Abstract 537: Alcohol exposure in utero induces histophysiological changes in prostate and increases susceptibility to prostate tumorigenesis in rat offspring

Abstract

Abstract Prostate cancer remains the second leading cause of cancer death in men. While some of the causes of prostate neoplasia are subject of intensive research, the influence of genetic predisposition as well as diet and other environmental factors are not well studied. Recently it has been shown that prenatal exposure to ethanol makes the offspring more susceptible to the development of childhood cancers. However, it is not known whether prenatal ethanol induces fetal programming for prostate neoplasia. In order to test this, we fed pregnant rats a liquid diet containing alcohol, some were pair-fed with isocaloric liquid diet, or other were fed ad libitum with rat chow between gestational days 7 and 21. A group of male offspring rats were sacrificed at 7 to 8 months of age and their prostates were removed for histopathology. Another group of male offspring rats were treated with N-Nitroso-N-methylurea (NMU) and testosterone to induce prostate neoplasia. After the tissue was processed, the ventral, lateral, and dorsal parts of the epithelium were viewed under a microscope to determine whether the tissue exhibited normal histology, or abnormalities in the form of atypia, low-grade, or high-grade prostatic intraepithelial neoplasia (PIN). Additionally, levels of various cellular proteins associated with prostate pathology were determined by immunohistochemistry. The prostates of most (77%) of the alcohol exposed animals, but not ad lib-fed or pair-fed animals, demonstrated atypical hyperplasia, atypia-dysplasia characterized by nuclear stratification, and epithelial evagination with intense inflammatory infiltration in the ventral prostate gland. Furthermore, a significant number of in utero alcohol exposed animals developed high-grade PIN, whereas control animals developed hyperplasia and low grade PIN during adulthood in response to NMU and testosterone treatments. We also found increased levels of estradiol receptor (ER)-alpha, decreased levels of androgen receptor (AR) in the dorsal and ventral prostate, and low levels of circulating testosterone in alcohol-fed offspring who were not treated with carcinogens. In addition, these rats showed a decreased level of E-cadherin and increased Ki-67 in the ventral prostate. Fetal alcohol exposed rats treated with carcinogens showed increased levels of Ki-67 with concomitant decreased levels of PTEN and Nkx3.1 in the ventral prostate epithelium. The protein data corroborates well with the increased neoplastic transformation of the ventral prostatic cells in fetal alcohol exposed rats. These results suggest for the first time that prenatal ethanol exposure induces pre-malignant lesions in prostatic cells and increases the susceptibility toprostate cancer. (Supported by NIH Grants AA11591 and R37 AA08757) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 537. doi:1538-7445.AM2012-537