Application of a global screening method to probe the role of epigenetics in an experimental model of DES-induced, estrogen-dependent uterine cancer

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Simpson, Megan Odetta
Hendry, William J. III

Diethylstilbestrol (DES), a synthetic estrogen, was widely administered to pregnant women between 1947 and 1971 on account of a misconception that it could prevent miscarriages. Due to the wide use of this estrogen-mimicking drug, at least four million women and their fetuses were exposed to DES. The offspring of these women developed various reproductive tract abnormalities, including cancer. We primarily focus on neonatal DES-induced abnormalities in the uterus and this study analyzed altered DNA methylation patterns. DNA methylation is a major component of the emerging topic of epigenetics and epigenetic modifications may be just as important to the development of cancer as are the classic genetic phenomena of DNA mutations. We use Syrian golden hamsters to study the consequences of early developmental DES exposure. The methodology of Methylation Sensitive Restriction Fingerprinting (MSRF) was tested as a means to screen for the presence of altered DNA methylation patterns in uteri from control vs. neonatally DES-treated hamsters. As a result of this screening process, we found 9 DNA fragments containing abnormal methylation or demethylation events. Of these 9 fragments, 5 showed enhanced hypermethylation, 2 showed complete hypermethylation, and 2 showed incomplete hypomethylation. Sequence analyses yielded results and alignment matches for 5 of the 9 fragments of interest, 4 of which showed significant homologies to regions of the mouse and rat genomes.

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Thesis (M.S.)--Wichita State University, College of Liberal Arts and Sciences, Dept. of Biological Sciences