title: Possible Role of Phthalate in the Pathogenesis of Endometriosis: In Vitro, Animal, and Human Data.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  The study was conducted at an academic center.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  These findings strongly suggest that exposure to phthalate may lead to establishment of endometriosis by enhancing invasive and proliferative activities of endometrial cells.
authors.affiliation: 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.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: SiHyun
authors.initials: S
authors.lastname: Cho
authors.affiliation: 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.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Ihm
authors.affiliation: 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.
authors.forename: Young Sang
authors.initials: YS
authors.lastname: Oh
authors.affiliation: 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.
authors.forename: Seung-Ho
authors.initials: SH
authors.lastname: Heo
authors.affiliation: 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.
authors.forename: Sail
authors.initials: S
authors.lastname: Chun
authors.affiliation: 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.
authors.forename: Hosub
authors.initials: H
authors.lastname: Im
authors.affiliation: 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.
authors.forename: Hee Dong
authors.initials: HD
authors.lastname: Chae
authors.affiliation: 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.
authors.forename: Chung-Hoon
authors.initials: CH
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Byung Moon
authors.initials: BM
authors.lastname: Kang
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D004715:Endometriosis / Q000139:chemically induced* / Q000453:epidemiology; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010795:Phthalic Acids / Q000652:urine; D010968:Plasticizers / Q000633:toxicity*; D011446:Prospective Studies; D017154:Stromal Cells / Q000378:metabolism; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D010795:Phthalic Acids; D010968:Plasticizers; C032279:phthalic acid; D004051:Diethylhexyl Phthalate; C116367:PAK4 protein, human; D054462:p21-Activated Kinases; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9