Mancozeb-induced genotoxicity and apoptosis in cultured human lymphocytes.

Abstract

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.

• Authors: Amit Kumar Srivastava, Wahid Ali, Richa Singh, Kulpreet Bhui, Shilpa Tyagi, Abdulaziz A Al-Khedhairy, Pramod Kumar Srivastava, Javed Musarrat, Yogeshwer Shukla
• Journal: Life sciences (Life Sci) Vol. 90 Issue 21-22 Pg. 815-24 (Jun 06 2012) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 22289270 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Annexin A5
• Fungicides, Industrial
• Reactive Oxygen Species
• Maneb
• Cytochromes c
• Fluorescein-5-isothiocyanate
• mancozeb
• Zineb

Topics

• Annexin A5 (chemistry)
• Apoptosis (drug effects)
• Cells, Cultured
• Chromosome Aberrations (chemically induced)
• Cytochromes c (metabolism)
• Dose-Response Relationship, Drug
• Flow Cytometry
• Fluorescein-5-isothiocyanate (chemistry)
• Fungicides, Industrial (administration & dosage, toxicity)
• Humans
• Lymphocytes (drug effects, pathology)
• Maneb (administration & dosage, toxicity)
• Membrane Potential, Mitochondrial (drug effects)
• Micronuclei, Chromosome-Defective (drug effects)
• Mitochondria (metabolism)
• Mutagenicity Tests
• Reactive Oxygen Species (metabolism)
• Zineb (administration & dosage, toxicity)