Watch out! pesticide exposure contributes to tumor angiogenesis in our breasts

ZARATE, LORENA; MIRET NOELIA; ALEJANDRO J .ESPAÑOL; ALVAREZ L; COCCA CLAUDIA; RANDI, ANDREA; MARÍA E. SALES; PONTILLO, CAROLINA; CHIAPPINI FLORENCIA; DE PISAREV DIANA KLEIMAN

TOXICOLOGY LETTERS

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2018 vol. 295

0378-4274

Hexachlorobenzene (HCB) is a fungicide detected in maternalmilk, and Chlorpyrifos (CPF) is a pesticide currently used in agriculture.Breast cancer is by far the most frequently diagnosedcancer in women. HCB and CPF act as endocrine disruptor in ratmammary gland. Vascular endothelial growth factor (VEGF) andcyclooxygenase-2 (COX-2) promote tumor growth and angiogenesis.Nitric oxide (NO) and abnormal expression of nitric oxidesynthases (NOS1, NOS2, NOS3) are implicated in tumor progression.Our aim was to examine the action of HCB and CPF onangiogenesis in mammary carcinogenesis in vivo and in vitro. Ina breast cancer xenograft model with MCF-7 cells, HCB (3 mg/kgbw) and CPF (0.1 mg/kg bw) stimulate angiogenic switch (numberof vessels/mm2) and increase VEGF expression (p < 0.05) by WesternBlot (WB) in mice skin. In MCF-7, HCB (0.005M) increasesCOX-2 and VEGF levels at 3 h, while at 0.005-5Mat 24h (p < 0.01).CPF (0.05M) enhances COX-2 and VEGF expression at 6 h, while at50Mat24h(p < 0.05). In addition,HCB(0.005M)at 3 h increasesNOS2/NOS3 and at 24 h enhances NOS1, while at 5M decreasesNOS expression (WB, p < 0.05). CPF (0.05M) increases NOS levelsat 6 h, while at 50Menhances at 24 h (p < 0.05). The pesticidesincrease the production of NO at lower doses, however reduces it athigher doses (HCB, CPF, p < 0.05). Besides, the pretreatment of MCF-7 with an inhibitor of NOS prevents the increased expression ofVEGF and COX-2 by HCB or CPF, suggesting that pesticides enhanceangiogenic factors through NO-dependent pathway. Our resultsdemonstrate that both pesticides increase angiogenesis and VEGFexpression in vivo and in vitro. In MCF-7, at low doses, the pesticidesenhance VEGF, COX-2 and NOS expression, and NO production. Athigh doses, increase VEGF and COX-2 levels, but differential effectson NOS expression were observed. In conclusion, our findings suggestthat HCB and CPF may be a risk factor for human breast cancerprogression