Skin Carcinogen Research Articles

ALKBH4 Stabilization Is Required for Arsenic-Induced 6mA DNA Methylation Inhibition, Keratinocyte Malignant Transformation, and Tumorigenicity.

Inorganic arsenic is one of the well-known human skin carcinogens. However, the molecular mechanism by which arsenic promotes carcinogenesis remains unclear. Previous studies have established that epigenetic changes, including changes in DNA methylation, are among the critical mechanisms that drive carcinogenesis. N6-methyladenine (6mA) methylation on DNA is a widespread epigenetic modification that was initially found on bacterial and phage DNA. Only recently has 6mA been identified in mammalian genomes. However, the function of 6mA in gene expression and cancer development is not well understood. Here, we show that chronic low doses of arsenic induce malignant transformation and tumorigenesis in keratinocytes and lead to the upregulation of ALKBH4 and downregulation of 6mA on DNA. We found that reduced 6mA levels in response to low levels of arsenic were mediated by the upregulation of the 6mA DNA demethylase ALKBH4. Moreover, we found that arsenic increased ALKBH4 protein levels and that ALKBH4 deletion impaired arsenic-induced tumorigenicity in vitro and in mice. Mechanistically, we found that arsenic promoted ALKBH4 protein stability through reduced autophagy. Together, our findings reveal that the DNA 6mA demethylaseALKBH4 promotes arsenic tumorigenicity and establishes ALKBH4 as a promising target for arsenic-induced tumorigenesis.

Inhibition of 6-formylindolo[3,2-b]carbazole metabolism sensitizes keratinocytes to UVA-induced apoptosis: Implications for vemurafenib-induced phototoxicity

Ultraviolet (UV) B irradiation of keratinocytes results in the formation of the tryptophan photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) which is a high-affinity ligand for the aryl hydrocarbon receptor (AHR). The resulting activation of AHR signaling induces the expression of cytochrome P450 (CYP) 1A1 which subsequently metabolizes FICZ. Importantly, FICZ is also a nanomolar photosensitizer for UVA radiation. Here, we assess whether a manipulation of the AHR-CYP1A1 axis in human epidermal keratinocytes affects FICZ/UVA-induced phototoxic effects and whether this interaction might be mechanistically relevant for the phototoxicity of the BRAF inhibitor vemurafenib. Treatment of keratinocytes with an AHR agonist enhanced the CYP1A1-catalyzed metabolism of FICZ and thus prevented UVA photosensitization, whereas an inhibition of either AHR signaling or CYP1A1 enzyme activity resulted in an accumulation of FICZ and a sensitization to UVA-induced oxidative stress and apoptosis. Exposure of keratinocytes to vemurafenib resulted in the same outcome. Specifically, CYP phenotyping revealed that vemurafenib is primarily metabolized by CYP1A1 and to a lesser degree by CYP2J2 and CYP3A4. Hence, vemurafenib sensitized keratinocytes to UVA-induced apoptosis by interfering with the CYP1A1-mediated oxidative metabolism of FICZ. In contrast to this pro-apoptotic effect, a treatment of UVB-damaged keratinocytes with vemurafenib suppressed apoptosis, a process which might contribute to the skin carcinogenicity of the drug. Our results provide insight into the mechanisms responsible for the photosensitizing properties of vemurafenib and deliver novel information about its metabolism which might be relevant regarding potential drug-drug interactions. The data emphasize that the AHR-CYP1A1 axis contributes to the pathogenesis of cutaneous adverse drug reactions.

Risks and Benefits of UV Radiation.

While UV radiation is a skin carcinogen, this should not obscure the growing evidence that sunlight has significant health benefits, including impacts on cardiovascular and metabolic health. Epidemiological and mechanistic evidences for the importance of different wavelengths of sunlight, including blue light and UV radiation, are presented.

Development, characterization and evaluation of cinnamon oil and usnic acid blended nanoemulsion to attenuate skin carcinogenicity in swiss albino mice

The objective of the present study was to formulate and characterize cinnamon oil and usnic acid blended nanoemulsion (CUN) and evaluate its efficacy against chemical induced skin carcinogenesis. CUN was prepared using ultrasonic emulsification method and prepared nanoformulations (CN1–CN9) were characterized for particle size, surface morphology, zeta potential, polydispersity index and transmittance. Anticarcinogenic effect of topical CUN was determined in DMBA/croton oil-induced skin carcinogenic swiss albino mice. Biochemical study was performed on isolated skin tissues homogenate of mice at the end of experiment (16th week). Histopathological analysis was performed to observe the effect of CUN on animals skin. Results exhibited that all the formulations were spherical and of nanosized range. Batch CN7 was considered as optimized formulation due to lowest particle size (96.39 nm), optimum zeta potential (-27.13 mV) and highest percentage transmittance (99.76%). CUN significantly reduce tumors in chemical induced carcinogenic mice. It restored all antioxidant enzymes in skin tissues. Histopathological study showed a minor disturbance in the skin architecture, reduced number and size of keratinized pearls, acanthosis and tumor in comparison to negative control group. It can be concluded from the study CUN may be used as an effective topical formulation to attenuate skin carcinogenesis.

Establishment and Validation of an Ultra-Short-Term Skin Carcinogenicity Bioassay Using Tg-rasH2 Mice.

After initiation with 7,12-dimethylbenz[a]anthracene (DMBA), the promoting potential of 12-O-tetradecanoylphorbol-13-acetate (TPA) on skin tumor development can be detected by an ultra-short-term skin carcinogenicity bioassay using Tg-rasH2 mice. In the present study, 10 chemicals were assessed using this ultra-short-term bioassay as a first step to validate this practical and easy-to-use skin carcinogenicity bioassay. These chemicals belonged to 4 categories: dermal vehicles (acetone, 99.5% ethanol, anhydrous ethanol, and Vaseline), skin noncarcinogens (oleic acid diethanolamine condensate, benzethonium chloride, and diisopropylcarbodiimide), skin tumor promoters (TPA and benzoyl peroxide), and a skin carcinogen (4-vinyl-1-cyclohexene diepoxide). In a first study, DMBA was used as the initiator at a dose of 50 μg according to previous data, but skin tumors were observed in the no-treatment and vehicle groups. Therefore, the dose of DMBA for skin tumor initiation was reevaluated using 12.5 or 25 μg, with 12.5 μg found to be sufficient for initiation activity. In the ultra-short-term assay, the vehicles and skin noncarcinogens were negative while the skin tumor promoters and the skin carcinogen were positive. The detection of skin tumor promotion and carcinogenicity was feasible in only 8 weeks. In conclusion, this carcinogenicity bioassay may represent a useful tool for the assessment of the carcinogenicity potential of topically applied chemicals.

Corrigendum to: Parallel responses of human epidermal keratinocytes to inorganic SbIII and AsIII

Environmental contextIncreasing commercial use of antimony is raising its environmental presence and thus possible effects on humans and ecosystems. An important uncertainty is the risk that exposure poses for biological systems. The present work explores the similarity in response of human epidermal keratinocytes, a known target cell type, to antimony and arsenic, where deleterious consequences of exposure to the latter are better known. AbstractSbIII and AsIII are known to exhibit similar chemical properties, but the degree of similarity in their effects on biological systems merits further exploration. The present work compares the responses of human epidermal keratinocytes, a known target cell type for arsenite-induced carcinogenicity, to these metalloids after treatment for 1 week at environmentally relevant concentrations. Previous work with these cells has shown that arsenite and antimonite have parallel effects in suppressing differentiation, altering levels of several critical enzymes and maintaining colony-forming ability. More globally, protein profiling now reveals parallels in SbIII and AsIII effects. The more sensitive technique of transcriptional profiling also shows considerable parallels. Thus, gene expression changes were almost entirely in the same directions for the two treatments, although the degree of change was sometimes significantly different. Inspection of the changes revealed that RYR1 and LRIG1 were among the genes strongly suppressed, consistent with reduced calcium-dependent differentiation and maintenance of epidermal growth factor-dependent proliferative potential. Moreover, levels of microRNAs in the cells were altered in parallel, with nearly 90% of the 198 most highly expressed ones being suppressed. Among these was miR-203, which is known to decrease proliferative potential. Finally, both SbIII and AsIII were seen to attenuate bone morphogenetic protein 6 induction of dual-specificity phosphatases 2 and 14, consistent with maintaining epidermal growth factor receptor signalling. These findings raise the question of whether SbIII, like AsIII, could act as a human skin carcinogen.

Rice Consumption and Squamous Cell Carcinoma of the Skin in a United States Population.

Background:Rice contains arsenic, a known skin carcinogen. Rice intake has been associated with arsenic-related skin lesions in South Asia, but its association with skin cancers is as yet unknown.Objectives:We aimed to investigate whether rice intake contributes to urinary arsenic concentration and risk of squamous cell carcinoma (SCC) of the skin in a U.S. population.Methods:Rice consumption was assessed using a food frequency questionnaire administered as part of a population-based case–control study of 487 SCC cases and 462 age- and gender-matched controls. Arsenic concentration in household tap water and urine samples were measured using inductively coupled mass spectrometry (ICP-MS) and high-resolution ICP-MS, respectively. Odds ratios (OR) for SCC associated with the frequency of rice consumption were estimated using logistic regression, with adjustment for age, gender, and caloric intake.Results:Those who reported any rice consumption had higher urinary arsenic concentrations than those who did not consume rice, and the association was most pronounced among those with arsenic in their household water (19.2% increase in total urinary arsenic, 95% CI: 5.0, 35.3%). Any rice consumption was associated with a 1.5-fold (95% CI: 1.1, 2.0) higher odds of SCC compared with those who reported no rice consumption, and the relation appeared to be largely among those with water arsenic.Conclusion:Rice consumption may be related to the occurrence of SCC in the United States, especially among those with relatively low drinking water arsenic exposure. https://doi.org/10.1289/EHP1065

The Role of Fibroblast Growth Factor-Binding Protein 1 in Skin Carcinogenesis and Inflammation

Fibroblast growth factor-binding protein 1 (FGFBP1) is a secreted chaperone that mobilizes paracrine-acting FGFs, stored in the extracellular matrix, and presents them to their cognate receptors. FGFBP1 enhances FGF signaling including angiogenesis during cancer progression and is upregulated in various cancers. Here we evaluated the contribution of endogenous FGFBP1 to a wide range of organ functions as well as to skin pathologies using Fgfbp1-knockout mice. Relative to wild-type littermates, knockout mice showed no gross pathologies. Still, in knockout mice a significant thickening of the epidermis associated with a decreased transepidermal water loss and increased proinflammatory gene expression in the skin was detected. Also, skin carcinogen challenge by 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoyl-phorbol-13-acetate resulted in delayed and reduced papillomatosis in knockout mice. This was paralleled by delayed healing of skin wounds and reduced angiogenic sprouting in subcutaneous matrigel plugs. Heterozygous green fluorescent protein (GFP)-knock-in mice revealed rapid induction of gene expression during papilloma induction and during wound healing. Examination of wild-type skin grafted onto Fgfbp1 GFP-knock-in reporter hosts and bone marrow transplants from the GFP-reporter model into wild-type hosts revealed that circulating Fgfbp1-expressing cells migrate into healing wounds. We conclude that tissue-resident and circulating Fgfbp1-expressing cells modulate skin carcinogenesis and inflammation.

Abstract 4800: A next-gen animal model to Study PIK3CA-mTOR driven HPV-related oral malignancies

Abstract The rising incidence of HPV-associated malignancies, especially for head and neck squamous cell carcinoma (HNSCC), has highlighted the urgent need to understand the role of HPV-16 E6/E7 oncogenes in cancer initiation and progression. For that propose we decided to generate a doxycycline inducible E6/E7 transgenic mouse targeting E6/E7 onco-proteins to the basal epithelia layer, including the stem cell compartment, through a doxycycline inducible cytokeratin 5 promoter (cK5-rtTA). This system allows to turn on the expression of HPV genes after birth, minimizing the negative effect that viral E6/E7 expression may have during embryonic development, and mimicking the natural infection process that usually happens in adults after initiation of sexual activities. Interestingly, we found that after doxycycline induction, both E6 and E7 were highly expressed, resulting in a clear increase in the number of proliferative cells even in the suprabasal layers, which results in rapid epidermal hyperplasia. However, in our animal mouse model HPV-16 E6/E7 expression alone was not sufficient to induce spontaneous squamous carcinomas (SCC). Due that we decided to challenge the oncogenic role of HPV using a classical chemical carcinogenesis protocol (DMBA-TPA). These mice develop SCC rapidly after a single exposure to a skin carcinogen, DMBA, which was increased by the prolonged exposure to a tumor promoter, TPA. These data suggest that only few oncogenic hits may be sufficient to induce cancer in humans already infected with HPV-16 E6/E7. Then, we decided to elucidate whether or not a few genomic alterations in combination with HPV-16 expression may be sufficient to induce cancer. One of the most frequent mutations in HNSCC, including HPV-associated cancers, are those affecting the PI3K-mTOR pathway. Based on that, we engineered a genetically defined mouse model combining HPV-16 E6/E7 and PIk3CAH1047R expression under the control of a cytokeratin 14 promoter driven tamoxifen-regulated Cre recombinase (cK14-CreERTM). Surprisingly, we found that upon tamoxifen activation mice develop oral cancer in only few weeks. Furthermore, our HPV-related cancer mouse models exhibited a marker increase of mTOR activation which is a key oncogenic driver in malignant progression to SCC. Remarkably, rapamycin, an mTOR inhibitor, was able to block tumor development, supporting the potential clinical use of direct and indirect mTOR inhibitors as a molecular targeted approach for prevention of HPV-associated malignancies. Citation Format: Juan Luis Callejas-Valera, Ramiro Iglesias-Bartolome, Panomwat Amornphimoltham, Julia Palacios-Garcia, Daniel Martin, Joseph A. Califano, Alfredo A. Molinolo, J.Silvio Gutkind. A next-gen animal model to Study PIK3CA-mTOR driven HPV-related oral malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4800. doi:10.1158/1538-7445.AM2017-4800

Minimum standards on prevention, diagnosis and treatment of occupational and work‐related skin diseases in Europe – position paper of the COST Action StanDerm (TD 1206)

Skin diseases constitute up to 40% of all notified occupational diseases in most European countries, predominantly comprising contact dermatitis, contact urticaria, and skin cancer. While insufficient prevention of work-related skin diseases (WRSD) is a top-priority problem in Europe, common standards for prevention of these conditions are lacking. To develop common European standards on prevention and management of WRSD and occupational skin diseases (OSD). Consensus amongst experts within occupational dermatology was achieved with regard to the definition of minimum evidence-based standards on prevention and management of WRSD/OSD. By definition, WRSDs/OSDs are (partially or fully) caused by occupational exposure. The definition of OSD sensu stricto additionally includes diverging national legal requirements, with an impact on registration, prevention, management, and compensation. With the implementation of the classification of WRSD/OSD in the International Classification of Diseases (ICD) 11th Revision in future, a valid surveillance and comparability across countries will be possible. Currently, WRDS and OSD are still under-reported. Depending on legislation and regulations, huge differences exist in notification procedures in Europe, although notification is crucial to prevent chronic and relapsing disease. Facilities for early diagnosis, essential for individual patient management, should be based on existing guidelines and include a multidisciplinary approach. Patch testing is essential if contact dermatitis persists or relapses. Workplace exposure assessment of WRSD/OSD requires full labelling of product ingredients on material safety data sheets helping to identify allergens, irritants and skin carcinogens. Comparable standards in primary, secondary and tertiary prevention must be established in Europe to reduce the burden of WRSD/OSD in Europe. The adoption of common European standards on prevention of WRSD/OSD will contribute to reduce the incidence of OSD and their socio-economic burden.

Combining QSAR Modeling and Text-Mining Techniques to Link Chemical Structures and Carcinogenic Modes of Action.

There is an increasing need for new reliable non-animal based methods to predict and test toxicity of chemicals. Quantitative structure-activity relationship (QSAR), a computer-based method linking chemical structures with biological activities, is used in predictive toxicology. In this study, we tested the approach to combine QSAR data with literature profiles of carcinogenic modes of action automatically generated by a text-mining tool. The aim was to generate data patterns to identify associations between chemical structures and biological mechanisms related to carcinogenesis. Using these two methods, individually and combined, we evaluated 96 rat carcinogens of the hematopoietic system, liver, lung, and skin. We found that skin and lung rat carcinogens were mainly mutagenic, while the group of carcinogens affecting the hematopoietic system and the liver also included a large proportion of non-mutagens. The automatic literature analysis showed that mutagenicity was a frequently reported endpoint in the literature of these carcinogens, however, less common endpoints such as immunosuppression and hormonal receptor-mediated effects were also found in connection with some of the carcinogens, results of potential importance for certain target organs. The combined approach, using QSAR and text-mining techniques, could be useful for identifying more detailed information on biological mechanisms and the relation with chemical structures. The method can be particularly useful in increasing the understanding of structure and activity relationships for non-mutagens.

MTOR inhibition prevents rapid-onset of carcinogen-induced malignancies in a novel inducible HPV-16 E6/E7 mouse model.

The rising incidence of human papillomavirus (HPV)-associated malignancies, especially for oropharyngeal cancers, has highlighted the urgent need to understand how the interplay between high-risk HPV oncogenes and carcinogenic exposure results in squamous cell carcinoma (SCC) development. Here, we describe an inducible mouse model expressing high risk HPV-16 E6/E7 oncoproteins in adults, bypassing the impact of these viral genes during development. HPV-16 E6/E7 genes were targeted to the basal squamous epithelia in transgenic mice using a doxycycline inducible cytokeratin 5 promoter (cK5-rtTA) system. After doxycycline induction, both E6 and E7 were highly expressed, resulting in rapid epidermal hyperplasia with a remarkable expansion of the proliferative cell compartment to the suprabasal layers. Surprisingly, in spite of the massive growth of epithelial cells and their stem cell progenitors, HPV-E6/E7 expression was not sufficient to trigger mTOR activation, a key oncogenic driver in HPV-associated malignancies, and malignant progression to SCC. However, these mice develop SCC rapidly after a single exposure to a skin carcinogen, DMBA, which was increased by the prolonged exposure to a tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). Thus, only few oncogenic hits may be sufficient to induce cancer in E6/E7 expressing cells. All HPV-E6/E7 expressing SCC lesions exhibited increased mTOR activation. Remarkably, rapamycin, an mTOR inhibitor, abolished tumor development when administered to HPV-E6/E7 mice prior to DMBA exposure. Our findings revealed that mTOR inhibition protects HPV-E6/E7 expressing tissues form SCC development upon carcinogen exposure, thus supporting the potential clinical use of mTOR inhibitors as a molecular targeted approach for prevention of HPV-associated malignancies.

Sun-Protective Behaviors of Student Spectators at Inter-school Swimming Carnivals in a Tropical Region Experiencing High Ambient Solar Ultraviolet Radiation

Skin cancer is the most common cancer in humans and Australia (particularly in Queensland) has the highest incidence globally. Sunlight is a known skin carcinogen and reflects off water, exacerbating the risk of sunburn. In 1988, the “SunSmart Program” was developed to promote sun-protection to Australian children. Within a decade, it evolved to include a voluntary national accreditation program for schools, known as the SunSmart Schools (SSS) Program. Additionally, in 2008, it became compulsory for primary schoolchildren attending Queensland government-funded schools to wear a shirt during all water-based activities, except when competing. We observed the proportion of student spectators from 41 Townsville (latitude 19.3°S) primary schools (65.9% SSS) wearing hats at inter-school swimming carnivals in 2009–2011 and 2015 and the proportion wearing a shirt. Overall, a median of 30.7% student spectators from each school wore a hat [max 46.2% (2009); min 18% (2015)] and 77.3% wore a shirt [max 95.8% (2009); min 74.5% (2015)], suggesting that hats are under-utilized. Students from non-government (private) schools were twice as likely as students from government schools to wear a hat (41 vs. 18.2% p = 0.003). Neither the hat nor the shirt-wearing behaviors of student spectators were significantly influenced by their school’s size (number of students), educational advantage, sun-protection policy score, or SunSmart status, indicating that other socioeconomic factors, not assessed here, may have influenced the results. Our findings suggest that the mandatory swim-shirt policy introduced in 2008 was very effective, especially initially. However, monitoring and feedback of results to schools may be needed to maintain high levels of compliance in the longer-term. Schoolchildren attending swimming carnivals should not rely on sunscreen or shade alone to protect against direct and reflected-sunlight, and need prompting to put a hat and shirt back on immediately after a race. This responsibility could be delegated to either a parent or a student prefect, if teachers are too busy to encourage and monitor sun-safety compliance among the students in their care.

中期皮膚発がん性試験におけるCrl:CD1(ICR)マウス(IGS)を用いた皮膚腫瘤発生に対する雌雄差の検討

中期皮膚発がん性試験におけるCrl:CD1(ICR)マウス(IGS)を用いた皮膚腫瘤発生に対する雌雄差の検討

Arsenic in drinking water and prostate cancer in Illinois counties: An ecologic study

BackgroundInorganic arsenic is a lung, bladder, and skin carcinogen. One of the major sources of exposure to arsenic is through naturally contaminated drinking water. While positive associations have been observed between arsenic in drinking water and prostate cancer, few studies have explored this association in the United States. ObjectivesTo evaluate the association between inorganic arsenic concentrations in community water systems and prostate cancer incidence in Illinois using an ecologic study design. MethodsIllinois Environmental Protection Agency data on arsenic concentrations in drinking water from community water systems throughout the state were linked with county-level prostate cancer incidence data from 2007 to 2011 from the Illinois State Cancer Registry. Incidence rates were indirectly standardized by age to calculate standardized incidence ratios (SIRs) for each county. A Poisson regression model was used to model the association between county-level SIRs and mean arsenic tertile (0.33–0.72, 0.73–1.60, and 1.61–16.23ppb), adjusting for potential confounders. ResultsFor counties with mean arsenic levels in the second tertile, the SIR was 1.05 (95% CI: 0.96–1.16). For counties with mean arsenic levels in the third tertile, the SIR was 1.10 (95% CI: 1.03–1.19). There was a significant linear dose-response relationship observed between mean arsenic levels and prostate cancer incidence (p for trend=0.003). ConclusionsIn this ecologic study, counties with higher mean arsenic levels in community water systems had significantly higher prostate cancer incidence. Individual-level studies of prostate cancer incidence and low-level arsenic exposure are needed.

Parallel responses of human epidermal keratinocytes to inorganic SbIII and AsIII.

SbIII and AsIII are known to exhibit similar chemical properties, but the degree of similarity in their effects on biological systems merits further exploration. Present work compares the responses of human epidermal keratinocytes, a known target cell type for arsenite-induced carcinogenicity, to these metalloids after treatment for a week at environmentally relevant concentrations. Previous work with these cells has shown that arsenite and antimonite have parallel effects in suppressing differentiation, altering levels of several critical enzymes and maintaining colony forming ability. More globally, protein profiling now reveals parallels in SbIII and AsIII effects. The more sensitive technique of transcriptional profiling also shows considerable parallels. Thus, gene expression changes were almost entirely in the same directions for the two treatments, although the degree of change was sometimes significantly different. Inspection of the changes revealed that RYR1 and LRIG1 were among the genes strongly suppressed, consistent with reduced calcium-dependent differentiation and maintenance of EGF-dependent proliferative potential. Moreover, levels of miRNAs in the cells were altered in parallel, with nearly 90% of the 198 most highly expressed ones being suppressed. Among these was miR-203, which is known to decrease proliferative potential. Finally, both SbIII and AsIII were seen to attenuate bone morphogenetic protein 6 induction of dual specificity phosphatases 2 and 14, consistent with maintaining epidermal growth factor receptor signaling. These findings raise the question whether SbIII, like AsIII, could act as a human skin carcinogen.

Alternative Toxicity Testing: Analyses on Skin Sensitization, ToxCast Phases I and II, and Carcinogenicity Provide Indications on How to Model Mechanisms Linked to Adverse Outcome Pathways

This article studies alternative toxicological approaches, with new (skin sensitization, ToxCast) and previous (carcinogenicity) analyses. Quantitative modeling of rate-limiting steps in skin sensitization and carcinogenicity predicts the majority of toxicants. Similarly, successful (Quantitative) Structure-Activity Relationships models exploit the quantification of only one, or few rate-limiting steps. High-throughput assays within ToxCast point to promising associations with endocrine disruption, whereas markers for pathways intermediate events have limited correlation with most endpoints. Since the pathways may be very different (often not simple linear chains of events), quantitative analysis is necessary to identify the type of mechanism and build the appropriate model.

Development and validation of a new transgenic hairless albino mouse as a mutational model for potential assessment of photocarcinogenicity

Short-term phototoxicity testing is useful in selecting test agents for the longer and more expensive photocarcinogenesis safety tests; however, no validated short-term tests have been proven reliable in predicting the outcome of a photocarcinogenesis safety test. A transgenic, hairless, albino (THA) mouse model was developed that carries the gpt and red/gam [Spi−] genes from the gpt delta mouse background and the phenotypes from the SKH-1 mouse background to use as a short-term test in lieu of photocarcinogenesis safety tests. Validation of the THA mouse model was confirmed by exposing groups of male mice to sub-erythemal doses of ultraviolet B (UVB) irradiation for three consecutive days emitted from calibrated overhead, Kodacel-filtered fluorescent lamps and measuring the mutant frequencies (MFs) in the gpt and red/gam (Spi−) genes and types of mutations in the gpt gene. The doses or irradiation were monitored with broad-spectrum dosimeters that were calibrated to a NIST-traceable standard and cumulative CIE-weighted doses were 20.55 and 41.0mJ/cm2 (effective). Mice were sacrificed 14 days after the final UVB exposure and MFs in both the gpt and red/gam genes were evaluated in the epidermis. The exposure of mice to UVB induced significant ten- to twelve-fold increases in the gpt MF and three- to five-fold increases in the Spi− MF over their respective background MF, 26±3×10−6 and 9±1×10−6. The gpt mutation spectra were significantly different between that of the UVB-irradiated and that of non-irradiated mice although the mutation spectra of both groups were dominated by C→T transitions (84% and 66%). In mice exposed to UVB, the C→T transitions occurred almost exclusively at dipyrimidine sites (92%), whereas in non-irradiated control mice, the C→T transitions occurred at CpG sites (86%). These results suggest that the newly developed THA mice are a useful and reliable model for testing UVB-induced mutagenicity in skin tissue. The application of this model for short-term prediction of solar-induced skin carcinogenicity is presently under investigation.

Crl:CD1(ICR)マウス(IGS)を用いた中期皮膚発がん性試験における12-O-tetradecanoylphorbol-13-acetate (TPA)の皮膚腫瘍発生への影響

Crl:CD1(ICR)マウス(IGS)を用いた中期皮膚発がん性試験における12-O-tetradecanoylphorbol-13-acetate (TPA)の皮膚腫瘍発生への影響

Development of a Reproducible Rating System for Sun Protective Clothing That Incorporates Body Surface Coverage

Sunlight is a known skin carcinogen. Skin cancer is the most common form of cancer in humans, and typically affects sun-exposed parts of the body. Sunny Australia and New Zealand have the highest incidence of skin cancer globally. Clothing provides a protective barrier that reduces the amount of ultraviolet radiation (UVR) reaching the skin. Australia pioneered the development of a relative ranking of the sun-protective capabilities of clothing based on the transmission of UVR through fabric. Standardized Ultraviolet Protection Factor (UPF) measurement procedures and associated labeling specifications are documented in the Australian and New Zealand Standard, AS/NZS 4399:1996. The standard was intended to enable consumers to make informed choices. Since its introduction, this standard has been adopted almost universally by the textile industry, and is still in use almost two decades on, with plans to revise it only commencing recently. However, AS/NZS 4399:1996 does not consider garment design, particularly in relation to body surface coverage. Although swim-shirts have grown in popularity in Australia since the late 1990s, particularly among children, clothing remains under-utilized as a form of sun-protection in contemporary society. Skin cancer prevention campaigns should emphasize the sun-protective benefits of clothing and collaboration with the fashion industry is urgently needed to improve the aesthetic appeal, comfort, durability and affordability of sun-protective clothing to increase its popularity in skin cancer prone populations. In light of recent evidence showing that high UPF clothing which covers more of the body surface reduces pigmented mole development in children (major risk factor for melanoma), the rating system for sun-protective clothing should incorporate body surface covered as well as the UPF of the fabric. We discuss progress towards developing a protocol for measuring the extent of coverage of sun-protective garments. Once fully evaluated and refined, the testing protocol developed from this research may influence future revisions of international standards for evaluating and classifying sun-protective clothing.