Fetal exposure to PhlP and prostate cancer

描述(申请人提供)：前列腺癌(CAP)是美国最常见的男性恶性肿瘤，目前尚无治疗转移性疾病的有效方法。据估计，2004年将有超过23万名美国男性被诊断出患有CAP，其中29900人将死于这种疾病。除了衰老过程外，CAP还被认为是遗传、激素、饮食和环境因素相互作用的结果。此外，在子宫内暴露于激素、脂肪和其他环境和生物“致癌物”的水平升高，被认为会使前列腺癌在晚年罹患癌症的风险升高。最近，食品制备方法作为癌症病因学中的一个重要变量受到了密切关注。肉类烧烤过程中产生的杂环胺已成为CAP的主要致癌物质和重要的致病因素。PhIP(2-amino-1-methyl-6-phenylimidazol[4，5-b]pyridine)是熟肉、鱼、葡萄酒、啤酒和香烟烟雾中的主要杂环胺。ACI大鼠是一种已建立的自发的、自然发生的、与年龄相关的帽的大鼠模型。与对照组大鼠相比，PhIP诱发急性脑梗塞大鼠CAP的发生率更高，发生的时间也更早。大鼠在子宫和围产期暴露于PhIP已被证明会增加患乳腺癌和结肠癌的终身风险，但尚未对CAP进行调查。我们建议用含有PhIP的饲料喂养怀孕和哺乳期的ACI大鼠，并对雄性幼鼠的前列腺进行结构、组织学和基因表达(微阵列)分析，以检测PhIP对发育中的前列腺的影响。结构研究将包括对第21天的胎儿进行3D重建分析。我们还将确定由于胎儿/围产期暴露于PhIP以及基因表达变化而导致的CAP终生风险。这些实验的完成将有助于我们了解胎儿/围产期暴露于PhIP在CAP病因中的作用，使我们能够识别干预的靶分子，并设计合理的预防CAP的策略。

DESCRIPTION (provided by applicant): Prostate cancer (CaP) is the most common malignancy of men in America, with no curative treatment for metastatic disease. It is estimated that over 230,000 American men will be diagnosed with CaP in the year 2004 and 29,900 deaths will be attributed to the disease. In addition to the aging process, CaP is thought to result from the interplay of genetic, hormonal, dietary and environmental factors. Further, in utero exposure to elevated levels of hormones, fats and other environmental and biological "carcinogens" are thought to predispose or imprint the prostate to an elevated level of risk for the development of cancer later in life. Recently, the method of food preparation has come under scrutiny as a significant variable in the etiology of cancer. Heterocyclic amines produced during the grilling of meats have emerged as major food carcinogens and important etiologic factors in CaP. PhIP (2-amino-1-methyl-6-phenylimidazol[4,5-b]pyridine) is the predominant heterocyclic amine in cooked meat and fish, wine, beer and cigarette smoke. The ACI rat is an established rat model for spontaneous, naturally occurring, age-associated CaP. PhIP induces CaP in ACI rats at a higher incidence, and earlier in life, than control rats. In utero and perinatal exposure of rats to PhIP has been demonstrated to increase the lifelong risk of breast and colon cancer, but has not been investigated for CaP. We propose to feed pregnant and lactating ACI rats a diet containing PhIP and perform structural, histological and gene expression (microarray) analyses on prostates of male pups to detect effects of PhIP on the developing prostate. Structural studies will include 3-D reconstruction analyses will be performed on day 21 fetuses. We will also determine the lifelong risk of CaP due to fetal/perinatal exposure to PhIP as well as alterations in gene expression. The completion of these experiments will contribute to our understanding of the role of fetal/perinatal exposure to PhIP in the etiology of CaP enable us to identify target molecules for intervention and design rational strategies for the prevention of CaP.