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. !
The main goal of this proposal is to use an established rat animal model for fetal alcohol exposure to identify how epigenetic modification of the dopamine receptor 2 gene makes the pituitary susceptible to mitogens, leading to the development of prolactinomas and hyperprolactinemia. The findings of these experiments will form a basis for the development of novel therapeutic tools in the treatment of this highly prevalent pituitary disease in humans. !
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