Toxicological Comparison of Mancozeb and Zoxamide Fungicides at Environmentally Relevant Concentrations by an In Vitro Approach

Abstract

Mancozeb (MZ) and zoxamide (ZOX) are fungicides commonly used in pest control programs to protect vineyards. Their toxic and genotoxic potential were investigated in vitro on HepG2 and A549 cell lines at environmentally relevant concentrations. Cytotoxicity, apoptosis, necrosis and intracellular reactive oxygen species (ROS), comet assay and a micronucleus test with CREST immunofluorescence were used. The expression of a panel of genes involved in apoptosis/necrosis (BAX/BCL2), oxidative stress (NRF2), drug metabolism (CYP1A1) and DNA repair (ERCC1/OGG1) was evaluated by real-time PCR. Both fungicides were cytotoxic at the highest tested concentrations (295.7 and 463.4 µM, respectively); MZ induced necrosis, ZOX did not increase apoptosis but modulated BAX and BCL2 expression, suggesting a different mechanism. Both compounds did not increase ROS, but the induction of CYP1A1 and NRF2 expression supported a pro-oxidant mechanism. The comet assay evidenced MZ genotoxicity, whereas no DNA damage due to ZOX treatment was observed. Positive micronuclei were increased in both cell lines treated with MZ and ZOX, supporting their aneugenic potential. ERCC1 and OGG1 were differently modulated, indicating the efficient activation of the nucleotide excision repair system by both fungicides and the inhibition of the base excision repair system by MZ. Overall, MZ confirmed its toxicity and new ZOX-relevant effects were highlighted.

A Critical Scoping Review of Pesticide Exposure Biomonitoring Studies in Overhead Cultures

“…Moreover, workers exposed to mancozeb in the iodine-deficient area tended to have lower thyroid volumes (≤6 mL). These findings fit well with experimental evidence that the thyroid was a major toxicological target of mancozeb as found both in vitro by Lori et al (2021) and in laboratory animals as summarized by the European Food Safety Authority (EFSA) in a recent evaluation in 2019 [49,50].…”

Producing Crops without Mancozeb? Perspectives on Recent Regulatory Dilemmas and Ways Out

“…At the beginning of this millennium, studies showed that mancozeb can act as an ED, which may affect many bodily functions and cause health hazards (e.g., male infertility) . Researchers have further confirmed its genotoxicity; that is, under acute exposure, it can affect the fertilization capacity of spermatozoa . In another in vitro study, functional impairment of bovine spermatozoa was found after acute exposure to mancozeb .…”

“…21 Researchers have further confirmed its genotoxicity; that is, under acute exposure, it can affect the fertilization capacity of spermatozoa. 22 In another in vitro study, functional impairment of bovine spermatozoa was found after acute exposure to mancozeb. 23 In a recent study, mancozeb's estrogenic activity was demonstrated.…”

Low concentrations of ethylene bisdithiocarbamate pesticides maneb and mancozeb impair manganese and zinc homeostasis to induce oxidative stress and caspase-dependent apoptosis in human hepatocytes

“…We next studied the mechanism of cytotoxicity induced by the pesticide mixture and DTCs (Figure 4) postulating that maneb and mancozeb may induce apoptosis in hepatocytes since previous publications reported that mancozeb at high concentrations (10 to 300 M) triggered apoptosis in human gastric, colon and hepatoma cells (Kumar et al, 2019 ;Dhaneshwar and Hardej, 2021 ;Lori et al, 2021). We measured caspase 3, 8 and 9 catalytic activities in total cell lysates of hepatocyte-like HepaRG cells exposed to the pesticide mixture or mancozeb alone (Figure 4A).…”