Hexachlorobenzene as angiogenic promoter in in vitro and in vivo models

PONTILLO, CAROLINA; ALEJANDRO ESPAÑOL; CHIAPPINI FLORENCIA; MIRET NOELIA; COCCA CLAUDIA; ALVAREZ L; KLEIMAN, D; MARÍA E. SALES; RANDI, ANDREA

Congreso; 50th Congress of the European Societies of Toxicology. EUROTOX.; 2014

Exposureto environmental pollutants may alter proangiogenic ability and promotes tumorgrowth. Hexachlorobenzene (HCB) is an organochlorine pesticide found inmaternal milk and it is a weak ligand of the aryl hydrocarbon receptor (AhR).We have demonstrated that HCB induces proliferation, migration and invasion inhuman breast cancer cell lines, as well as tumor growth and metastasis inanimal models. In the present study, we examined HCB action on angiogenesis inmammary carcinogenesis. Our results from a xenograft model with MDA-MB-231human breast cancer cells in HCB treated-nude mice, shows that HCB (3 and 30mg/kg body weight) increase angiogenesis and VEGF expression in a concentrationmanner.. The treatment of Human microvascular endothelial cell line HMEC-1 withdifferent concentrations of HCB (0.005 to 5 µM) increased cyclooxygenase-2(COX-2) and VEGF expression at all concentrations assayed, as well as AhRexpression in a concentration dependent manner. Besides, we determinate that only0.5 µM of the pesticide increases VEGFR2 expression and activates their downstreampathways p38 and ERK1/2. On the other hand, HCB increases migration andneovasculogenesis in a concentration dependent manner, without affecting cell proliferation. These effects were suppresses with a Pretreatment cells with inhibitorsfor AhR, COX-2 and VEGFR2. In conclusion, our results demonstrated that HCB promotesangiogenesis in vivo, as well as HCB-inducedcell migration and neovasculogenesis that are mediated by AhR, COX-2 and VEGFR2proteins in HMEC-1. These findings may help understanding the associationbetween HCB exposure, angiogenesis and mammary carcinogenesis.