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. ? ?
| Hofkamp, Luke E; Bradley, Sarahann; Geliebter, Jan et al. (2010) Atypical fetal prostate development is associated with ipsilateral hypoplasia of the wolffian ducts in the ACI rat. Anat Rec (Hoboken) 293:747-53 |
