic acid photo-isomerisation and epidermal DNA damage.

Photochemistry and PhotobiologyVolume 61, Issue 3 p. 223-247 SOLAR ULTRAVIOLET RADIATION AND THE RISK OF INFECTIOUS DISEASE: SUMMARY OF A WORKSHOP*† First published: March 1995 https://doi.org/10.1111/j.1751-1097.1995.tb03966.xCitations: 51 † *Editor's note: This Invited Review departs from the standard review format of Photochemistry and Photobiology in order to provide readers with reviews of previously published literature in several areas related to possible links between exposure to solar UV radiation and infectious disease. Because these reviews were part of a workshop, discussion summaries are included which provide information and alternative opinions. Citations could not be included for the statements made in the discussion. ‡ †Disclaimer: The research paper has been reviewed by the U.S. Environmental Protection Agency Health Effects Research Laboratory and the UV Monitoring and Assessment Program Panel (UMAP) and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency and UMAP, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. All direct costs for the workshop were borne by UMAP. The EPA did not contribute any funds toward the meeting. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume61, Issue3March 1995Pages 223-247 RelatedInformation

Abstract The immunological consequences of exposure to UVA (320–400 nm) radiation are unclear. This study describes the relationship between the generation of epidermal cis‐urocanic acid and the ability to respond to a contact‐sensitizing agent, in hairless mice exposed to different UV radiation sources, which incorporate successively greater short‐wavelength cutoff by filtration of the radiation from fluorescent UV tubes. Mice were exposed to these radiation sources at doses systematically varying in UVB radiation content but supplying increasing proportions of UVA radiation. All radiation sources were found to generate approximately 35%cis‐urocanic acid in the epidermis, thus normalizing the sources for cis‐urocanic acid production. However, only those sources richest in short‐wavelength UVB resulted in suppression of the systemic contact hypersensitivity response. These sources also induced the greatest erythema reaction, measured as its edema component, in the exposed skin. A strong correlation was thus demonstrated between the induction of edema and the suppression of contact hypersensitivity, but there appeared to be no correlation between the generation of epidermal cis‐urocanic acid and suppression of contact hypersensitivity. The sources richest in UVA content did not result in suppression of contact hypersensitivity: furthermore mice previously irradiated with such UVA‐rich sources were refractory to the immunosuppressive action of exogenous cis‐urocanic acid. A protective effect of the increased UVA content thus appeared to be inhibiting immunosuppression by the available endogenously generated or exogenously applied cis‐urocanic acid.

Monodelphis domestica, the laboratory opossum, develops hyperplasia and neoplasia of shaved skin after repeated exposure to ultraviolet radiation (UVR). We exposed Monodelphis from genetically diverse families within our colony to determine whether there are any heritable components to the risk of two distinct skin lesion phenotypes-melanocytic nevus (MN) and advanced hyperkeratosis (HK). From about 5 months of age, animals were shaved and exposed three times a week to a dose of about 125 J/m2 of UVR (spectral peak, 302 nm; range, 280–400 nm). Of 33 sibships (151 individuals) that completed at least 30 weeks of the protocol, 137 completed 45 weeks. For genetic analyses, each animal was classified at 30 and 45 weeks as affected with MN and HK or not affected. Heritabilities were estimated using a variance decomposition approach. Susceptibility to MN showed no significant evidence for a genetic component at 30 or 45 weeks. In sharp contrast, susceptibility to HK was under virtually complete genetic control (heritability, 0.999; P<0.001) at 30 weeks, and had a moderately high heritability (0.702; P<0.001) at 45 weeks. We conclude that this model has great potential for identifying genes that confer susceptibility to UVR-induced skin lesions and for investigating environmental factors that may contribute to the increasing incidence of skin cancer in human populations.

We have isolated and characterized a 1,593-bp cDNA containing the ceding region of the basic fibroblast growth factor (BFGF) gene of a marsupial, the opossum Monodelphis domestica. The encoded protein is 156 amino acids long. The BFGF gene of M. domestica is 82-87% identical to the BFGF genes of placental mammals at the nucleotide level and 92-93% identical to these genes at the level of the amino acids encoded. Regions of the BFGF molecule important in heparin binding, high-affinity receptor binding, and biologic function are highly conserved between placental mammals and this marsupial. There are several AUG and CUG codons in the 5' region of the marsupial cDNA that may serve as alternate sites of translation initiation; use of these sites would produce amino-terminally extended BFGF proteins. Amino-terminal extensions of BFGF in other species serve as nuclear localization signals. Conservered A+T-rich motifs in the 3' untranslated region of the marsupial mRNA probably serve to regulate mRNA stability. The high degree of evolutionary conservation of BFGF in mammals suggests that the molecule plays an important role in normal growth and development and that stringent control of its activity is essential.

The patch size for excision repair of ultraviolet radiation (UV)-induced pyrimidine dimers was determined in cultured murine epithelial cells with normal and enhanced pyrimidine dimer repair capabilities. Cells with enhanced pyrimidine dimer repair were produced by transfecting 308 cells with the denV gene of bacteriophage T4; this gene encodes the enzyme endonuclease V. Pyrimidine dimer repair following exposure to UV from an FS-40 sunlamp was determined by micrococcal dimer-specific nuclease digestion and alkaline sucrose ultracentrifugation. Patch size ws estimated based on the photolytic lability of bromodeoxyuridine-substituted DNA. Excision repair of UV-induced pyrimidine dimers in denV-transfected 308 cells was enhanced two- to threefold. Production of mRNA from the denV gene in cell lines with enhanced repair was confirmed by RNA blotting. In control cells, the patch size for excision repair of DNA photoproducts was estimated to be 34 nucleotides per photoproduct removed; in denV-transfected cells, a smaller average patch size of 10-16 nucleotides per photoproduct removed was calculated. Thus, endonuclease V activity appears to alter not only the extent, but also the nature of excision repair in UV-exposed mammalian epithelial cells.