Effects of Phthalate Esters on Human Myometrial and Fibroid Cells: Cell Culture and NOD-SCID Mouse Data
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GENERAL GYNECOLOGY: ORIGINAL ARTICLE
Effects of Phthalate Esters on Human Myometrial and Fibroid Cells: Cell Culture and NOD-SCID Mouse Data Hyun Jin Kim 1 & Sung Hoon Kim 2 Sa Ra Lee 2 & Hee Dong Chae 2
&
Young Sang Oh 2 & Seung-Ho Heo 3 & Kang-Hyun Kim 3 & Do Young Kim 2 &
Received: 28 May 2020 / Accepted: 1 October 2020 # Society for Reproductive Investigation 2020
Abstract Evidence is growing that phthalate esters play an important role in the pathogenesis of estrogen-dependent gynecologic diseases, especially uterine fibroids. We aimed to investigate whether in vitro treatment with di-(2-ethylhexyl)-phthalate (DEHP) affects angiogenesis, proliferation, and apoptosis in uterine fibroids. To ascertain this, we evaluated vascular endothelial growth factor (VEGF) expression and AKT/ERT phosphorylation and compared the fibroid volume between nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice fed with and without DEHP. VEGF expression was measured using enzyme-linked immunosorbent assay, and AKT/ERK phosphorylation was analyzed by western blot analysis in human myometrial and fibroid cells. The volume of the fibroid tissues implanted to NOD/SCID mice was measured, and the expression of collagen type I protein, Ki-67, proliferating cell nuclear antigen, and B cell lymphoma 2 were analyzed using immunohistochemistry. We could see significant increases in VEGF expression and AKT phosphorylation in human myometrial and fibroid cells treated with DEHP. The volume of the fibroid tissues was significantly increased in NOD/SCID mice fed with DEHP, which was accompanied by increased expression of collagen type I and AKT phosphorylation. Taken together, these results suggest that exposure to phthalate esters may influence uterine fibroid pathogenesis by increasing VEGF and collagen expression and upregulating AKT phosphorylation. Keywords Phthalate esters . Uterine fibroids . Myometrium . Pathogenesis
Introduction Uterine fibroid is the most common gynecologic tumor in premenopausal women, and approximately 25% of patients are symptomatic and present with various symptoms including heavy menstrual bleeding, dysmenorrhea, and infertility [1]. Moreover, uterine fibroid is the most common reason for hysterectomy in USA [1, 2]. However, our current
* Sung Hoon Kim [email protected] 1
Department of Obstetrics and Gynecology, University of Kyung Hee College of Medicine, Kyung Hee University Hospital, Seoul, South Korea
2
Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, South Korea
3
Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
understanding of the pathophysiology of uterine fibroids is extremely limited, which has hindered our ability to identify biomarkers for disease progression, risk assessment, and response to treatment. Recently, several studies have focused on understanding the key factors in the development of uterine fibroid
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