Alcohol and Hyperprolactinemia

描述（由申请人提供）：高水平的血浆催乳素，即高催乳素血症，已知是生殖功能障碍的主要原因之一，如女性闭经、泌乳和不孕症。许多高催乳素血症的患者也表现为分泌催乳素的垂体腺瘤（催乳素瘤）。虽然在建立用于治疗泌乳素瘤的疗法方面已经取得了相当大的进展，但泌乳素瘤的根本原因仍然不清楚。妇女在怀孕期间的生活方式选择和接触环境毒素可能会影响其后代患各种癌症的风险，这是一个新出现的概念。疾病控制中心的统计数据表明，相当多的妇女在怀孕期间饮酒或酗酒。因此，在胎儿发育期间暴露于酒精的大鼠在成年后对经尿道诱导的垂体瘤的易感性增加的报告表明，这组女性的后代患泌乳素瘤的风险可能增加。最近在动物中的研究已经确定了多巴胺受体2（D2 R）在介导下丘脑多巴胺对垂体中分泌催乳素的催乳素的抑制控制中的作用。然而，尚不清楚酒精使用如何在D2 R基因中产生持久的变化以刺激催乳素生长。表观遗传机制，例如组蛋白乙酰化和DNA甲基化，已被证明在维持基因表达的长期变化方面发挥着作用。这项研究测试了酒精对DNA甲基转移酶和/或组蛋白脱乙酰酶的调节作用对D2受体基因产生表观遗传标记的假设，该基因减少了D2受体的产生及其对催乳素细胞增殖的抑制控制，导致对有丝分裂原的敏感性增加。因此，拟议的研究将提供有关产前乙醇诱导的D2 R表观遗传修饰的重要线索，创造一种易受成年期生殖功能障碍和垂体瘤影响的细胞基质。!

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. !