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.

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Picut, Catherine A; Dixon, Darlene; Simons, Michelle L et al. (2015) Postnatal ovary development in the rat: morphologic study and correlation of morphology to neuroendocrine parameters. Toxicol Pathol 43:343-53
Waalkes, Michael P; Qu, Wei; Tokar, Erik J et al. (2014) Lung tumors in mice induced by "whole-life" inorganic arsenic exposure at human-relevant doses. Arch Toxicol 88:1619-29
Gohner, Claudia; Svensson-Arvelund, Judit; Pfarrer, Christiane et al. (2014) The placenta in toxicology. Part IV: Battery of toxicological test systems based on human placenta. Toxicol Pathol 42:345-51
Segars, James H; Parrott, Estella C; Nagel, Joan D et al. (2014) Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations. Hum Reprod Update 20:309-33
Cline, J Mark; Dixon, Darlene; Ernerudh, Jan et al. (2013) The Placenta in Toxicology. Part III: Pathologic Assessment of the Placenta. Toxicol Pathol :
Buse, Eberhard; Haeger, Jan-Dirk; Svensson-Arvelund, Judit et al. (2013) The Placenta in Toxicology. Part I: Animal Models in Toxicology: Placental Morphology and Tolerance Molecules in the Cynomolgus Monkey (Macaca fascicularis). Toxicol Pathol :
Svensson-Arvelund, Judit; Ernerudh, Jan; Buse, Eberhard et al. (2013) The Placenta in Toxicology. Part II: Systemic and Local Immune Adaptations in Pregnancy. Toxicol Pathol :
Hill, Georgette D; Moore, Alicia B; Kissling, Grace E et al. (2011) Effects of hormonally active agents on steroid hormone receptor expression and cell proliferation in the myometrium of ovariectomized macaques. Toxicol Pathol 39:508-15
Yu, Linda; Saile, Katrin; Swartz, Carol D et al. (2008) Differential expression of receptor tyrosine kinases (RTKs) and IGF-I pathway activation in human uterine leiomyomas. Mol Med 14:264-75
Smoak, Kathleen; Madenspacher, Jennifer; Jeyaseelan, Samithamby et al. (2008) Effects of liver X receptor agonist treatment on pulmonary inflammation and host defense. J Immunol 180:3305-12

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