Laboratorio de Genética y Cáncer, Departamento de Genética Humana, Instituto Nacional de Pediatría, Insurgentes Sur 3700 Letra C. Delegación Coyoacán, CP 04530 Ciudad de México, Mexico; Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México, Av. Ciudad Universitaria 3000, C.P. 04510, Coyoacán, Ciudad de México, Mexico.
Laboratorio de Genética y Cáncer, Departamento de Genética Humana, Instituto Nacional de Pediatría, Insurgentes Sur 3700 Letra C. Delegación Coyoacán, CP 04530 Ciudad de México, Mexico.
Toxicol In Vitro. 2017 Oct;44:17-26. doi: 10.1016/j.tiv.2017.06.013. Epub 2017 Jun 15.
Epidemiological studies have associated the exposure to permethrin and malathion with increased risk of leukemia and lymphoma. The aim of this study was to evaluate whether in vitro exposure to permethrin and malathion induces aberrations in genes involved in the etiology of these hematological malignancies. Genetic abnormalities in the IGH, KMT2A (MLL), ETV6 and RUNX1 genes, and aneuploidy induced by the in vitro exposure to permethrin and malathion (200μM, 24h), were analyzed by FISH in peripheral blood mononuclear cells (PBMCs). The gene fusions IGH-BCL2, KMT2A-AFF1 and ETV6-RUNX1 were further analyzed with nested RT-PCR in PBMCs, and in K562 cells exposed to acute and chronic treatments (0.1μM, 24h or every third day for two weeks) of insecticides. FISH analysis revealed that permethrin induces aneuploidy and structural alterations in IGH and KMT2A genes, and malathion induces breaks in KMT2A. RT-PCR detected ETV6-RUNX1 fusion in PBMCs acutely exposed to permethrin. Permethrin also induced ETV6-RUNX1 and IGH-BCL2 fusions in K562 cells, and malathion induced KMT2A-AFF1 and ETV6-RUNX1 fusions. Overall, we identified that both insecticides induce breaks and fusions in the studied genes, and permethrin induces aneuploidy. This study presents evidence of damage in cancer genes caused by these insecticides.
流行病学研究表明，接触氯菊酯和马拉硫磷与白血病和淋巴瘤风险增加有关。本研究旨在评估体外接触氯菊酯和马拉硫磷是否会导致这些血液系统恶性肿瘤病因相关基因的异常。通过荧光原位杂交（FISH）分析外周血单个核细胞（PBMCs）中基因 IGH、KMT2A（MLL）、ETV6 和 RUNX1 发生的异常，以及氯菊酯和马拉硫磷（200μM，24 小时）体外暴露引起的非整倍体。进一步通过巢式 RT-PCR 分析 PBMCs 和急性（0.1μM，24 小时）和慢性（每三天一次，共两周）暴露于杀虫剂的 K562 细胞中IGH-BCL2、KMT2A-AFF1 和 ETV6-RUNX1 基因融合。FISH 分析显示，氯菊酯诱导 IGH 和 KMT2A 基因的非整倍体和结构改变，马拉硫磷诱导 KMT2A 断裂。RT-PCR 检测到 PBMCs 中急性接触氯菊酯时发生的 ETV6-RUNX1 融合。氯菊酯还诱导 K562 细胞中发生 ETV6-RUNX1 和 IGH-BCL2 融合，马拉硫磷诱导 KMT2A-AFF1 和 ETV6-RUNX1 融合。总之，我们发现这两种杀虫剂都会引起研究基因的断裂和融合，氯菊酯还会引起非整倍体。本研究为这些杀虫剂引起的这些癌症基因损伤提供了证据。
