Sung Hoon Kim1, SiHyun Cho1, Hyo Jin Ihm1, Young Sang Oh1, Seung-Ho Heo1, Sail Chun1, Hosub Im1, Hee Dong Chae1, Chung-Hoon Kim1, Byung Moon Kang1. 1. Department of Obstetrics & Gynecology (S.H.K., H.J.I., Y.S.O., H.D.C., C.-H.K., B.M.K.), University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Korea; Department of Obstetrics & Gynecology (S.Cho.), Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 135-720, Korea; Asan Institute for Life Sciences (S.-H.H.), University of Ulsan College of Medicine, Seoul 138-736, Korea; Department of Laboratory Medicine (S.Chu.), University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, Korea; and Center for Life & Environmental Science (H.I.), Seegene Medical Foundation, Seoul 138-828, Korea.
Abstract
CONTEXT: Although phthalates were shown to have several negative effects on reproductive function in animals, its role in the pathogenesis of endometriosis remains to be elucidated. OBJECTIVE: We aimed to investigate the in vitro and in vivo effects of di-(2-ethylhexyl)-phthalate (DEHP) and to compare the urinary levels of several phthalate metabolites between women with and without endometriosis. DESIGN: For experimental studies, we used endometrial cell culture and nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse models. We also performed a prospective case-control study for human sample analyses. SETTING: The study was conducted at an academic center. MAIN OUTCOME MEASURES: The activities of matrix metalloproteinase (MMP)-2 and 9, cellular invasiveness, phosphorylation of extracellular signal-regulated kinase (Erk), and expression of p21-activated kinase 4 were analyzed in endometrial cells treated with DEHP. The implant size was compared between NOD/SCID mice fed with and without DEHP. Urinary concentrations of several phthalate metabolites were compared between women with and without endometriosis. RESULTS: In vitro treatment of endometrial cells with DEHP led to significant increases of MMP-2 and 9 activities, cellular invasiveness, Erk phosphorylation, and p21-activated kinase 4 expression. The size of the endometrial implant was significantly larger in the NOD/SCID mice fed with DEHP compared with those fed with vehicle. The urinary concentration of mono (2-ethyl-5-hydroxyhexyl) phthalate, mono (2-ethyl-5-oxohexyl) phthalate, and mono (2-ethyl-5-carboxyphentyl) phthalate were significantly higher in women with endometriosis compared with controls. CONCLUSION: These findings strongly suggest that exposure to phthalate may lead to establishment of endometriosis by enhancing invasive and proliferative activities of endometrial cells.
CONTEXT: Although phthalates were shown to have several negative effects on reproductive function in animals, its role in the pathogenesis of endometriosis remains to be elucidated. OBJECTIVE: We aimed to investigate the in vitro and in vivo effects of di-(2-ethylhexyl)-phthalate (DEHP) and to compare the urinary levels of several phthalate metabolites between women with and without endometriosis. DESIGN: For experimental studies, we used endometrial cell culture and nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse models. We also performed a prospective case-control study for human sample analyses. SETTING: The study was conducted at an academic center. MAIN OUTCOME MEASURES: The activities of matrix metalloproteinase (MMP)-2 and 9, cellular invasiveness, phosphorylation of extracellular signal-regulated kinase (Erk), and expression of p21-activated kinase 4 were analyzed in endometrial cells treated with DEHP. The implant size was compared between NOD/SCIDmice fed with and without DEHP. Urinary concentrations of several phthalate metabolites were compared between women with and without endometriosis. RESULTS: In vitro treatment of endometrial cells with DEHP led to significant increases of MMP-2 and 9 activities, cellular invasiveness, Erk phosphorylation, and p21-activated kinase 4 expression. The size of the endometrial implant was significantly larger in the NOD/SCIDmice fed with DEHP compared with those fed with vehicle. The urinary concentration of mono (2-ethyl-5-hydroxyhexyl) phthalate, mono (2-ethyl-5-oxohexyl) phthalate, and mono (2-ethyl-5-carboxyphentyl) phthalate were significantly higher in women with endometriosis compared with controls. CONCLUSION: These findings strongly suggest that exposure to phthalate may lead to establishment of endometriosis by enhancing invasive and proliferative activities of endometrial cells.
Authors: Hyun Jin Kim; Sung Hoon Kim; Young Sang Oh; Seung-Ho Heo; Kang-Hyun Kim; Do Young Kim; Sa Ra Lee; Hee Dong Chae Journal: Reprod Sci Date: 2020-10-09 Impact factor: 3.060
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