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.

阳光暴露和多环芳烃（PAHS）与人类皮肤癌有关。假定过量暴露于长波长紫外A（UVA）与吸烟或环境污染中的PAH相结合的可能与造成令人震惊的皮肤癌的增加有关。该提议的中心假设是，宽广泛的环境污染物苯并（A）pyrene（BAP）用作光敏剂，以产生UVA成立后产生活性氧（ROS）。通过BAP-UVA处理产生的ROS会诱导氧化DNA损伤，增强BAP-DNA加合物的Fonnation（遗传效应）并激活信号转导级联（表观遗传效应）。因此，亚癌性BAP和UVA的结合既可以发起和促进活动，又导致了协同的致癌性。为了检验已建立的假设，已经提出了四个具体目标。最初的目的是确定UVA和BAP是否协同增强皮肤致癌作用。 BAP将局部应用于无毛小鼠或口服的背皮，然后进行UVA辐照。将记录潜在时期，肿瘤的发病率和多样性，以评估协同作用。第二个目的是阐明体内协同作用的机制。我们将确定BAP的应用是否增强了氧化剂的形成，氧化的DNA碱基和笨重的DNA加合物，原子质基因的表达以及MS Oncogenes的突变和p53肿瘤抑制基因在UVA辐射的小鼠皮肤和肿瘤组织中。第三个目的是表征体外协同作用的分子机制。鼠和人角质形成细胞将用于研究BAP调节UVA诱导的氧化DNA损伤的机制，表皮生长因子受体的磷酸化以及酪氨酸蛋白激酶的激活以及有丝裂原激活的蛋白激酶的激活。最后，我们将检查SOD仿生型的局部应用是否抑制了BAP-UVA的氧化剂产生，DNA氧化以及皮肤肿瘤性。 BAP加上UVA增强的氧化DNA损伤和皮肤致癌的干预将证实ROS的重要作用，并帮助我们阐明长波长紫外线光和BAP的协同作用的分子机制。