title: Enhanced cyclooxygenase-2 expression levels and metalloproteinase 2 and 9 activation by Hexachlorobenzene in human endometrial stromal cells.
abstract: Hexachlorobenzene (HCB) is an organochlorine pesticide that induces toxic reproductive effects in laboratory animals. It is a dioxin-like compound and a weak ligand of the aryl hydrocarbon receptor (AhR). Endometriosis is characterized by the presence of functional endometrial tissues outside the uterine cavity. Experimental studies indicate that exposure to organochlorines can interfere with both hormonal regulation and immune function to promote endometriosis. Altered expression of metalloproteinases (MMPs) in patients with endometriosis, suggests that MMPs may play a critical role. In the endometriotic lesions, prostaglandin E2 (PGE2) produced by cyclooxygenase-2 (COX-2), binds to its EP4 receptor (EP4), and via c-Src kinase induces MMPs activation, promoting endometriosis. We examined the HCB action on MMP-2 and MMP-9 activities and expression, COX-2 levels, PGE2 signaling, and the AhR involvement in HCB-induced effects. We have used different in vitro models: (1) human endometrial stromal cell line T-HESC, (2) primary cultures of Human Uterine Fibroblast (HUF), and (3) primary cultures of endometrial stromal cells from eutopic endometrium of control (CESC) and subjects with endometriosis (EESC). Our results show that HCB enhances MMP-2 and MMP-9 activities in T-HESC, HUF and ESC cells. The MMP-9 levels were elevated in all models, while the MMP-2 expression only increased in ESC cells. HCB enhanced COX-2 and EP4 expression, PGE2 secretion and the c-Src kinase activation in T-HESC. Besides, we observed that AhR is implicated in these HCB-induced effects. In conclusion, our results show that HCB exposure could contribute to endometriosis development, affecting inflammation and invasion parameters of human endometrial cells.
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Depto de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 5to piso, CP1121, Buenos Aires, Argentina. Electronic address: florenciachiappini@hotmail.com.
authors.forename: Florencia
authors.initials: F
authors.lastname: Chiappini
authors.affiliation: Laboratorio de Fisiopatología Endometrial, Instituto de Biología y Medicina Experimental (IBYME)-CONICET, Vuelta de Obligado 2490, CP1428, Buenos Aires, Argentina. Electronic address: jibaston@gmail.com.
authors.forename: Juan Ignacio
authors.initials: JI
authors.lastname: Bastón
authors.affiliation: Centro de Estudios Biomédicos, Biotecnológicos, Ambientales y de Diagnóstico (CEBBAD), Universidad Maimónides, Hidalgo 775, CP1405, Buenos Aires, Argentina. Electronic address: agusvacc@hotmail.com.
authors.forename: Agustina
authors.initials: A
authors.lastname: Vaccarezza
authors.affiliation: Servicio de Ginecología, Hospital de Clínicas José de San Martín, Av. Córdoba 2351, CP1120, Buenos Aires, Argentina. Electronic address: jjsingla@gmail.com.
authors.forename: José Javier
authors.initials: JJ
authors.lastname: Singla
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Depto de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 5to piso, CP1121, Buenos Aires, Argentina. Electronic address: caroponti@hotmail.com.
authors.forename: Carolina
authors.initials: C
authors.lastname: Pontillo
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Depto de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 5to piso, CP1121, Buenos Aires, Argentina. Electronic address: noeliamiret@hotmail.com.ar.
authors.forename: Noelia
authors.initials: N
authors.lastname: Miret
authors.affiliation: Laboratorio de Fisiopatología Placentaria, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), CONICET-UBA, Paraguay 2155, 15 piso, CP1121, Buenos Aires, Argentina. Electronic address: marifarina@yahoo.com.
authors.forename: Mariana
authors.initials: M
authors.lastname: Farina
authors.affiliation: Laboratorio de Fisiopatología Endometrial, Instituto de Biología y Medicina Experimental (IBYME)-CONICET, Vuelta de Obligado 2490, CP1428, Buenos Aires, Argentina. Electronic address: gabriela.meresman@gmail.com.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Meresman
authors.affiliation: Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Depto de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 5to piso, CP1121, Buenos Aires, Argentina. Electronic address: andybiol@yahoo.com.ar.
authors.forename: Andrea
authors.initials: A
authors.lastname: Randi
mesh_terms: D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002461:Cell Line, Transformed; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D004715:Endometriosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005659:Fungicides, Industrial / Q000633:toxicity*; D005786:Gene Expression Regulation; D006581:Hexachlorobenzene / Q000633:toxicity*; D006801:Humans; D007247:Infertility, Female; D020778:Matrix Metalloproteinase 2 / Q000235:genetics* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D005659:Fungicides, Industrial; D018336:Receptors, Aryl Hydrocarbon; D058309:Receptors, Prostaglandin E, EP4 Subtype; D006581:Hexachlorobenzene; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D015232:Dinoprostone
keywords: Aryl hydrocarbon receptor; Cyclooxygenase-2; Endometriosis; Hexachlorobenzene; Hexachlorobenzene (PubChem CID: 8370); Metalloproteinases; Prostaglandin E(2) (PubChem CID: 5280360)