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Mancozeb-induced genotoxicity and apoptosis in cultured human lymphocytes

机译：Mancozeb诱导的人类淋巴细胞遗传毒性和凋亡

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Aims: Mancozeb is a dithiocarbamate fungicide known to be genotoxic and induces tumors in rodents at various sites. There is no report in the literature about its genotoxicity in humans. Here, we investigated the association between mancozeb exposure and induction of genotoxic and proapoptotic changes in cultured human lymphocytes (CHLs). Main methods: Lymphocytes were isolated from peripheral blood of healthy non-smoking donors. Induction of micronuclei and chromosomal aberrations was recorded both by conventional and flow cytometric methods. Annexin-V FITC was used for the differentiation of apoptotic and necrotic cells by flow cytometry. Key findings: Mancozeb exposure (0.5, 2 and 5 μg/ml) to CHLs leads to significant induction in the frequency of chromosomal aberrations (CAs) and micronuclei (MN), in a dose-dependent manner. Concomitantly, pro-oxidant potential of mancozeb was also recorded, by increase in the levels of reactive oxygen species (ROS) generation. Our results demonstrated that ROS plays a critical role in the initiation of mancozeb induced apoptosis in CHLs through two ways, primarily through mitochondria-mediated pathway including induction of ROS, decrease in mitochondrial membrane potential (ΔΨm), along with cytochrome c release from mitochondria, and activation of the caspase cascade. The other pathway includes increase in ROS, which resulted in activation of NF-κB, expression of FasL and triggered FasL-dependent pathway, which also involves caspase-8. Therefore, exposure to mancozeb can lead to induction of apoptosis in CHLs through both mechanisms. Significance: The results of study confirm that mancozeb exposure can induce genotoxicity and apoptosis in CHLs, thus pose a potential risk to exposed human population.
机译：目的：Mancozeb是一种二硫代氨基甲酸酯类杀菌剂，已知具有遗传毒性，可在啮齿动物的各个部位诱发肿瘤。文献中没有关于其对人的遗传毒性的报道。在这里，我们调查了mancozeb暴露与人类培养的淋巴细胞（CHLs）的遗传毒性和促凋亡变化的诱导之间的关联。主要方法：从健康非吸烟供者的外周血中分离淋巴细胞。通过常规和流式细胞术方法记录了微核和染色体畸变的诱导。 Annexin-V FITC通过流式细胞仪用于分化凋亡细胞和坏死细胞。关键发现：Mancozeb暴露于CHL（0.5、2和5μg/ ml）以剂量依赖的方式显着诱导染色体畸变（CAs）和微核（MN）的发生频率。同时，通过增加活性氧（ROS）的生成水平，还记录了代森锰锌的促氧化潜能。我们的研究结果表明，ROS通过两种途径主要通过线粒体介导的途径（包括诱导ROS），线粒体膜电位（ΔΨm）的降低以及线粒体中释放的细胞色素c，在Mancozeb诱导的CHL凋亡中起关键作用。和半胱天冬酶级联反应的激活另一个途径包括ROS的增加，从而导致NF-κB的激活，FasL的表达和触发FasL依赖性途径，这也涉及caspase-8。因此，暴露于mancozeb可通过这两种机制导致CHLs凋亡的诱导。启示：研究结果证实，暴露于曼考昔可引起CHLs的遗传毒性和细胞凋亡，从而对暴露人群构成潜在风险。

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