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SYNERGISTIC CARCINOGENICTY OF UVA AND BENZO(A)PYRENE

UVA 和苯并(A)芘的协同致癌作用

基本信息

批准号：
6635489
负责人：
HUACHEN WEI
金额：
$ 27.49万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2005-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6635489
关键词：
DNA damage benzopyrenes carcinogen testing chemical carcinogen chemical carcinogenesis cocarcinogen free radical oxygen laboratory mouse mutagen testing mutagens radiation carcinogen radiation carcinogenesis skin neoplasms ultraviolet radiation

项目摘要

Sunlight exposure and polycyclic aromatic hydrocarbons (PAHs) have been implicated in human skin cancers. It is assumed that excess exposure to long wavelength ultraviolet A (UVA) combined with PAHs from cigarette smoking or environmental pollution may be associated with the alarmingly increased skin cancers. The central hypothesis of this proposal is that a wide-spread environmental pollutant benzo(a)pyrene (BaP) serves as a photosensitizer to generate reactive oxygen species (ROS) upon UVA inadiation. ROS preduced by BaP-UVA treatment induce oxidative DNA damage, enhance the BaP-DNA adduct fonnation (genetic effect) as well as activate the signal transduction cascades (epigenetic effects). Thus, combination of subcaminogenic BaP and UVA potentiates both initiating and promoting activities, and subsequently leads to synergistic carcinogenicity. To test the established hypothesis, four specific aims have been proposed. The initial aim is to determine if UVA and BaP synergistically enhance skin carcinogenesis. BaP will be topically applied to dorsal skin of hairless mice or orally administered, then followed by UVA irradiation. The latent period, tumor incidence and multiplicity will be recorded to evaluate the synergetic action. The second aim is to elucidate the mechanisms of synergistic action in vivo. We will determine if application of BaP potentiates the formation of oxidants, oxidized DNA bases and bulky DNA adducts, expression of protooncogenes, and mutation of ms oncogenes and p53 tumor suppressor genes in UVA-irradiated mouse skin and tumor tissues. The third aim is to characterize molecular mechanisms of synergetic action in vitro. Murine and human keratinocytes will be used to investigate the mechanisms by which BaP modulates UVA-induced oxidative DNA damage, phosphorylation of epidermal growth factor receptor and activation of tyrosine protein kinases and mitogen-activated protein kinases. Finally, we will examine if topical application of a SOD biomimetic inhibits oxidant generation, DNA oxidation as well as skin tumorigenicity by BaP-UVA. Intervention of BaP plus UVA-enhanced oxidative DNA damage and skin carcinogenesis will confirm the important role of ROS and help us elucidate the molecular mechanisms of synergetic action of long wavelength UV light and BaP.

阳光照射和多环芳烃 (PAH) 与人类皮肤癌有关。据推测，过度暴露于长波紫外线 A (UVA) 以及吸烟或环境污染产生的多环芳烃可能与皮肤癌的惊人增加有关。该提案的中心假设是，广泛存在的环境污染物苯并（a）芘（BaP）作为光敏剂，在 UVA 照射下产生活性氧（ROS）。 BaP-UVA 处理产生的 ROS 会诱导 DNA 氧化损伤，增强 BaP-DNA 加合物的形成（遗传效应）并激活信号转导级联（表观遗传效应）。因此，亚致癌 BaP 和 UVA 的组合可增强启动和促进活性，并随后导致协同致癌性。为了检验既定的假设，提出了四个具体目标。最初的目的是确定 UVA 和 BaP 是否可以协同增强皮肤癌的发生。将BaP局部涂抹于无毛小鼠的背部皮肤或口服，然后进行UVA照射。将记录潜伏期、肿瘤发生率和多重性以评价协同作用。第二个目的是阐明体内协同作用的机制。我们将确定 BaP 的应用是否会增强 UVA 照射的小鼠皮肤和肿瘤组织中氧化剂、氧化 DNA 碱基和大体积 DNA 加合物的形成、原癌基因的表达以及 ms 癌基因和 p53 肿瘤抑制基因的突变。第三个目标是表征体外协同作用的分子机制。小鼠和人类角质形成细胞将用于研究 BaP 调节 UVA 诱导的氧化 DNA 损伤、表皮生长因子受体磷酸化以及酪氨酸蛋白激酶和丝裂原激活蛋白激酶激活的机制。最后，我们将检查局部应用 SOD 仿生剂是否会抑制 BaP-UVA 产生的氧化剂、DNA 氧化以及皮肤致瘤性。 BaP加UVA的干预增强的DNA氧化损伤和皮肤癌发生将证实ROS的重要作用，并帮助我们阐明长波长UV光和BaP协同作用的分子机制。