MECHANISM OF PESTICIDE MIREX INDUCED TUMOR PROMOTION

描述：灭蚁灵是一种氯化杀虫剂，代表着一种有效的 典型的皮肤肿瘤启动子：i)通过一种未知的 不同于其他皮肤肿瘤促进剂的机制；ii)似乎促进 独特的表皮或表皮附属物细胞群体， 然而，与佛波酯促进的不同，这一群体 不能通过突变的Ha-ras基因来区分；iii)是4-5倍 在雌性小鼠中更有效；以及iv)克隆地扩大突变的种群 似乎依赖雌激素的HA-ras细胞。外用雌激素 治疗本身通过以下方式对毛囊周期产生深远影响 阻断了生长期卵泡向生长期卵泡的转变， 可能是通过它的直接作用或通过它对皮肤的调节- 或影响增殖和/或毛乳头来源的因子 假性肿胀干细胞的分化/瞬时扩增(TA) 手机。成纤维细胞生长因子家族的成员是已知的强有力的毛发调节剂 毛囊以及表皮的生长和分化。我们假设 雌激素通过成纤维细胞生长因子家族直接或间接地影响 可能的干细胞/TA细胞的分化导致表型 这对灭蚁灵的推广很敏感。这项建议的具体目的 是；i)确凿地证明了雌激素和雌激素 灭蚁灵启动子的受体依赖性；ii)定位表达 皮肤和周期毛囊中的雌激素受体，并确定 雌激素调节成纤维细胞生长因子成员及其受体的表达 确定灭蚁灵所致乳头状瘤的皮肤来源和表型 关于雌激素受体和FGFs，它们的同源受体和 四)展示灭蚁灵与安非他明之间的功能互动 雌激素/雌激素调节角质形成细胞中的成纤维细胞生长因子。对此的进一步研究 新的肿瘤促进剂将从根本上理解灭蚁灵，一种 环境氯农药，与雌激素相互作用，发挥作用 作为一种有效的皮肤肿瘤促进剂。拟议的研究还将 有助于我们理解雌激素和成纤维细胞生长因子在 调节毛囊生长发育和分化； 上皮/间充质相互作用；以及影响血管内皮生长的因素 表皮干细胞/TA细胞向肿瘤分化的实验研究 启动子特有的表型。对灭蚁灵作用机制的认识 在确定本组织其他成员的身份时，推广将是重要的 类，并最终对非遗传毒性进行合理的风险评估 致癌物质。

DESCRIPTION: Mirex is a chlorinated pesticide and represents a potent prototypical skin tumor promoter that: i) functions through an unidentified mechanism distinct from other skin tumor promoters; ii) appears to promote a unique population of epidermal or epidermal appendage cells that are different than those promoted by phorbol ester, however, this population cannot be distinguished by its mutant Ha-ras genotype; iii) is 4-5 times more potent in female mice; and iv) clonally expands a population of mutant Ha-ras cells that appears to be dependent upon estrogen. Topical estrogen treatment itself has a profound effect on the hair follicle cycle by blocking the transition of the telogen follicle to an anagen follicle, presumably through its direct effect or through its modulation of dermally- or dermal papilla-derived factors that influence proliferations and/or differentiation of the putative bulge stem cell/transient amplifying (TA) cell. Members of the FGF family are known potent modulators of hair follicle as well as epidermal growth and differentiation. We hypothesize that estrogen directly or indirectly through the FGF family influences the differentiation of the putative stem cell/TA cell resulting in a phenotype that is sensitive to mirex promotion. The specific aims of this proposal are to; i) conclusively demonstrate the estrogen- and estrogen receptor-dependent nature of mirex promotion; ii) localize the expression of the estrogen receptor in skin and the cycling hair follicle and determine if estrogen modulates the expression of FGF members and their receptors; iii) identify the cutaneous origin and phenotype of the mirex promoted papillomas with respect of the estrogen receptor, and FGFs, their cognate receptors and iv) demonstrate a functional interaction between mirex and estrogen/estrogen-modulated FGF in keratinocytes. Further study of this novel tumor promoter will yield a fundamental understanding of how mirex, an environmental chlorinated pesticide, interfaces with estrogen, to function as a potent tumor promoter in skin. The proposed studies will also contribute to our understanding of the role of estrogen and FGF in the regulation hair follicle growth, development and differentiation; epithelial/mesenchymal interactions; and factors that influence the differentiation of putative epidermal stem cells/TA cells to a tumor promoter specific phenotype. An understanding of the mechanism of mirex promotion will be important in the identification of other members of this class and ultimately to the rational risk assessment of nongenotoxic carcinogens.