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Effects of Phthalate Esters on Human Myometrial and Fibroid Cells: Cell Culture and NOD-SCID Mouse Data

  • General Gynecology: Original Article
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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.

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Funding

This research was supported by the Asan Institute for Life Sciences, Seoul, South Korea (grant 2018-323).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Kyung Hee College of Medicine, Kyung Hee University Hospital, Seoul, South Korea

    Hyun Jin Kim

  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

    Sung Hoon Kim, Young Sang Oh, Do Young Kim, Sa Ra Lee & Hee Dong Chae

  3. Asan Institute for Life Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea

    Seung-Ho Heo & Kang-Hyun Kim

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  1. Hyun Jin Kim
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Contributions

Conceptualization, S.H.K.; methodology, Y.S.O., S.H.H., and K.H.K; software, Y.S.O; validation, Y.S.O., S.H.H., and K.H.K; formal analysis, Y.S.O., S.H.H., and K.H.K; investigation, H.J.K.; resources, D.Y.K.; data curation, H.J.K and Y.S.O.; writing (original draft preparation), H.J.K.; writing (review and editing), H.J.K. and S.H.K.; visualization, H.J.K.; supervision, S.H.K., S.R.L, and H.D.C.; project administration, S.H.K., S.R.L, and H.D.C. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Sung Hoon Kim.

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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.

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Kim, H.J., Kim, S.H., Oh, Y.S. et al. Effects of Phthalate Esters on Human Myometrial and Fibroid Cells: Cell Culture and NOD-SCID Mouse Data. Reprod. Sci. 28, 479–487 (2021). https://doi.org/10.1007/s43032-020-00341-0

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