Residues of maneb, ethylenethiuram monosulfide, ethylenethiourea, and ethylenediamine on beans and tomatoes field treated with maneb.
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Status of antioxidant defense system and expression of toxicant responsive genes in striatum of maneb- and paraquat-induced Parkinson's disease phenotype in mouse: mechanism of neurodegeneration.
Parkinson's disease (PD) is a progressive neurodegenerative disorder contributed by the combination of age, genetic and environmental factors. Several studies have clearly shown increase in the incidences of PD in the rural environments and hypothesized the involvement of pesticides such as paraquat and maneb in neurodegeneration. These studies have prompted researchers to develop paraquat and maneb models to study the effect of co-treatment of maneb and paraquat on neuronal toxicity; however, the mechanism underlying maneb and paraquat co-treatment induced neuronal toxicity has not yet been clearly understood. The involvement of cytochrome P4502E1 and glutathione S-transferases A4-4 enzymes in the detoxification of several pesticides such as atrazine, fenamirol, organophosphorous insecticide parathion, methoxychlor, diethyl dithiocarbamate and paraquat has been known. The contribution of CYP2E1 and GSTA4-4 in neuronal toxicity has also been reported. The present study was therefore undertaken to investigate the mechanism of maneb- and paraquat-induced neurodegeneration by estimating the level of antioxidant defense enzymes in the striatum and measuring the differential expressions of CYP2E1 and GSTA4-4 genes. Animals were treated with and without maneb (30 mg/kg, i.p.) or paraquat (10 mg/kg, i.p.) either alone or in combination in exposure time-dependent manner. A significant increase in catalase, glutathione S-transferase and lipid peroxidation in the striatum was found following 3, 6 and 9 weeks of co-treatment as compared with individual treatment or controls. Individual treatment of maneb or paraquat did not exhibit any significant alteration in CYP2E1 and GSTA4-4 expression up to 6 weeks; however, an augmentation in CYP2E1 and GSTA4-4 expression was observed in the animals exposed to maneb or paraquat for 9 weeks. Augmentation in the expression of CYP2E1 and GSTA4-4 was more pronounced in the animals treated with maneb and paraquat in combination for nine weeks. A significant reduction in the augmented lipid peroxidation in the striatum was observed when the striatum was pre-administered with CYP2E1 inhibitors; however, glutathione pre-administration induced lipid peroxidation. Results obtained from the present investigation suggest the involvement of CYP2E1 and GSTA4-4 in the augmentation of the lipid peroxidation thereby enhancing neurodegeneration.
Analysis of Variance↗
Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype.
While advancing age is the only unequivocally accepted risk factor for idiopathic Parkinson's disease, it has been postulated that exposure to environmental neurotoxicants combined with ageing could increase the risk for developing Parkinson's disease. The current study tested this hypothesis by exposing C57BL/6 mice that were 6 weeks, 5 months or 18 months old to the herbicide paraquat, the fungicide maneb or paraquat + maneb, a combination that produces a Parkinson's disease phenotype in young adult mice. Paraquat + maneb-induced reductions in locomotor activity and motor coordination were age dependent, with 18-month-old mice most affected and exhibiting failure to recover 24 h post-treatment. Three months post-treatment, reductions in locomotor activity and deficits in motor coordination were sustained in 5-month-old and further reduced in 18-month-old paraquat + maneb groups. Progressive reductions in dopamine metabolites and dopamine turnover were greatest in 18-month-old paraquat + maneb and paraquat groups 3 months post-treatment. Increased tyrosine hydroxylase enzyme activity compensated for striatal tyrosine hydroxylase protein and/or dopamine loss following treatment in 6-week-old and 5-month-old, but not 18-month-old paraquat and paraquat + maneb mice. Numbers of nigrostriatal dopaminergic neurons were reduced in all age groups following paraquat alone and paraquat + maneb exposure, but these losses, along with decreases in striatal tyrosine hydroxylase protein levels, were progressive in 18-month-old paraquat and paraquat + maneb groups between 2 weeks and 3 months post-exposure. Collectively, these data demonstrate enhanced sensitivity of the ageing nigrostriatal dopamine pathway to these pesticides, particularly paraquat + maneb, resulting in irreversible and progressive neurotoxicity.
Aging↗
Acute exposure to maneb alters some behavioral functions in the mouse.
Maneb, an organomanganese fungicide, is largely used in agricultural regions for control of field crop pathologies. Despite its apparent low toxicity, there are reports showing that maneb has harmful effects on peripheral and central nervous systems. In this work the effects of acute administration of maneb were studied on some experimental animal models. Male adult mice were treated with several doses of maneb, IP, and submitted to gross behavioral observation (200-1000 mg/kg) and measurement of locomotor activity, barbiturate-induced sleeping time, isolation-induced aggressiveness, catatonia, climbing behavior and of rota-rod performance (30, 60 and 100 mg/kg). The results showed that maneb has an inhibitory effect on locomotor activity and aggressiveness and increases barbiturate-induced sleeping time and haloperidol-induced catatonia. However, maneb did not affect the apomorphine-induced climbing behavior of animals. These data indicate that maneb has a CNS depressant-like effect, and suggest, at least partially, the involvement of dopaminergic systems in the mediation of this effect.
Aggression↗
[WITHDRAWN] Overexpression of superoxide dismutase or glutathione peroxidase protects against the paraquat + maneb-induced Parkinson disease phenotype.
Oxidative stress has been implicated in the pathogenesis of Parkinson disease based on its role in the cascade of biochemical changes that lead to dopaminergic neuronal death. This study analyzed the role of oxidative stress as a mechanism of the dopaminergic neurotoxicity produced by the combined paraquat and maneb model of the Parkinson disease phenotype. Transgenic mice overexpressing either Cu,Zn superoxide dismutase or intracellular glutathione peroxidase and non-transgenic mice were exposed to saline, paraquat, or the combination of paraquat + maneb twice a week for 9 weeks. Non-transgenic mice chronically exposed to paraquat + maneb exhibited significant reductions in locomotor activity, levels of striatal dopamine and metabolites, and dopaminergic neurons in the substantia nigra pars compacta. In contrast, no corresponding effects were observed in either Cu,Zn superoxide dismutase or glutathione peroxidase transgenic mice. Similarly, the increase in levels of lipid hydroperoxides in the midbrain and striatum of paraquat + maneb-treated non-transgenic mice was not detected in either Cu,Zn superoxide dismutase or glutathione peroxidase transgenic mice. To begin to determine critical pathways of paraquat + maneb neurotoxicity, the functions of cell death-inducing and protective mechanisms were analyzed. Even a single injection of paraquat + maneb in the non-transgenic treated group modulated several key pro- and anti-apoptotic proteins, including Bax, Bad, Bcl-xL, and upstream stress-induced cascade. Collectively, these findings support the assertion that protective mechanisms against paraquat + maneb-induced neurodegeneration could involve modulation of the level of reactive oxygen species and alterations of the functions of specific signaling cascades.
Animals↗
Genotoxic and mono-oxygenase system effects of the fungicide maneb.
The in vivo effects of a commercial preparation of maneb on mono-oxygenase activities of hepatic microsomes of basal and induced rats were examined. In vitro experiments with the D7 strain of yeast Saccharomyces cerevisiae were also performed. In both basal and induced rats maneb caused a decrease in cytochrome P-450 content and aniline hydroxylase. Immunoblotting analysis using anti-P-450 IIE1 antibodies confirmed the data obtained for aniline hydroxylase activity. Maneb was toxic in cells of S. cerevisiae. On the basis of in vivo and in vitro experiments it can be concluded that maneb possesses a toxic activity attributable to its main metabolite ethylene thiourea. Immunoblotting analysis indicates that maneb biotransformation influences the IIEI P-450 isoform.
Aniline Hydroxylase↗
Teratogenic effects of the fungicide maneb on chick embryos.
The teratogenicity of a commercial formulation of the fungicide maneb (Maneb 80, containing 80% manganese ethylenebisdithiocarbamate and 20% inert ingredients) in chick embryos was evaluated. Unincubated eggs (157-207 per treatment group) were immersed in 0.5, 1.5, 4.5, or 13.5 g/liter maneb aqueous solutions for 30 sec. Two control groups were used: one group of 200 eggs was immersed in tap water and a second group of 205 eggs was immersed in a solution of the inert ingredients (sodium lignin sulfonate and n-butylnaphthalene sulfonate) at the concentration present in the 13.5 g/liter maneb solution. Eggs were then incubated for 19 days. A single treatment with maneb was teratogenic at all concentrations tested, producing mainly unilateral lower limb deformities. No adverse effects on development were noticed after exposure to the inert ingredients.
Animals↗
Sister-chromatid exchanges and chromosomal aberrations in chick embryos after treatment with the fungicide maneb.
The genotoxic potential of a commercial formulation of the fungicide maneb (Maneb 80, containing 80% manganese ethylenebisdithiocarbamate as active ingredient) in chick embryos was evaluated, using as genetic end-points the frequency of sister-chromatid exchanges (SCE) and of chromosomal aberrations. Unincubated eggs were dipped in 0, 0.5, 1.5, 4.5, 13.5 or 27 g/l maneb aqueous solutions for 30 sec. Eggs were then incubated for 4 days. Maneb significantly increased SCE values at 13.5 g/l and at 27 g/l (means 1.33 and 1.74) over the control value (mean 0.87). The concentration of 27 g/l, which corresponds to 10.8 times the recommended maximum application level for use in the field, also resulted in a high mortality rate. No clastogenic effects following exposure to maneb were observed.
Animals↗
Kinetics of maneb degradation during thermal treatment of tomatoes.
The kinetics of maneb degradation in tomato homogenates at high temperatures and at two pH values (4 and 9) and the rate of formation of the toxic metabolite, ethylenethiourea (ETU), were studied. Maneb was measured as carbon disulfide by headspace gas-chromatography and ETU by high-performance liquid chromatography with photodiode array detection. First-order kinetics adequately described the degradation of maneb in tomato homogenates. The degradation rate constants exhibited an Arrhenius temperature dependence in the range from 50 to 90 degrees C and the apparent activation energy (E(a)) was calculated to be 36 KJ mol(-1) in homogenates with natural pH (4). Raising temperature from 60 to 75 and to 90 degrees C, ETU formation was significantly increased. Interestingly, the selectivity toward ETU showed a downward trend when the total conversion increased at longer heating times. When the pH of the tomato homogenates was adjusted to 9, the degradation of maneb proceeded faster at both 60 and 90 degrees C. The combination of alkaline pH and the highest temperature (90 degrees C) resulted in the maximum ETU conversion rates. The results of the present study on the fate of maneb and ETU residues during tomato processing, may prove valuable in estimating potential risk from dietary exposure.
Chromatography, Gas↗
Stability of the dithiocarbamate pesticide maneb in tomato homogenates during cold storage and thermal processing.
The effect of storage at 5 degrees C and of thermal processing by cooking at 100 degrees C and sterilization at 121 degrees C for 15 min on maneb residues in tomato homogenates was investigated. Remaining maneb and its toxic metabolite ethylenethiourea (ETU) were measured after each treatment by headspace gas chromatography with flame-photometric detection and by high-performance liquid chromatography with photo-diode array detection, respectively. No significant loss of maneb was observed during cold storage for up to 6 weeks, taking into account analytical variability. Conversely, thermal treatment resulted in substantial degradation of maneb with extensive conversion to ETU. After cooking, only 26 +/- 1% (+/- SE, n = 8) of initial maneb residues remained in the samples, whilst the conversion to ETU was 28 +/- 1% (mol mol(-1)) (+/- SE, n = 4). Sterilization eliminated the residues of the parent compound giving rise to conversion to ETU up to 32 +/- 1% (mol mol(-1)) (+/- SE, n = 4).
Cold Temperature↗
Perinatal toxicity of maneb, ethylene thiourea, and ethylenebisisothiocyanate sulfide in rodents.
The potential of the fungicide maneb and two of its metabolites, ethylenebisisothiocyanate sulfide (EBIS) and ethylene thiourea (ETU), to induce perinatal toxicity in four species of rodents was investigated. The compounds were admininistered to rats and mice during the period of organogenesis, and ETU was also administered to rats and mice during the period of organogenesis, and ETU was also administered by oral gavage for a similar period to hamsters and guinea pigs. Treatment also continued through the lactational period in groups of rats that were allowed to give birth. Fetuses were examined for signs of toxicity, including terata, and neonates for reflex developement and open-field behavior. Maneb produced hydrocephalus in fetuses in litters of rats receiving 480 mg/kg . d. No fetotoxic effects were noted in litters of rats receiving EBIS at doses at high as 30 mg/kg . d. ETU proved to be a potent teratogen in the rat. Among the effects seen at doses of 40 mg/kg . d or greater were hydrocephalus, encephalocele, kyphosis, and various defects of the digits. Neither maneb (up to 1500 mg/kg . d), ETU (up to 200 mg/kg . d), nor EBIS (up to 200 mg/kg . d) elicited signs of fetal toxicity in the mouse. ETU also failed to result in fetal toxicity when administered to the hamster (100 mg/kg . d) or the guinea pig (100 mg/kg . d). Neither maneb nor EBIS produced significant dose-related alterations in the behavioral development of perinatally exposed rat neonates. At doses that also produced neonatal hydrocephalus, ETU produced significant increases in the open-field activity of the neonates. In addition to the perinatal effects noted above, both maneb and EBIS caused maternal limb paralysis in the rat, an effect not noted in the mouse at much higher doses.
Abnormalities, Drug-Induced↗
Abnormal limb regeneration in adult newts exposed to the fungicide Maneb 80. A histological study.
The effects of the fungicide Maneb 80 (manganese ethylenebisdithiocarbamate, 80% active ingredient) on the regenerating limb of the adult crested newt, Triturus cristatus carnifex, was studied. Female newts were exposed percutaneously to 5 ppm Maneb 80. One group of control newts was exposed to the inert ingredients of Maneb 80 (sodium lignin sulfonate and n-butylnaphthalene sulfonate), and another control group was kept in tap water. The limbs were examined histologically at weekly intervals throughout the regeneration period and at the end of the experiment (10-12 wk postamputation). The regenerating limbs of all the animals exposed to Maneb 80 showed growth retardation and skeletal abnormalities. Histological examination provided evidence that vascular disturbances are important for the genesis of the developmental abnormalities induced by Maneb 80. The inert ingredients had a promoting effect on limb growth and had no teratogenic effects under our experimental conditions. There were no histological differences between the two control groups.
Abnormalities, Drug-Induced↗
Study of possible teratogenic effects of the fungicide maneb on chick embryos.
The teratogenicity of the fungicide maneb (80% active ingredient and 20% inert ingredients) in chick embryos was evaluated. Eggs, before incubation, were dipped in 0.2% or 1.2% aqueous dispersions of maneb for 30 seconds. An untreated group, a water group and a formulation ingredient group, at the concentration present in the 1.2% maneb group, ensured control in the study. Eggs were incubated for 18 days then transferred to hatching racks and allowed to hatch normally. Viable chicks and chicks "dead in shell" were assessed for external deformities. There was no evidence that maneb or its formulation ingredients were teratogenic or embryotoxic to developing chick embryos.
Animals↗
Evaluation of genotoxicity of captan, maneb and zineb in the wing spot test of Drosophila melanogaster: role of nitrosation.
The wing spot test in Drosophila melanogaster is a suitable system for the analysis of genotoxic activity of compounds that need metabolic transformation to render them active. We have analysed the genotoxicity of three fungicides for which it was reported that the metabolic processes taking place in vivo may determine their activity. The compounds analysed are captan, maneb, zineb and ethylenethiourea (ETU) (a metabolic derivative of ethylenebisdithiocarbamates like maneb and zineb). We have also evaluated the ability of ETU to form genotoxic derivatives in vivo analysing this compound in combined treatments with sodium nitrite. Both standard and high bioactivation NORR strains have been used. Captan, usually considered a mutagen in vitro but a non-mutagen in vivo, gave negative results in the wing spot test with both crosses. Positive results were obtained for maneb in the standard cross and for ETU in both the standard and the high bioactivation cross. The genotoxicities of maneb and ETU were higher when treatments were made on media in which nitrosation is favoured. A low absorption of the fungicide and an inefficient availability of the compound in the target may explain negative results obtained with zineb in both crosses. The results obtained in this study with the wing spot test demonstrate once again the suitability of this in vivo assay, in which absorption, distribution and metabolism processes take place, for the evaluation of genotoxicity of compounds to which humans are exposed.
Animals↗
Testing of the fungicide maneb for carcinogenicity in two populations of the European crested newt.
The carcinogenic effects of the fungicide manganese ethylenebisdithiocarbamate (maneb) have been investigated in 2 populations of adult crested newt, which have different prevalences of spontaneous melanoma. Animals were exposed percutaneously to a 5 ppm solution of maneb 4 days a week for 37 weeks. No differences in tumor incidence were found between control and maneb-treated animals of either population. Most of the control and treated animals from Settala (Milan) died within 7 months because of the development of widely disseminated melanomas. Tumor incidence was 94% in controls and 98% in maneb-treated newts. In the population from Bagnaia (Perugia) the incidences of melanoma were 7% and 2%, respectively.
Animals↗
[Modification of maneb toxicity by chronic ethanol intake--prenatal toxicologic studies on a high-risk group].
Rats, dose-dependent on maneb during pregnancy and lactation (20, 110, 200 or 290 ppm maneb in their food) obtained water or 20 percent alcohol to drink. The animals given pure water indicated no effect. Alcohol in combination with the same concentrations of maneb in the food raised embryotoxicity and produced retardation of the skeletons and postnatal growths in the F1-generation. There was dose-dependent coergistic effect in the breeding results from the alcoholic mothers. The practical significance of this over 15-fold higher susceptibility of alcoholic animals is discussed.
Abnormalities, Drug-Induced↗
Studies of teratogenic effects of the dithiocarbamates maneb, mancozeb, and propineb.
Oral administration of high dosages of the dithiocarbamate pesticides maneb and mancozeb was teratogenic in rats but not in mice. The malformations, severe limb and craniofacial defects, were pronounced after maneb treatment but less so after mancozeb and propineb, zinc-containing compounds. The teratogenic effect of maneb was progressively reduced by simultaneously administering increasing amounts of zinc acetate. The mechanism of the teratogenic effect may involve the compounds being chelating agents, trapping zinc required for many important enzyme systems.
Abnormalities, Drug-Induced↗
The effect of maneb, zineb, and ethylenethiourea on the humoral activity of the pituitary-thyroid axis in rat.
Ethylenebisdithiocarbamates (EBDCs) maneb and zineb are widely used fungicides the final metabolite of which is ethylenethiourea (ETU). EBDCs distort the humoral activity of the thyroid gland, and ETU is especially active in this respect. Male Wistar rats were exposed either to exogenous (100 ng i.p.) or endogenous (+4 degrees C) TRH stimulation. ETU (100-500 mg/kg i.p.) caused no changes in serum TSH levels whereas zineb (70-500 mg/kg i.p.) significantly decreased the bursts induced by cold or exogenous TRH. Maneb (20-200 mg/kg i.p.) significantly decreased the cold-induced TSH response while it had no effect on the TRH-stimulated TSH secretion. None of the agents caused significant changes in serum T3 or T4 levels. It seems that maneb, and zineb, but not ETU, inhibit rat TSH secretion through an action on the endogenous TRH at the hypothalamic or pituitary level. The mechanism behind this action may be the inhibition of dopamine-beta-hydroxylase.
Animals↗