Enhanced cyclooxygenase-2 expression levels and metalloproteinase 2 and 9 activation by Hexachlorobenzene in human endometrial stromal cells

CHIAPPINI F; BASTON JI; VACCAREZZA A; SINGLA JJ; PONTILLO C; MIRET N; FARINA M; MERESMAN G; RANDI A

BIOCHEMICAL PHARMACOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2016 vol. 109 p. 91 - 104

0006-2952

Hexachlorobenzene (HCB) is a widely distributed 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 an inflammatory disease of reproductive-age woman characterized by the presence of functional endometrial tissues outside the uterine cavity. Experimental studies on rodents and primates indicate that exposure to organochlorines can interfere with both hormonal regulation and immune function to promote endometriosis. Altered expression patterns of metalloproteinases (MMPs) have been reported in endometrial tissues from patients with endometriosis, suggesting that MMPs may play critical roles in this pathology. In the endometriotic lesions, prostaglandin E2 (PGE2) produced by ciclooxigenase 2 (COX-2), binds to its EP4 receptor (EP4R), and via c-Src kinase induces MMPs secretion and activation, promoting endometriosis development. Our objective was to investigate if HCB promotes alterations that could trigger endometriosis. We examined the HCB (0.005, 0.05, 0.5 and 5 µM) action on MMP-2 and MMP-9 activities and expression, COX-2 protein levels and the PGE2 signaling. In addition, we evaluated if AhR is involved in HCB induced effects. We have used different in vitro models: 1) human endometrial stromal cell line T-HESC, 2) primary culture of Human Uterine Fibroblast (HUF) cells, and 3) human endometrial stromal primary cultures (ESC) from human biopsies with endometriosis (EESC) and controls (CESC). Our results show that HCB enhances MMP9-2 activities in T-HESC, HUF and ESC cells. The MMP-9 expression levels were increased in all models by HCB exposure, while the MMP-2 expression only in ESC cells. HCB enhanced COX-2 and EP4R expression, PGE2 secretion and the c-Src kinase activation in T-HESC. Besides, we observed that AhR is implicated in HCB-induced increase on MMPs activities, COX-2 expression and c-Src phosphorylation in T-HESC. In conclusion, our results show that HCB exposition could contribute to endometriosis development, affecting inflammation and invasion parameters of human endometrial cells.