Early environmental and hormonal exposure influences on human myometrial cell population

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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. .