The pesticide hexachlorobenzene disrupts hormonal signaling and induces cell migration and invasion in human endometrial stromal cells

CHIAPINNI F; CEBALLOS L; OLIVARES C; BASTON JI; PONTILLO CA; MIRET N; FARINA MG.; SINGLA JJ; MERESMAN G; RANDI A

Mar del Plata

Congreso; Reunión anual de sociedades de biociencias SAIC-SAI-AAFE-Nanomed:; 2021

Endometriosis is a frequent and chronic illness which is defined by the presence and growth of endometrial tissue outside of the uterus. Progesterone and estrogen signaling are disrupted, commonly resulting in progesterone resistance and estrogen dominance. Several studies have suggested that endocrine disrupting chemicals such as organochlorine pesticides could be a risk factor for endometriosis. Hexachlorobenzene (HCB) is a pesticide that acts as an endocrine disruptor in uterus and mammary gland, modulating the hormonal signaling. Is a weak ligand of the aryl hydrocarbon receptor (AhR) and promotes metalloproteinase and cyclooxygenase-2 (COX-2) expression, as well as, c-Src kinase activation in human endometrial stromal cells (T-HESC) and in rat endometriosis models. Our aim was to evaluate the HCB effect on hormonal pathways, studding hormone receptor expression and activation (WB), and on cell migration (scratch motility assay) and invasion (transwell assay) in endometrial stromal cells (T-HESC). Moreover, we examine the dependence of AhR, c-Src, COX-2 and ER on this events. T-HESC cells were exposed to different doses of HCB (0.005, 0.05, 0.5 and 5 μM) at different lapse of time. Results show that HCB treatment increased ERɑ levels at 0.5 and 5 µM (p≤0.05) and reduced PR levels at 5 µM (p≤0.05), in concordance with endometriosis estrogen-dependent and progesterone-resistant. In addition, the protein levels of aromatase were also raised by HCB at 0.005 - 0.5 µM (p≤0.01; p≤0.05). Moreover, cell migration (HCB 0.005 ? 5 µM) and invasion (HCB 0.05 and 5 µM) were promoted by the pesticide exposure involving the AhR, c-Src, COX-2 and ER pathways. HCB also triggered ERɑ activation via phosphorylation in Y537 (HCB 0.5 µM) through the AhR/c-Src pathway. Our results provide experimental evidence that HCB induces alterations associated with endometriosis; the pesticide could act as a xenoestrogen inducing an invasive profile contributing to the development and progression of the disease.