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The worldwide and intensive use of phytosanitary compounds results in environmental and food contamination by chemical residues. Human exposure to multiple pesticide residues is a major health issue. Considering that the liver is not only the main organ for metabolizing pesticides but also a major target of toxicities induced by xenobiotics, we studied the effects of a mixture of 7 pesticides (chlorpyrifos-ethyl, dimethoate, diazinon, iprodione, imazalil, maneb, mancozeb) often detected in food samples. Effects of the mixture was investigated using metabolically competent HepaRG cells and human hepatocytes in primary culture. We report the strong cytotoxicity of the pesticide mixture towards hepatocytes-like HepaRG cells and human hepatocytes upon acute and chronic exposures at low concentrations extrapolated from the Acceptable Daily Intake (ADI) of each compound. Unexpectedly, we demonstrated that the manganese (Mn)-containing dithiocarbamates (DTCs) maneb and mancozeb were solely responsible for the cytotoxicity induced by the mixture. The mechanism of cell death involved the induction of oxidative stress, which led to cell death by intrinsic apoptosis involving caspases 3 and 9. Importantly, this cytotoxic effect was found only in cells metabolizing these pesticides. Herein, we unveil a novel mechanism of toxicity of the Mn-containing DTCs maneb and mancozeb through their metabolization in hepatocytes generating the main metabolite ethylene thiourea (ETU) and the release of Mn leading to intracellular Mn overload and depletion in zinc (Zn). Alteration of the Mn and Zn homeostasis provokes the oxidative stress and the induction of apoptosis, which can be prevented by Zn supplementation. Our data demonstrate the hepatotoxicity of Mn-containing fungicides at very low doses and unveil their adverse effect in disrupting Mn and Zn homeostasis and triggering oxidative stress in human hepatocytes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Bernard FROMENTY reports financial support was provided by Agence Française pour la Biodiversité. Pascal LOYER reports financial support was provided by Cancéropole Grand-Ouest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Mancozeb is a dithiocarbamate non-systemic fungicide widely used to control fungal diseases of plants, commonly applied in apple orchards in Brazil. Instead of its common use, there are no reports about the risk to non-target organisms in Brazilian soils. We studied the risk of Mancozeb (in the commercial formulation Dithane ® NT) for standard invertebrate species (Folsomia candida, Eisenia andrei and Enchytraeus crypticus) in two subtropical Brazilian soils, Oxisol and Ultisol, which are representative of apple production areas in Brazil. Reproduction and survival tests were carried out following ISO guidelines. Results showed that Mancozeb in Oxisol reduced the survival and reproduction of collembolans (LC 50 54.43 and EC 50 2.72 mg a.i. kg -1 ) and enchytraeids (LC 50 6.97 and EC 50 3.56 mg a.i. kg -1 ), in lowest values than those observed in Ultisol (F. candida LC 50  > 1000 and EC 50  > 100 mg a.i. kg -1 ; E. crypticus LC 50 280.21 and EC 50 29.67). Effects to E. andrei were similar in both soils and indicated a lower sensitivity of this species to Mancozeb. The species F. candida and E. crypticus were more sensitive than E. andrei. These results reinforce the need to include other soil organisms besides earthworms, using chronical endpoints and considering different types of soils, to better predict the risk of pesticides for subtropical soils., (Copyright © 2019. Published by Elsevier Ltd.)

The present experiment was designed to monitor the morphotoxic, cytotoxic and genotoxic potential of Mancozeb (fungicide) in non-target plants using bulbs of Allium cepa. Mancozeb is classified as a contact fungicide and is registered for use on a variety of crop plants. In the present monitoring, Allium cepa bulbs were exposed to different concentrations of mancozeb viz., 10, 30, 50, 70, 90, 110, 130 and 150 ppm for 24 and 48 h. The potential morphotoxic and cytotoxic effects of mancozeb were examined by determining the average root number, average root length, mitotic index, relative abnormality rate (%) and frequency of abnormalities (%). A progressive significant concentration and time dependent inhibition of the average root number, average root length indicated the morphotoxic nature. The cytotoxic effect was significantly increased for 48 h treatment as compared to 24 h treatment time, by reducing the mitotic index of meristematic cells. The results indicated an indirect genotoxic effect by inducing different types of chromosomal abnormalities, likely sticky, disoriented and fragmented chromosomes. Thus indicating that the investigated fungicide have genotoxic potential due to abnormal DNA condensation and chromosome coiling by spindle inactivation. The observations of cyto and genotoxic effects suggest that the fungicide mancozeb is clastogenic agent. Thus the different concentrations used in the field could be harmful for the end-receptors of food-chain and needs constant monitoring and management for the better development of crop plants., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A main source of uncertainty currently associated with environmental risk assessment of chemicals is the poor understanding of the influence of environmental factors on the toxicity of xenobiotics. Aiming to reduce this uncertainty, here we evaluate the joint-effects of two pesticides (chlorpyrifos and mancozeb) on the terrestrial isopod Porcellionides pruinosus under different soil moisture regimes. A full factorial design, including three treatments of each pesticide and an untreated control, were performed under different soil moisture regimes: 25%, 50%, and 75% WHC. Our results showed that soil moisture had no effects on isopods survival, at the levels assessed in this experiment, neither regarding single pesticides nor mixture treatments. Additivity was always the most parsimonious result when both pesticides were present. Oppositely, both feeding activity and biomass change showed a higher sensitivity to soil moisture, with isopods generally showing worse performance when exposed to pesticides and dry or moist conditions. Most of the significant differences between soil moisture regimes were found in single pesticide treatments, yet different responses to mixtures could still be distinguished depending on the soil moisture assessed. This study shows that while soil moisture has the potential to influence the effects of the pesticide mixture itself, such effects might become less important in a context of complex combinations of stressors, as the major contribution comes from its individual interaction with each pesticide. Finally, the implications of our results are discussed in light of the current state of environmental risk assessment procedures and some future perspectives are advanced., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The widely used fungicide Mancozeb (Man) has been shown to cause genotoxic effects in rodents and toxicological manifestations in different cells, mainly by altering the antioxidant defense in cells. On the other hand, curcumin (Cur), a natural phenolic compound, is thought to possess anti-inflammatory and antioxidant properties. Here, we investigated the possible protective role of Cur on Man-induced toxicity in rat thymocytes and potential mechanism involved. Rat thymocytes were treated with Man(0.01 μg/ml) and/or increasing Cur(0.3, 1, 3 μM) concentrations and levels of cell viability, apoptosis, mitochondrial membrane potential (MMP),Bcl-2, Bax protein expression, caspase-3 and -9 activity and p38 MAPK signaling involvement were examined. Cells treated with Man displayed increased cell toxicity, hypodiploid cells, caspase-3 and -9 activity, Bax protein expression, followed with decreased MMP and Bcl-2 protein expression. Inhibition of p38 MAPK signaling pathway markedly reduced apoptosis rate and caspase-3 activity in thymocytes exposed to Man. Application of increasing Cur (1, 3 μM) concentrations resulted with significantly reduced cytotoxicity, apoptosis, caspase-3, -9 activity, Bax protein expression, together with increased MMP and Bcl-2 protein expression in rat thymocytes. These result suggest that certain Cur concentrations may mediate Man-induced rat thymocytes toxicity through mitochondrial survival pathway, which may be useful in preventing possible secondary immunological consequences induced by Man., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Thyroid is an important homeostatic regulator of metabolic activities as well as endocrine mechanisms including those of reproduction. Present investigation elucidated the thyroid disrupting potential of a neonicotinoid imidacloprid and a dithiocarbamate mancozeb in a seasonally breeding wildlife bird, Red Munia (Amandava amandava) who is vulnerable to these two pesticides through diet (seed grains and small insects). Adult male birds were exposed to 0.5% LD50 mgkg(-1)bwd(-1) of both the pesticides through food for 30days during the preparatory and breeding phases. Weight, volume and histopathology of thyroid gland were distinctly altered. Disruption of thyroid follicles reflected in nucleus-to-cytoplasm ratio (N/C) in epithelial and stromal cells, epithelial cell hypertrophy and altered colloid volume. Impairment of thyroid axis was pesticide and phase specific as evident from the plasma levels of thyroid (T4 and T3) and pituitary (TSH) hormones. In preparatory phase, plasma TSH was increased in response to decrease of T4 on mancozeb exposure showing responsiveness of the hypothalamic-pituitary-thyroid (HPT) axis to feedback regulation. On imidacloprid exposure, however, plasma levels of both T4 and TSH were decreased indicating non-functioning of negative feedback mechanism. Increased plasma T3 in response to both the pesticides exposure might be due to synthesis from non-thyroidal source(s) in a compensatory response to decrease level of T4. In breeding phase, impairment of HPT axis was more pronounced as plasma T4, T3 and TSH were significantly decreased in response to both mancozeb and imidacloprid. Thus, low dose pesticide exposure could affect the thyroid homeostasis and reproduction., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Oxidative stress is one of the major factors leading to Maneb- and Zineb-induced disorders. The aim of this in vitro study was to examine (i) the potency of Maneb and Zineb to induce changes in antioxidant enzyme activities in Chinese hamster fibroblasts V79 cells and (ii) the role of N-acetyl-L-cysteine (NAC) in the preventing their action. Maneb increased mitochondrial superoxide dismutase (SOD2) activity but failed to affect the activity of cytoplasmic superoxide dismutase (SOD1), whereas Zineb did not change the activity of any of superoxide dismutases. The activity of catalase (CAT) was reduced only by Zineb. The activity of both glutathione peroxidases (non-Se-GPx, Se-GPx) and glutathione reductase (GR) was decreased after exposure to these agents. After NAC pre-treatment Maneb increased the activity of GR, whereas the activity of non-Se-GPx was decreased as compared to that in NAC-treated cells. On the other hand, the activity of both SODs and CAT was decreased. Zineb decreased the activity of both GPxs and SOD2 with a concomitant increase in CAT activity comparing to NAC-treated cells. The results obtained thus suggest that Zineb acts by another mechanism, than Maneb does, and that one of the mechanisms of NAC protection against Maneb or Zineb-induced effects in V79 cells is its impact on enzymatic defense. Activity of GR, SOD2, and GPxs are the most affected enzymes., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Earthworm avoidance behaviour test is an important screening tool in soil eco-toxicology. This test has been developed and validated under North American and European conditions. However, little research has been performed on the avoidance test in the tropics. This work demonstrates the potential suitability of the avoidance behaviour test as screening method in the highlands of Colombia using Eisenia fetida as the bio-indicator species on contaminated soils with carbofuran and chlorpyrifos. Though for the two active ingredients 100% avoidance was not reached, a curve with six meaningful concentrations is provided. No significant avoidance behaviour trend was found for mancozeb and methamidophos. Tests were conducted in the field yielded similar results to the tests carried out in the laboratory for chlorpyrifos and mancozeb. However, for the case of carbofuran and methamidophos, differences of more than double in avoidance were obtained. Divergence might be explained by soil and temperature conditions., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Field tests are useful for the evaluation of the pesticides' impact in realistic use situations. However, the distinction between the direct and indirect effects of a pesticide is not always possible in field, with consequences on the conclusions about pesticides toxicity. Generalist predatory mites belonging to the Phytoseiidae family are widely considered as non-target organisms in pesticide side-effect evaluations. Plant pathogens of several cultivated plants can be of importance as food resources for various phytoseiids. Pesticides with fungicidal activity may have a direct impact on phytoseiids, but they can also have an indirect effect reducing food availability for predatory mites. Here, we present the results of field experiments performed on grapevine, where we investigate whether the availability of the plant pathogen grape downy mildew has an effect on fungicides impact on the predatory mites Typhlodromus pyri Scheuten and Amblyseius andersoni (Chant). In these experiments we used fungicides characterized by differential selectivity to predatory mites in laboratory: copper compounds, folpet, and mancozeb. Results indicated that the abundance of predatory mites was associated with the plant pathogen foliar symptoms presence. The presence of predatory mites was different among treatments in response of the toxicological traits of a pesticide (direct effects), but also as consequences of differential plant pathogen availability induced by fungicide applications (indirect effects). During the investigation, the variable plant pathogen spread on untreated control determined contrasting results on pesticides effect. We segregated the direct effects from the indirect food resource-mediated effects including a non-toxic reference in the experimental protocols., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Unlabelled: We have previously shown that a single i.p. injection of nitrosomethylurea (NMU) in 3-day-old rats orally treated with the pesticide mancozeb (MZ), the flavonoid quercetin (Q) or in combination (MZ-Q) induces hyperplasia, atypical acinar cell proliferation and carcinoma in situ (CIS) in the pancreas. This work studies the effect of oral administration of phenobarbital (PB) on this model of pancreatic carcinogenesis. The animals were fed on a diet supplemented by MZ or/and Q from the 10th day of pregnancy, thorough lactation and as pups after weaning until being sacrificed at week 24. Saline injection with non-supplemented diet was used for the control group (SAL). The experimental groups were (1) SAL (control), (2) SAL-PB, (3) NMU, (4) NMU-PB, (5) MZ-NMU, (6) MZ-NMU-PB, (7) Q-NMU, (8) Q-NMU-PB, (9) MZ-Q-NMU and (10) MZ-Q-NMU-PB. Acinar cell hyperplasia was found in all groups of NMU-treated rats. Dysplastic foci (DYS) were seen in groups 3-10 at the following percentages: 19, 48, 71, 27, 71, 35, 100 and 30, respectively. CIS were recorded in groups 4 to 10 at percentages: 4, 36, 13, 11, 0, 16, 5, respectively., Conclusion: Although PB, Q or MZ given alone enhance DYS lesions in NMU-treated rats, the MZ/Q/PB combined treatments may increase (mainly in males) or decrease (mainly in female) the DYS and CIS proportion. Because PB, MZ and Q influence P450 enzymes, we suggest that these enzymes play a role in the carcinogenesis process.

A subacute toxicological study of the effects of the ethylene-bisdithiocarbamate-containing fungicide Dithane M-45 (80% mancozeb) was carried out in male Wistar rats. The rats were given Dithane mixed in the feed at doses of 0, 10, 50, 75, 113, 169, 253 or 379 mg/kg body weight for 12 wk. One-third of the rats given 379 mg Dithane/kg body weight died, and doses of greater than or equal to 169 mg/kg decreased the growth of the rats as well as the nutrient utilization. The relative weights of the liver and thyroid were significantly increased in rats given greater than or equal to 75 mg Dithane/kg body weight, and those of the kidneys, adrenals and testes were significantly increased in the two highest dose groups. The serum cholesterol level was increased significantly in groups given greater than or equal to 75 mg/kg, and doses of 113, 169 or 253 mg/kg caused the elevation of the triglyceride content of the liver. The two highest doses of Dithane decreased the detoxicating capacity of the liver. The function of the thyroids was impaired even by very small doses of Dithane: at a dose of 10 mg/kg body weight the quantity of iodine stored in the thyroids was decreased by 20%. At doses of greater than or equal to 50 mg/kg statistically significant decreases in thyroid iodine content were observed. Histological examination of the thyroids showed dose-dependent hyperplasia in rats treated with Dithane.