Arsenic induced signaling pathways in human epidermis

描述(取自应用程序) 通过饮食暴露于高水平砷的毒性， 职业或医疗路线已经在不同的 国家。砷中毒最明显和最普遍的表现 皮肤的变化是否涉及角化过度和增加 色素沉着、潜伏性基底细胞癌和鳞状细胞癌。后两者 皮肤癌的类型与阳光诱发的皮肤癌的不同之处在于 它们主要发生在手掌和脚掌上，而不是暴露在阳光下。 解剖部位，更具侵袭性和转移性。虽然砷 诱发的皮肤变化在组织学上有很好的特征， 它们产生的分子机制还知之甚少。特别是， 砷影响基因组DNA并诱导其表达的机制 或者特定基因的抑制在很大程度上是未知的。考虑到 皮肤是人体与环境的第一个界面， 皮肤表现通常反映内脏功能障碍，这是 对阐明砷对人体皮肤的作用机制具有重要意义。那里 是否有足够的证据支持砷导致氧化的观点 哺乳动物细胞中的压力。在皮肤表皮中，角质形成细胞增多 导致角化过度并最终导致癌症肿瘤的增殖，如 以及色素沉着，可能是砷诱导氧化的结果 角质形成细胞和黑素细胞分别处于应激状态。我们正在提议 探讨砷引起皮肤变化的假说 从氧化应激，破坏正常的表皮细胞增殖和 差异化。为此，我们将使用正常人的原代培养 黑素细胞和角质形成细胞，以及模仿 皮肤在原位。砷对调控基因的影响 角质形成细胞增殖分化与黑素细胞色素沉着 将会被澄清。上述体外模型代表了一种最佳方法 阐明砷对人体细胞和组织的作用机制。这个 所获得的结果应与其他上皮组织相关，例如 肺和膀胱组织，受砷影响。本研究特此进行 提议应为进一步调查这些机制奠定基础 其中砷可能会促进其他环境致癌物的影响， 例如紫外线辐射和多环芳烃。这个 这一提议的结果应导致更有效的干预手段 和治疗砷中毒的表现，并为设置更多 关于砷暴露安全水平的有效政策。

DESCRIPTION (Taken from application) Toxicity due to exposure to high levels of arsenic through dietary, occupational, or medicinal routes has been well documented in different countries. The most obvious and prevalent manifestations of arsenic toxicity are the cutaneous changes that involve hyperkeratosis and increased pigmentation, and latent basal and squamous cell carcinoma. The latter two types of skin cancer differ from the sun induced skin cancer tumors in that they occur mainly on the palms and soles, rather than on sun exposed anatomical sites, and are more invasive and metastatic. Although arsenic induced cutaneous alterations are histologically well characterized, the molecular mechanisms by which they arise are poorly understood. In particular, the mechanisms by which arsenic affects genomic DNA and induces the expression or suppression of specific genes are for the most part unknown. Given that the skin is the first interface between the human body and the environment, and that cutaneous manifestations often reflect internal organ dysfunction, it is important to elucidate the mechanism of action of arsenic on human skin. There is sufficient evidence to support the notion that arsenic induces oxidative stress in mammalian cells. In the cutaneous epidermis, increased keratinocyte proliferation that leads to hyperkeratosis and eventually cancer tumors, as well as hyperpigmentation, may be the outcome of arsenic induced oxidative stress in keratinocytes and melanocytes, respectively. We are proposing to investigate the hypothesis that arsenic induced cutaneous alterations result from oxidative stress that disrupts normal epidermal cell proliferation and differentiation. For this, we will use primary cultures of normal human melanocytes and keratinocytes, as well as a skin substitute model that mimics the skin in situ. The effects of arsenic on genes involved in regulating keratinocyte proliferation and differentiation, and melanocyte pigmentation will be elucidated. The above in vitro models represent an optimal approach to elucidate the mechanism of action of arsenic on human cells and tissues. The results to be obtained should be relevant to other epithelial tissues, such as lung and bladder tissues, that are affected by arsenic. The studies hereby proposed should set the stage for further investigations of the mechanisms by which arsenic might promote the effects of other environmental carcinogens, such as ultraviolet radiation and polycyclic aromatic hydrocarbons. The outcome of this proposal should lead to more effective means for intervening in, and treating the manifestations of arsenic toxicity, and for setting more effective policies regarding safe levels of arsenic exposure.