Mancozeb-induced genotoxicity and apoptosis in cultured human lymphocytes

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• 作者：Amit Kumar Srivastava^a ; ^c ; Wahid Ali^b ; Richa Singh^a ; Kulpreet Bhui^a ; Shilpa Tyagi^a ; Abdulaziz A. Al-Khedhairy^c ; ^d ; Pramod Kumar Srivastava^f ; Javed Musarrat^c ; ^d ; ^e ; Yogeshwer Shukla^a ; ^{yshukla@iitr.res.in} ; ^{yogeshwer_shukla@hotmail.com}
• 关键词：Mancozeb ; Micronuclei ; Chromosomal aberration ; Reactive oxygen species ; Mitochondria-mediated ; Death receptors
• 刊名：Life Sciences
• 出版年：2012
• 期刊代码：62_00243205
• 类别：imm
• 出版时间：6 June, 2012
• 卷：90
• 期：21-22
• 页码：815-824
• 文件大小：1591 K

摘要

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 渭g/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 (螖唯m), 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-魏B, 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.