High susceptibility of the ACI and spontaneously hypertensive rat (SHR) strains to 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine (PhIP) prostate carcinogenesis

Abstract

rostate cancer is the most common non-cutaneous cancer in men in Western countries such as Europe and the United States 1) and its prevalence has also been increasing in Japan, 2) concomitantly with change in life style. Androgen ablation therapy is widely accepted and carried out for prostate cancers because androgens are essential for the development and growth of normal prostate and prostate cancer cells.3) However, outgrowth of hormone-independent cancer cells occurs within 1-2 years and eventually leads to a fatal outcome in many cases. 4)In vivo rat model systems for prostate cancer have been established in our laboratory. In these animal models, 3,2′-dimethyl-4-aminobiphenyl (DMAB) induces androgen-dependent non-invasive carcinomas in the ventral prostate while additional long-term treatment with testosterone propionate (TP) causes development of invasive and metastasizing androgen-independent carcinomas in the dorsolateral and anterior prostate and seminal vesicles.5-7) We have found that 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), an environmental heterocyclic amine, also induces prostate adenocarcinomas in the ventral lobe in male F344 rats.8) This might be an especially suitable model to investigate risk factors or chemoprevention of prostate cancer, because PhIP is naturally occurring carcinogen which is produced during the ordinary cooking process of meat and fish 9) and humans are often exposed to PhIP in ordinary daily life via cooked food, wine, beer and cigarette-smoke.In the present study, we investigated strain differences in susceptibility of male rats to PhIP-induction of prostate carcinogenesis. Materials and MethodsChemicals and animals. PhIP hydrochloride with a purity of >99.9% was obtained from the Nard Institute (Osaka). Male 6-week-old F344 (F344/DuCrj), Spontaneously Hypertensive Rat (SHR) (SHR/NCrj), Lewis (LEW/Crj), Brown Norway (BN) (BN/Crj), Sprague-Dawley (SD)(Crj:CD(SD)) and Wistar (Crj:Wistar) rats were purchased from Charles River Japan, Inc. (Atsugi). ACI (ACI/N Slc) rats were from Nihon SLC (Shizuoka). All were housed 3/cage on wood-chip bedding in an air-conditioned animal room at 23±2°C and 50±10% humidity. Food (Oriental MF, Oriental Yeast Co., Tokyo) and tap water were available ad libitum. Experiment 1. Twelve rats for each group received PhIP in the diet at a dose of 400 ppm for 20 weeks starting at the age of 10 weeks. One of the SD rats and three of the Wistar rats were eliminated from the experimental numbers, because of their accidental death. The experiment was terminated at week 54 and the animals were subjected to complete autopsy. All accessory sex organs were examined for gross abnormalities and fixed in 10% buffered formalin. After fixation, the ventral prostate was removed from the base of the bladder neck and the entire organ was weighed. For tissue preparation of the accessory sex organs, one sagittal slice through the ventral prostate, two sagittal samples of the dorsolateral prostate including the urethra, and four transverse slices from ea...

Development of animal models underlining mechanistic connections between prostate inflammation and cancer

“…Importantly, it has also been observed that the administration of high-fat stress diet to PhIP-treated CYP1A humanized mice promoted prostate carcinogenesis and formation of carcinoma in situ [22] . In the same pathway, the treatment of male Fischer rats with mutagenic heterocyclic amine PhIP in the diet for 20 wk also induced inflammation, post-inflammatory proliferative or glandular atrophy and PIN lesions in the ventral prostate that culminated to invasive carcinomas after a subsequent treatment of rats with testosterone propionate [23,34] . Hence, these in vivo data suggest a potential relationship between the induction of a persistent prostate inflammatory response and PC development.…”

Expression Quantitative Trait Loci Analysis of 13 Genes in the Rat Prostate

“…ACI is susceptible to prostate carcinogenesis, and Wister, the original strain of BUF, is resistant (Isaacs 1984;Inaguma et al 2003). By linkage mapping with prostate cancers, we have recently mapped Pcr1 (chromosome 2), Pcr2 (chromosome 1), Pcs1 (chromosome 19), and Pcs2 (chromosome 20) (Yamashitaet al 2005).…”

“…Here, we identified genes differentially expressed in the prostates of BUF/Nac (BUF) and ACI/N (ACI) rats that show different susceptibilities to prostate cancers (Isaacs 1984;Inaguma et al 2003). Loci responsible for different prostate cancer susceptibility in rats were recently mapped ( Yamashita et al 2005), and if differentially expressed genes or their controlling genes are present in the mapped loci, they are considered to be good candidates.…”

Inflammation in prostate carcinogenesis

“…The exposure of laboratory rats to dietary 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) 66 results in carcinomas of the intestine in both sexes, in the mammary gland in females and in the prostate in males 65 . Rodent prostates contain four different lobes that do not correspond anatomically to the zones of the human prostate, and PhIP induces cancer only in the ventral lobe of rats 67 . In a recent study we exposed laboratory rats to PhIP and found a similar increase in the mutation frequency in all lobes of the prostate, yet the ventral lobe selectively responded with increased cell proliferation and cell death 68 .…”