TY - JOUR TI - Fetal alcohol exposure increases susceptibility to tumorigenesis in the pituitary DO - https://doi.org/doi:10.7282/T3C53PZ6 PY - 2017 AB - Alcohol exposure during gestation increases susceptibility to the development of pituitary tumors in response to estrogen in rat offspring. While the mechanism underlie this effect is not fully understood, serum estradiol (E2) and pituitary aromatase mRNA expression are increased in fetal alcohol exposed (FAE) offspring, which suggests a role for the estrogen axis. To test our hypothesis, 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 rat chow (AD). At 60 days of age, animals were ovariectomized and received a subcutaneous estradiol implant. Rats were sacrificed at various times point after estradiol implantation. At the time of sacrifice, pituitaries of these animals were inspected for tumor growth. Estradiol treatment time-dependently increased pituitary weight in AF group as compared to AD and PF groups. After 120 days of estradiol treatment, inspection of the pituitary revealed that most tumors in the AF group were hemorrhagic and showed expansion to the surrounding tissue. Pituitary tumors from FAE offspring showed strong nuclear p53 and Ki67 expression. Significantly higher mRNA levels of hemorrhage-associated genes and proteins (PTTG, FGF4 and MMP-9) and multipotency genes and proteins (SOX2, Oct4 and CD133) were also observed in pituitary tumor tissues from AF group as compared with PF and AD groups. To test whether FAE enhances the population of cancer stem cells (CSCs) in the pituitary in response to estradiol, pituitaries were collected, and plated in ultra-low plates to promote pituisphere formation. The growing spheres were enzymatically dissociated to permit serial passaging. Assessment of a panel of genes related to multipotency (OCT4, NANOG, KLF4, SOX2, CD133, CD44, nestin and CD34) indicated that mRNA and protein expression of most of these genes was significantly higher in pituitary cells derived from spheres of AF animals as compared to AD. Pituitary cells derived from spheres of AF animals showed higher cell proliferation, migration and colony formation rates as compared to the control group. The pituitary cells derived from AF spheres were able to grow in immunodeficient mice. These data suggest that alcohol feeding enhances pituitary tumor development, and may program the pituitary to express pluripotent and growth promoting molecules under the estrogenic influence to induce aggressive pituitary tumor. KW - Animal Sciences KW - Fetal alcohol spectrum disorders KW - Pituitary gland LA - eng ER -