Alcohol and Hyperprolactinemia

描述(申请人提供)：高水平的血浆催乳素，高催乳素血症，被认为是女性生殖功能障碍的主要原因之一，如闭经，溢乳和不孕。许多高催乳素血症患者还表现为分泌催乳素的垂体腺瘤(催乳素瘤)。虽然在建立治疗催乳素瘤的治疗方法方面已经取得了相当大的进展，但催乳素瘤的潜在原因仍未得到很好的描述。女性在怀孕期间的生活方式选择和暴露于环境毒素可能会影响其后代患各种癌症的风险，这一想法是一个新出现的概念。疾病控制中心的统计数据显示，相当数量的女性在怀孕期间饮酒或狂饮。因此，有报道称，在胚胎发育期间暴露于酒精的大鼠在成年后对荷尔蒙诱导的垂体肿瘤的易感性增加，这表明这类女性的后代患催乳素瘤的风险可能会增加。最近在动物身上的研究发现，多巴胺受体2(D2R)在介导下丘脑多巴胺对垂体催乳素分泌的抑制控制中起到了作用。然而，目前尚不清楚饮酒如何在D2R基因中产生持久的变化来刺激乳酸菌的生长。表观遗传机制，如组蛋白乙酰化和DNA甲基化，已被证明在维持基因表达的长期变化方面发挥了作用。这项拟议的研究测试了一种假设，即酒精对DNA甲基转移酶和/或组蛋白脱乙酰酶的调节作用在D2受体基因上形成了一个表观遗传标记，减少了D2受体的产生，并抑制了对乳酸菌细胞增殖的控制，从而增加了对有丝分裂原的敏感性。因此，拟议的研究将为产前乙醇诱导D2R的表观遗传修饰提供重要线索，从而在成年后创造一种易受生殖功能障碍和脑垂体瘤影响的细胞底物。好了！

DESCRIPTION (provided by applicant): A high level of plasma prolactin, hyperprolactinemia, is known to be one of the major reasons for reproductive dysfunction such as amenorrhea, galactorrhea and infertility in women. Many of the patients with hyperprolactinemia also show prolactin-secreting pituitary adenomas (prolactinomas). While considerable gains have been made in establishing therapies for the treatment of prolactinomas, the underlying causes of prolactinomas remain poorly delineated. The idea that a woman's lifestyle choices and exposure to environmental toxins during pregnancy may affect her offspring's risk of various cancers is a newly emerging concept. Statistics from the Centers for Disease Control indicate that a significant number of women drink or binge-drink while pregnant. Therefore, the reports that rats exposed to alcohol during fetal development have increased susceptibility to hormonally induced pituitary tumors in adulthood suggest that offspring from this group of women may be at increased risk for prolactinomas. Recent studies in animals have identified a role for dopamine receptor 2 (D2R) in mediating the inhibitory control of hypothalamic dopamine on prolactin-secreting lactotropes in the pituitary. However, it is not known how alcohol use produces long-lasting changes in the D2R gene to stimulate lactotrope growth. Epigenetic mechanisms, such as histone acetylation and DNA methylation, have been shown to play a role in maintaining a long-lasting change in gene expression. The proposed research tests the hypothesis that alcohol's modulating effect on DNA methyltransferases and/or histone deacetylases makes an epigenetic mark on the D2 receptor gene that reduces D2 receptor production and its inhibitory control of cell proliferation of lactotropes, leading to an increased susceptibility to mitogens. Thus, the proposed studies will provide an important clue about prenatal ethanol-induced epigenetic modifications in D2R, creating a cellular substrate vulnerable to reproductive dysfunction and pituitary tumors in adulthood. !