Early environmental and hormonal exposure influences on human myometrial cell population

7.项目概要/摘要 子宫肌瘤代表了美国的一个主要种族差异，非洲裔美国人 患纤维瘤的女性比白种人多四倍而 纤维瘤发展的潜在机制仍然难以捉摸，有人提出，由于 推定的生命早期暴露于有毒环境因子，如内分泌干扰化学品 在非裔美国人（AA）妇女中，子宫肌层干细胞（MSC）群体 永久扩展，关键DNA修复相关基因的不可逆重编程发生在 早期发展。因此，这种早期生命中DNA修复机制的重编程降低了它们的生物学活性。 修复子宫肌层细胞DNA损伤的能力。如果没有功能性DNA修复相关基因， 体细胞突变，如MED 12（涉及约85%的自发性 纤维瘤），出现在这些干细胞中，并将其转化为子宫平滑肌瘤形成干细胞 子宫肌瘤的发生与子宫肌瘤的发展有关。 此外，众所周知，肌瘤肿瘤、原发性子宫肌层和肌瘤细胞以及 这些子宫肌层干细胞的生长受到卵巢激素（雌激素和 孕酮），表明生理雌激素和孕酮水平的差异（无论 由于体内周期性激素变化或代谢差异）。研究表明 与雌激素生物合成相关的基因中的不同表达和/或多态性，和/或 代谢，例如CYP 17、COMT，表明激素对子宫肌层干细胞（MSC）的影响 在非裔美国妇女中，这种扩张更大。综合这些观察， 研究种族和激素对MSC扩增对应物的影响可能会揭示 子宫肌瘤发展的潜在机制。 .

7. Project Summary/Abstract Uterine fibroids represents a major ethnic disparity in the United States, with African American women afflicted by fibroids four times more than their Caucasian counterparts. While the mechanism underlying fibroid development remains elusive, it is proposed that as a result of putative early-life exposure to toxic environmental agents, such as endocrine disrupting chemicals (EDCs), in African-American (AA) women, the uterine myometrial stem cell (MSC) population expands permanently, and irreversible reprogramming of key DNA repair-related genes occurs in early development. This early-life reprogramming of DNA repair mechanisms thus decreases their capacity to repair myometrial cell DNA damage. Without functional DNA repair-related genes, somatic mutations, such as MED12 (implicated in approximately 85% of spontaneously-emerging fibroid tumors), emerge in these stem cells and convert them into uterine leiomyoma-forming stem cells, ultimately leading to the development of uterine fibroids. In addition, it is well-established that fibroid tumors, primary myometrial and fibroid cells, and these myometrial stem cells’ growth is stimulated by ovarian hormones (estrogen and progesterone), suggesting differences in physiological estrogen and progesterone levels (whether due to cyclical hormonal changes or metabolic differences in the body). Research has shown different expression and/or polymorphisms in genes relating to estrogen biosynthesis and/or metabolism, e.g. CYP17, COMT, suggesting the hormonal impact on myometrial stem cell (MSC) expansion is greater in women of African American ethnicity. Combining these observations, studying the effects race and hormones have on MSC expansion counterparts may reveal underlying mechanisms of uterine fibroid development. .