Fetal exposure to PhlP and prostate cancer

描述（由申请人提供）：前列腺癌（CaP）是美国男性最常见的恶性肿瘤，转移性疾病无治愈性治疗。据估计，2004年将有超过230，000名美国男性被诊断患有CaP，29，900人死于该病。除了衰老过程，CaP被认为是遗传、激素、饮食和环境因素相互作用的结果。此外，在子宫内暴露于升高水平的激素、脂肪和其他环境和生物“致癌物”被认为使前列腺在以后的生活中发展成癌症的风险升高。最近，食物制备方法作为癌症病因学的一个重要变量受到审查。肉类烧烤过程中产生的杂环胺已成为主要的食品致癌物和CaP的重要致病因素。PhIP（2-amino-1-methyl-6-phenylimidazol[4，5-B]pyridine）是熟肉和鱼、葡萄酒、啤酒和香烟烟雾中的主要杂环胺。ACI大鼠是自发的、自然发生的、年龄相关的CaP的已建立的大鼠模型。PhIP在ACI大鼠中诱导CaP的发生率更高，并且比对照大鼠更早。大鼠在子宫内和围产期暴露于PhIP已被证明会增加乳腺癌和结肠癌的终身风险，但尚未对CaP进行研究。我们建议喂养怀孕和哺乳期ACI大鼠的饮食中含有PhIP和进行结构，组织学和基因表达（微阵列）分析的雄性幼崽的前列腺，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天胎仔进行3-D重建分析。我们还将确定由于胎儿/围产期暴露于PhIP以及基因表达的改变而导致的CaP的终身风险。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病因学中的作用，使我们能够确定干预的靶分子，并设计合理的预防策略。

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.