Benzo(a)pyrene [B(a)P] is a lipophilic aromatic hydrocarbon that belongs to the polycyclic aromatichydrocarbon family and has been implicated in toxicity and in increased incidence of cancer in variousorgans. The incidence of advanced prostate cancer and mortality has been disproportionately high in somepopulation groups which have also been exposed to higher concentrations of aromatic hydrocarbons(AHCs), the prototype of which is B(a)P. To test whether B(a)P alters the rate or extent of cancerdevelopment, we propose to study a genetically engineered mouse model that permits the study of prostatecarcinogenesis in an experimentally amenable time frame. This unique LPB-Tag transgenic mouse model ofprostate cancer which develops a spatial pathological pattern of preneoplastic lesions and small foci ofbcally invasive carcinoma. The central hypothesis to be tested is that exposure to B(a)P aerosol at levelsexperienced by human beings in certain environments results in alteration of prostatic function leading toinduction or acceleration of prostate cancer formation. This hypothesis can be narrowed down to twoquestions. 1) Does B(a)P alter specific steroidal hormone and androgen events in a temporal manner to alterprostatic function? and 2) Does B(a)P accelerate prostatic intraepithelial neoplasm (PIN) that progresses toprostate adenocarcinoma?We intend to address these questions and test our hypothesis that B(a)P accelerates prostate cancerprogression using two specific Aims.
Specific Aim I will exploit a range-finding study to determine thedisposition of B(a)P in the prostate of our mouse model in order to establish the dose of aerosolized B(a)P touse in our subsequent studies.
Specific Aim II will determine the effect of B(a)P on the progression ofprostatic intraepithelial neoplasia (PIN) to adenocarcinoma monitoring both histopathological changes andspecific gene expression. In adddition, we will also assess relative proliferation rate of prostate tissues incontrol and B(a)P exposed mice.These studies will advance our knowledge of the role of environmental toxicants on the initiation andprogression of prostate cancer and provide preliminary data to seek extramural funding to delinate themechanism by which environmental pollutants, like the ubiquitous AHCs, alter initiation and progression ofcancer as a first step in the prevention, diagnosis, prognosis and better management of prostate cancer.This will also help in redressing health disparity among our different population groups.
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