Early environmental and hormonal exposure influences on human myometrial cell population

7.项目摘要/摘要 子宫肌瘤代表了美国主要的种族差距，非裔美国人 患有子宫肌瘤的女性是高加索女性的四倍。而当 肌瘤发生的机制仍然难以捉摸，有人认为由于 假定早期接触有毒环境物质，如内分泌干扰物 在非裔美国人(AA)女性中，子宫肌层干细胞(MSC)群体 永久扩张，关键DNA修复相关基因发生不可逆转的重新编程 早期发展。这种早期生命中DNA修复机制的重新编程因此减少了它们 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MED12(与大约85%的自发出现有关 纤维瘤)，在这些干细胞中出现，并将其转化为子宫肌瘤形成干细胞 细胞，最终导致子宫肌瘤的发展。 此外，众所周知，子宫肌瘤、原发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 黄体酮)，表明生理雌激素和黄体酮水平存在差异(无论 由于体内激素的周期性变化或新陈代谢的差异)。研究表明， 雌激素生物合成和/或雌激素合成相关基因的不同表达和/或多态性 代谢，如CYP17，COMT，提示激素对子宫肌层干细胞(MSC)的影响 非裔美国人女性的扩张幅度更大。综合这些观察结果， 研究种族和激素对MSC扩增的影响可能会揭示 子宫肌瘤发生的潜在机制。 。

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. .