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A dithiocarbamate (DTC) fungicide, propineb, affects thyroid function and exerts immunotoxicity, cytotoxicity, and neurotoxicity in humans. Long-term exposure to propineb is associated with carcinogenicity, teratogenicity, malfunction of the reproductive system, and abnormalities in vital signs during organ development. However, there is no evidence of acute toxicity attributable to propineb in zebrafish. Therefore, in the present study, we assessed the toxicity of propineb in zebrafish by studying its adverse effects on embryo development, angiogenesis, and notochord development. Embryos with propineb exposure developed morphological and physiological defects and in larvae, apoptosis and notochord defects were induced in the early development stage. Transgenic fli1:eGFP zebrafish exposed to propineb showed abnormal larval development with defects in angiogenesis and deformed vasculature. Propineb induced irreversible damage to the neural development of embryos and neurogenic defects in developing zebrafish in transgenic olig2:dsRED zebrafish. These results show that exposure to propineb triggers abnormalities in different organ systems of zebrafish and suggests the physiological complexity of the response to propineb., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Early caregiving is one of the strongest influences on children's development, and among the most significant modifiable environmental factor. The aim of this study was to explore the association between quality of caregiver-infant interactions and neurodevelopment of infants living in banana-growing communities in rural Costa Rica characterized as having environmental toxic exposures. Home visits were conducted with 94 caregiver-infant dyads from the Infants' Environmental Health Study (ISA), living within Matina county, Limón province. One-year infant neurodevelopmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development®, Third Edition (Bayley-III). Quality of caregiver-infant interaction was assessed with a standardized observational task: Nursing Child Assessment Satellite Training Teaching scale (NCATS) at around two years of age. Multiple regression analyses examined associations between components of caregiver-infant interactions and neurodevelopmental outcomes, adjusting for mancozeb and manganese exposure and other potential confounders. Compared to NCATS normative data for U.S. Hispanic mothers, 35% of the sample had overall caregiving interaction scores ≤10th percentile cut-off, indicating less than optimal interactions. Higher quality of caregiver-infant interaction was associated with higher expressive communication ability in infants [ß = 0.03 (95% CI: 0.01, 0.06)], controlling for pesticide exposure and confounders. Aspects of caregiving such as stimulation and growth-fostering of infants were most strongly associated with language outcomes. Results suggest an association between positive caregiving on language development for infants living in a rural agricultural area in Costa Rica, and highlight aspects of caregiving that could be targeted to improve resilience of these children who live in vulnerable conditions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Food intake ensures energy resources sufficient for basic metabolism, immune system and reproductive investment. It is already known that food-seeking performances, which are crucially controlled by orexins (ORXs), may be under the influence of environmental factors including pollutants. Among these, mancozeb (mz) is becoming an environmental risk for neurodegenerative diseases. Due to few studies on marine fish exposed to mz, it was our intention to correlate feeding latency, food intake and feeding duration to potential neurodegenerative processes in key diencephalic sites and expression changes of the ORX neuroreceptor (ORXR) in the ornate wrasses (Thalassoma pavo). Hence, fish exposed for 4 days (d) to mz 0.2 mg/l (deriving from a 0.07, 0.14, 0.2, 0.3 mg/l screening test) displayed a significant reduction (p < 0.05) of food intake compared to controls as early as 1d that became more evident (p < 0.01) after 3d. Moreover, significant enhancements of feeding latency were reported after 1d up to 3d (p < 0.001) and even feeding duration was enhanced up to 3d (p < 0.001), which instead moderately increased after 4d (p < 0.05). A reduction (-120%; p < 0.001) of mean body weight was also detected at the end of exposure. Likewise, a notable (p < 0.001) activation of ORXR protein occurred together with mRNA up-regulations in diencephalic areas such as the diffuse nucleus of the inferior lobe (+48%) that also exhibited evident degenerative neuronal fields. Overall, these results highlight an ORX role as a vital component of the neuroprotective program under environmental conditions that interfere with feeding behaviors., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Non-target organisms, including human and wildlife, are susceptible to deleterious effects of pesticide mixtures in their environment. Present study demonstrated the disruption of the hypothalamic-pituitary-thyroid (HPT) axis in a seasonally breeding wildlife bird Amandava amandava on co-exposure to dithiocarbamate mancozeb/MCZ and neonicotinoid imidacloprid/IMI, at concentrations even lower than respective environmentally realistic exposure level of each of the pesticide. Adult male birds (n=8/group) were exposed individually to 0.25% LD 50 of each of MCZ (0.14mg) and IMI (2.75μl) followed by co-exposure to their equimixture as MIX-I (0.25% LD 50 of each) and MIX-II (0.5% LD 50 of each) through food for 30d in preparatory phase of reproductive cycle. Disruptions of thyroid gland and pituitary-thyroid axis were evident. Altered thyroid weight and volume, follicles with inactive colloids and lesions, decrease of height and nucleus-to-cytoplasm ratio of follicular epithelial cells were noted. Plasma levels of T4 and T3 were decreased, more significant in mixture groups than in individually exposed groups. Within co-exposed groups, comparatively high plasma T4 and T3 levels in MIX-II than MIX-I indicated dose non-responsiveness of the pesticides in mixtures; a characteristic displayed by endocrine disrupters. Plasma TSH level was increased in MCZ- and IMI- but decreased in MIX-I and MIX-II suggesting the disruption of the negative feedback and impairment of the HPT axis in co-exposed groups. Effects were more prominent in co-exposed groups due to combinatorial action and cumulative toxicity of pesticides. Considering the role of thyroid hormones in reproductive development, pesticides even in low dose could affect the thyroid homeostasis and reproductive axis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: The potential adverse reproductive and developmental effects of Mancozeb, especially in sensitive subpopulations, have not been fully reviewed for this widely used fungicide., Objective: To review the experimental and epidemiologic evidence for the association between exposure to Mancozeb and reproductive and developmental health outcomes using an adaptation of the National Toxicology Program's Office of Health Assessment and Translation (OHAT) systematic review framework., Data Sources: Four databases (PubMed, TOXNET, Web of Science, Google Scholar) were searched for published studies on Mancozeb. Of 403 identified articles, 30 met our inclusion criteria for systematic review., Results: Results from in vitro studies provide evidence that Mancozeb may indirectly disrupt or impair reproduction at the cellular level and should be regarded as a reproductive toxicant. Animal studies confirm reproductive and developmental toxicity in mammals and suggest that males chronically exposed to Mancozeb experience significant changes in physiological, biochemical, and pathological processes that may lead to infertility. Epidemiological studies were limited to indirect methods of exposure assessment and examined the effect of fungicides more broadly during pre-conception, pregnancy, and birth, yielding mixed results., Conclusions: High confidence ratings from in vitro and animal studies, in combination with moderate confidence ratings from epidemiologic studies employing indirect methods of exposure assessment, provide evidence that Mancozeb should be regarded as a suspected developmental hazard and a presumed reproductive hazard in humans. More population-based studies linking direct measures and/or biomarkers of exposure to adverse effects on male and female fertility, as well as in utero and early life development, are needed to improve the quality of the evidence base concerning the human reproductive and developmental consequences of Mancozeb exposure., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Manganese-containing fungicides like Mancozeb have been associated with neurodegenerative conditions like Parkinson's disease. We examined the behavioral damage and differential neuronal vulnerability resulting from Mancozeb exposure using Caenorhabditis elegans, an important mid-trophic level soil organism that is also a powerful model for studying mechanisms of environmental pollutant-induced neurodegenerative disease. The dopamine-mediated swim to crawl locomotory transition behavior is exquisitely vulnerable to Mancozeb, with functional impairment preceding markers of neuronal structural damage. The damage is partially rescued in mutants lacking the divalent metal transporter, SMF-1, demonstrating that some, but not all, of the damage is mediated by manganese. Increasing concentrations of Mancozeb recruit additional behavioral dysfunction, notably serotonin-mediated egg-laying behavior, but without evident serotonergic neuronal structural damage. Thus, measurements of behavioral dysfunction are a sensitive early marker of fungicide toxicity that could be exploited to examine further mechanisms of neuron damage and possible therapeutic interventions. These results also provide important insight into the consequences of fungicide use on the ecological behavior of nematodes., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Epidemiological evidence suggests positive correlations between pesticide usage and the incidence of Parkinson's disease (PD). To further explore this relationship, we used wild type (N2) Caenorhabditis elegans (C. elegans) to test the following hypothesis: Exposure to a glyphosate-containing herbicide (TD) and/or a manganese/zinc ethylene-bis-dithiocarbamate-containing fungicide (MZ) may lead to neurotoxicity. We exposed N2 worms to varying concentrations of TD or MZ for 30 min (acute) or 24h (chronic). To replicate agricultural usage, a third population was exposed to TD (acute) followed by MZ (acute). For acute TD exposure, the LC(50)=8.0% (r(2)=0.6890), while the chronic LC(50)=5.7% (r(2)=0.9433). Acute MZ exposure led to an LC(50)=0.22% (r(2)=0.5093), and chronic LC(50)=0.50% (r(2)=0.9733). The combined treatment for TD+MZ yielded an LC(50)=12.5% (r(2)=0.6367). Further studies in NW1229 worms, a pan-neuronally green fluorescent protein (GFP) tagged strain, indicated a statistically significant (p<0.05) and dose-dependent reduction in green pixel number in neurons of treated worms following each paradigm. This reduction of pixel number was accompanied by visual neurodegeneration in photomicrographs. For the dual treatment, Bliss analysis suggested synergistic interactions. Taken together, these data suggest neuronal degeneration occurs in C. elegans following treatment with environmentally relevant concentrations of TD or MZ., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Previous in vitro studies in our laboratory have shown that mancozeb (MZ) and maneb (MB), both widely used EBDC fungicides, are equipotent neurotoxicants that produce cell loss in mesencephalic dopaminergic and GABAergic cells after an acute 24h exposure. Mitochondrial uncoupling and inhibition were associated with fungicide exposure. Inhibition of mitochondrial respiration is known to increase free radical production. Here the mechanism(s) of neuronal damage associated with MZ exposure was further explored by determining the role that reactive oxygen species (ROS) played in toxicity. Damage to mesencephalic dopamine and GABA cell populations were significantly attenuated when carried out in the presence of ascorbate or SOD, indicative of a free radical-mediated contribution to toxicity. ROS generation monitored by hydrogen peroxide (H(2)O(2)) production using Amplex Red increased in a dose-dependent manner in response to MZ. Inhibition of intracellular catalase with aminotriazole had little effect on H(2)O(2) generation, whereas exogenously added catalase significantly reduced H(2)O(2) production, demonstrating a large extracellular contribution to ROS generation. Conversely, cells preloaded with the ROS indicator dye DCF showed significant MZ-induced ROS production, demonstrating an increase in intracellular ROS. Both the organic backbone of MZ as well as its associated Mn ion, but not Zn ion, were responsible and required for H(2)O(2) generation. The functionally diverse NADPH oxidase inhibitors, diphenylene iodonium chloride, apocynin, and 4-(2-aminoethyl)benzene-sulfonyl fluoride hydrochloride significantly attenuated H(2)O(2) production by MZ. In growth medium lacking cells, MZ produced little H(2)O(2), but enhanced H(2)O(2) generation when added with xanthine plus xanthine oxidase whereas, in cultured cells, allopurinol partially attenuated H(2)O(2) production by MZ. Minocycline, an inhibitor of microglial activation, modestly reduced H(2)O(2) formation in mesencephalic cells. In contrast, neuronal-enriched cultures or cultures treated with MAC-1-SAP to kill microglia, did not show an attenuation of ROS production. These findings demonstrate that Mn-containing EBDC fungicides such as MZ and MB can produce robust ROS generation that likely occurs via redox cycling with extracellular and intracellular oxidases. The findings further show that microglia may contribute to but are not required for ROS production by MZ.

Oxidative stress has been implicated in pesticide-induced neurotoxicity, based on its role in the cascade of biochemical changes that lead to dopaminergic neuronal cell death. We have, therefore, examined the role of oxidative stress caused by the pesticides endosulfan and zineb in human neuroblastoma cells (SH-SY5Y) in culture. Upon treatment with 50-200 microM concentrations of either of these pesticides, SH-SY5Y cells generated both superoxide anion and hydrogen peroxide in a dose-and time-dependent manner. Mixtures of the pesticides significantly enhanced the production of these reactive oxygen species compared to individual pesticide exposures. Pesticide treatment decreased superoxide dismutase, glutathione peroxidase, and catalase activities in SH-SY5Y cells. Additionally, these pesticides induced lipid peroxide (thiobarbituric acid reactive products) formation in these cells. While both pesticides individually (at 100 microM) increased caspase-3 activity, cells exposed to a mixture of the pesticides exhibited significantly low levels of this enzyme, probably due to excessive necrotic cell death. Furthermore, exposure to these pesticides increased nuclear NFkappaB activity. Taken together, these findings suggest that the cytotoxicity of endosulfan and zineb, both individually and in mixtures may, at least in part, be associated with the generation of reactive oxygen species with concomitant increased expression of NFkappaB.

Recent studies suggest that exposure to agrochemicals may contribute to the development of idiopathic Parkinson's disease. Maneb (MB), a widely used Mn-containing ethylene-bis-dithiocarbamate (EBDC) fungicide, has been implicated in selective dopaminergic neurotoxicity. In this study, we examine the potential neurotoxicity of mancozeb (MZ), a widely used EBDC fungicide that is structurally similar to MB, but contains both Zn and Mn. Primary mesencephalic cells isolated from Sprague-Dawley embryonic day 15 rat embryos were exposed in vitro to either MZ or MB to compare their cytotoxic potential. Exposure to 10-120 microM MZ or MB for 24h resulted in a dose-dependent toxicity in both the dopamine (DA) and GABA mesencephalic populations as assessed by a functional assay for high affinity transporter activity. Consistent with this, cell viability as well as tyrosine hydroxylase-positive neurons decreased with increasing doses of MZ or MB. Toxic potencies for MZ and MB were similar and no difference in sensitivity between the DA and GABA populations was observed with the fungicides. Exposure to ethylene thiourea, the major metabolite of either MZ or MB, was not toxic, implicating the parent compound in toxicity. Both the organic and Mn metal components of the fungicides were found to contribute to toxicity. Non-toxic exposures to the fungicides decreased ATP levels in a dose-dependent manner suggesting impairment of energy metabolism. In whole mitochondrial preparations isolated from adult rat brains, MZ and MB inhibited NADH-linked state 3 respiration. Mild to moderate mitochondrial uncoupling was also observed in response to the fungicides. In conclusion, our findings indicate that acute exposure to high doses of MZ and MB produce equipotent toxic effects in both DA and GABA neurons that may be associated with perturbations in mitochondrial respiration.