The Molecular Pathogenesis Group has focused much of its research on defining the pathogenesis of disorders affecting the reproductive tract of humans and rodents and assessing the role of environmental and endogenous hormones, and growth factors on the growth and induction of these disorders. In understating the role of proliferation in human uterine leiomyoma (fibroid) growth, we have found that both positive and negative regulators of apoptosis are not differentially expressed in fibroids compared to normal myometria, and that altered apoptosis does not appear to play a significant role in the development of these tumors. Our studies show that cell proliferation and extracellular matrix production may be the most significant contributors to fibroid growth, although, mitotic activity of fibroid cells appears to be phasic, does not correlate with tumor size, and is autonomous for each tumor within a uterus. In studies addressing the role of growth factors in the pathogenesis of fibroids, we have found that Receptor Tyrosine Kinases (RTKs) and their ligands are overexpressed in fibroids compared to normal myometria during the proliferative phase of the menstrual cycle and that the many of the RTKs are activated. These studies will help to define some of the basic biological and molecular pathways important in fibroid growth, which can then be applied to developing alternative noninvasive treatment regimens for fibroids. In vitro model systems for studying fibroids are limited in that human derived leiomyoma cells grow poorly in culture. We have overcome this obstacle by development of hTERT (human telomerase) immortalized uterine leiomyoma and myometrial cell lines. These cells are being used to study leiomyoma tumorigenesis in a prospective manner. In determining the role of environmental agents in fibroid development we have found that in CD-1 mice prenatal and neonatal exposures to diethylstilbestrol (DES) results in uterine leiomyomas similar to fibroids observed in women. Also, the phytoestrogen, genistein, can be stimulatory or inhibitory to uterine leiomyoma cell growth depending on its concentration. We have also found that an environmental pesticide, Fenvalerate, can induce cell proliferation and extracellular matrix production in uterine leiomyoma and myometrial cells, and may be a potential risk factor for fibroids.

Project Start
Project End
Budget Start
Budget End
Support Year
20
Fiscal Year
2013
Total Cost
$1,964,094
Indirect Cost
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Teng, Christina T; Hsieh, Jui-Hua; Zhao, Jinghua et al. (2017) Development of Novel Cell Lines for High-Throughput Screening to Detect Estrogen-Related Receptor Alpha Modulators. SLAS Discov 22:720-731
Hayes, A Wallace; Dixon, Darlene (2017) Cornerstones of Toxicology. Toxicol Pathol 45:57-63
Ramaiahgari, Sreenivasa C; Waidyanatha, Suramya; Dixon, Darlene et al. (2017) Three-dimensional (3D) HepaRG Spheroid Model with Physiologically-Relevant Xenobiotic Metabolism Competence and Hepatocyte Functionality for Liver Toxicity Screening. Toxicol Sci :
Vicetti Miguel, Rodolfo D; Quispe Calla, Nirk E; Dixon, Darlene et al. (2017) IL-4-secreting eosinophils promote endometrial stromal cell proliferation and prevent Chlamydia-induced upper genital tract damage. Proc Natl Acad Sci U S A 114:E6892-E6901
Irizarry, Armando R; Gropp, Kathryn E; Dixon, Darlene (2017) A Brief Overview of the STP 35th Annual Symposium on the Basis and Relevance of Variation in Toxicologic Responses. Toxicol Pathol 45:52-56
Elmore, Susan A; Dixon, Darlene; Hailey, James R et al. (2016) Recommendations from the INHAND Apoptosis/Necrosis Working Group. Toxicol Pathol 44:173-88
Castro, Lysandra; Gao, Xioahua; Moore, Alicia B et al. (2016) A High Concentration of Genistein Induces Cell Death in Human Uterine Leiomyoma Cells by Autophagy. Expert Opin Environ Biol 5:
Yu, Linda; Ham, Kyle; Gao, Xiaohua et al. (2016) Epigenetic regulation of transcription factor promoter regions by low-dose genistein through mitogen-activated protein kinase and mitogen-and-stress activated kinase 1 nongenomic signaling. Cell Commun Signal 14:18
Yan, Yitang; Cummings, Connie A; Sutton, Deloris et al. (2016) Immunogold electron microscopy and confocal analyses reveal distinctive patterns of histone H3 phosphorylation during mitosis in MCF-7 cells. Genes Chromosomes Cancer 55:397-406
Mozzachio, Kristie; Moore, Alicia B; Kissling, Grace E et al. (2016) Immunoexpression of Steroid Hormone Receptors and Proliferation Markers in Uterine Leiomyoma and Normal Myometrial Tissues from the Miniature Pig, Sus scrofa. Toxicol Pathol 44:450-7

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