Possible Role of Phthalate in the Pathogenesis of Endometriosis: In Vitro, Animal, and Human Data.

Abstract

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. 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. 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. The study was conducted at an academic center. 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. 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. These findings strongly suggest that exposure to phthalate may lead to establishment of endometriosis by enhancing invasive and proliferative activities of endometrial cells.