The long-term objectives are to: 1) determine the basic mechanisms whereby estrogen regulates normal patterns of cell proliferation and tissue morphogenesis in reproductive tract organs; and 2) identify causal links between disruption of normal estrogen responses and alterations in specific cellular events and molecular factors. The PI has determined that neonatal treatment with the established endocrine-disrupting agent, diethylstilbestrol (DES), directly and permanently alters the developing hamster uterus (initiation phase) so that the adult hamster uterus responds abnormally to stimulation (promotion phase) with the natural estrogen, estradiol. A primary working hypothesis (WH) that is consistent with that phenomenon and is responsive to the fetal/developmental focus of the Program Announcement is: 1' WH-Alterations in DNA methylation during early development are part of the mechanism by which neonatal DES exposure permanently disrupts uterine morphogenesis and estrogen responsiveness. A secondary working hypothesis that incorporates new information about the mechanisms that regulate development and function of estrogen-responsive organs is: 2' WH-The involvement of epithelial-stromal (mesenchymal) interactions in uterine development and function makes it likely that the extent or pattern of neonatal DES-altered methylation will differ between the two tissue compartments. The following set of Specific Aims (SA) represents an innovative but feasible strategy to test those linked hypotheses. SA#1-Screen for evidence of tissue specific differences in DNA methylation that occur during the initiation phase of neonatal DES-induced uterine disruption. SA#2-Determine if products from the screen are linked either to known genes or to previously unidentified (novel) genes that are differentially expressed in the control vs. neonatally DES-disrupted hamster uterus. SA#3-At the tissue-specific level, evaluate the relationship between neonatal DES-induced alterations in DNA methylation and subsequent changes in gene expression within the hamster uterus. A more complete understanding of such intercellular and genomic dynamics will help generate new strategies to: 1) better evaluate the stage/grade of disease progression, and 2) better choose and deliver therapeutic agents. It should also yield important new insight into the topic of 'endocrine disruption'.
| Hendry, William J; Hariri, Hussam Y; Alwis, Imala D et al. (2014) Altered gene expression patterns during the initiation and promotion stages of neonatally diethylstilbestrol-induced hyperplasia/dysplasia/neoplasia in the hamster uterus. Reprod Toxicol 50:68-86 |
