Abstract 3460: Fetal alcohol exposure increases susceptibility to carcinogenesis in the pituitary

The idea that exposure to adverse environmental conditions and lifestyle choices during pregnancy can result in fetal programming that underlies disease susceptibility in adulthood is now widely accepted. Fetal alcohol exposed offspring display many behavioral and physiological abnormalities including neuroendocrine-immune functions, which often carry over into their adult life. Since neuroendocrine-immune system is critically involved in the regulation of tumor surveillance, we determined whether fetal alcohol exposure increases the susceptibility to estrogen-induced pituitary prolactin-secreting tumors (prolactinomas), commonly occurring pituitary tumors in humans. Pregnant Fischer 344 rats were fed between gestational days 7 and 21 with a liquid diet containing alcohol (AF), pair-fed with isocaloric liquid diet (PF), or fed ad libitum with rat chow (AD). At 90 days of age, female offspring rats were ovariectomized and received a subcutaneous estradiol implant. These rats were sacrificed between 4 and 5 months after the estradiol implants. At the time of sacrifice, pituitaries of these animals were inspected for tumor and whole body were inspected for any tumor metastasis. Estradiol treatment increased pituitary weight about 5-folds in AD and PF treated groups and increased 20-30-folds in the AF treated group. Most tumors in the AF group were hemorrhagic. About 30% AF rats had some tumors in the non-pituitary sites. AD and PF rats did not show any non-pituitary site tumor. When AF rat pituitaries were grown in cultures, cells rapidly grew and formed colonies. Colony formation and rapid growth rate were not observed in cells of the pituitary from PF and AD rats. Histopathological evaluation revealed that tumors in AF group were more densely packed cells as compare to the PF and AD groups who showed uniform cells with abundant cytoplasm. Pituitary tumor from alcohol exposed animals showed strong nuclear p53 and monoclonal Ki67 immunoreactivity in almost all tumor cells. Significantly higher mRNA levels of hemorrhage-associated genes (VEGF and MMP-9) were also observed in pituitary tumor tissues from AF group as compare with PF and AD groups. Tumor cells showed positivity to prolactin staining but showed negativity to other pituitary hormones staining. Histological evaluation of the pituitary tissues revealed that tumors were prolactin producing in all groups, and tumors in AF pituitaries were highly proliferative. These data provide evidence for aggressive, possible neoplastic, prolactinoma development in the pituitary after estrogen treatment in fetal alcohol exposed female rats. (This work is supported by a National Institute of Health grant R01 AA11591). Citation Format: Shaima Jabbar, George Maglakelidze, Dipak K. Sarkar. Fetal alcohol exposure increases susceptibility to carcinogenesis in the pituitary. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3460. doi:10.1158/1538-7445.AM2015-3460