Sublethal exposure to thiamethoxam and pyraclostrobin affects the midgut and Malpighian tubules of the stingless bee Frieseomelitta varia (Hymenoptera: Apidae: Meliponini).

The stingless bee Frieseomelitta varia Lepeletier 1836 (Hymenoptera: Apidae) is an essential pollinator in natural and agricultural ecosystems in the Neotropical region. However, these bees may be exposed to pesticides during foraging, which can affect both individuals and their colonies. One example comes from the use of pyraclostrobin (a fungicide) and thiamethoxam (an insecticide) for pest control in pepper crops, which F. varia visits. This study aimed to evaluate the isolated and combined sublethal effects of thiamethoxam (TMX) (0.000543 ng a.i./µL) and pyraclostrobin (PYR) (1.5 ng i.a./µL) on the morphology of the midgut and Malpighian tubules of F. varia workers. Results showed that both pesticides, regardless of the exposure time (through feeding during 48 h or 96 h), disturbed the morphology of the analyzed organs. Specifically, F. varia exposed orally to sublethal concentrations of thiamethoxam and pyraclostrobin, either alone or in combination, exhibited a higher rate of damage to the midgut (e.g., vacuolization, apocrine secretion, and cellular elimination) compared to the bees in the control groups, both after 48 h and 96 h of exposure. In Malpighian tubules, vacuolation is the only damage present. As the observed morphological alterations likely compromise the excretion and absorption functions, exposure to pyraclostrobin and thiamethoxam may lead to disturbances at both the individual and colony levels. These results highlight the urgent need for a future reassessment of the safety of fungicides and insecticides regarding their potential effects on bee populations.

Exposure to pesticides used in rice farming (bentazone, chlorantraniliprole and tebuconazole) affects biochemical biomarkers and hepatic histopathological parameters of hammertoad tadpoles (Boana faber).

Pesticides used in rice cultivation can cause negative health effects to non-target organisms representative of natural biodiversity. In this context, the present study aimed to investigate the occurrence of pesticides in surface waters from a river that flows in the middle of a rice farming-dominated area. We were also interested in evaluate biochemical and histological effects caused by exposure (16 d) to the lower and higher concentrations of the main found herbicide (bentazone, BTZ), insecticide (chlorantraniliprole, CTP) and fungicide (tebuconazole, TBZ), isolated or mixed, in Boana faber tadpoles. No significant differences were observed in the development of the animals. Tadpoles exposed to the herbicide BTZ showed higher hepatic levels of malondialdehyde (MDA). In animals exposed to CTP, MDA levels were lower than controls. Animals exposed to the fungicide TBZ showed higher hepatic activity of glutathione S-transferase and carboxylesterase (CbE), as well as higher levels of carbonyl proteins and MDA. Animals exposed to Mix showed higher activity in CbE and glucose-6-phosphate dehydrogenase activity in the liver, as well as higher levels of MDA. In the brain and muscle of tadpoles exposed to Mix, acetylcholinesterase activity was higher. Histological changes were also observed in pesticide-exposed animals, such as increased occurrence of melanomacrophages, inflammatory infiltrates and congestion. Our data evidences the contamination of natural aquatic environments by rice pesticides, and the adverse effects of main ones in B. faber tadpoles, which suggests the contribution of pesticides derived from rice cultivation to the degradation of local biodiversity health.

Comparison of in vitro toxicity in HepG2 cells: Toxicological role of Tebuconazole-tert-butyl-hydroxy in exposure to the fungicide Tebuconazole.

Fungicides are often used prophylactically, to control fungal diseases. Although fungicides have been designed to control pests/fungi, they frequently share molecular targets with non-target species, including humans. Tebuconazole, a fungicide belonging to the class of triazoles, is widely employed, has moderate to high persistence in soil, and can be found in different environmental levels. This fungicide is metabolized to the main hydroxy-derived metabolite, Tebuconazole-tert-butyl-hydroxy (or hydroxytebuconazole). This study aims to unveil the action mechanism of Tebuconazole and the role played by its metabolite, Tebuconazole-tert-butyl-hydroxy (5-(4-Chlorophenyl)-2,2-dimethyl-3-(1H-1,2,4-triazol-1-ylmethyl)-1,3-pentanediol), within the expected spectrum of toxicity. In silico and in vitro analyses (MTT assay, cell cycle evaluation, annexin/PI assay, ROS accumulation assay, and mitochondrial membrane potential determination) were performed in HepG2 cells for 24 h and 48 h. Although in silico analysis suggested that both Tebuconazole and Tebuconazole-tert-butyl-hydroxy are potentially hepatotoxic, only Tebuconazole affected the tested cell line. Reduced MTT metabolism, and decreased mitochondrial membrane potential were the main findings. In conclusion, the action mechanism of Tebuconazole may be related to mitochondrial dysfunction. However, the findings of this study pointed out that Tebuconazole-tert-butyl-hydroxy does not play an important role in Tebuconazol toxicity. The study has generated new data that will help to understand how fungicides behave in the environment.

Toxicogenetic, biochemical, and physiological effects of azoxystrobin and carbendazim fungicides over Lactuca sativa L. and Phaseolus vulgaris L.

Fungicides are pesticides that are frequently used in agriculture because of their action against fungal diseases. However, the widespread application of pesticides around the world raises environmental and public health concerns, since these compounds are toxic and can pose risks to ecosystems and human health. The aim of this study was to evaluate the phytotoxic, cytogenotoxic, and biochemical effects of azoxystrobin and carbendazim on Lactuca sativa L. and their physiological effects on Phaseolus vulgaris L. by analyzing the cell cycle and chromosomal and nuclear alterations in L. sativa; the biochemical effects of azoxystrobin and carbendazim on Phaseolus vulgaris L. and their physiological effects on Phaseolus vulgaris L. by analyzing the cell cycle and chromosomal and nuclear alterations in L. sativa; the biochemical effects by analyzing the activity of antioxidant enzymes in L. sativa; and the physiological effects by analyzing chlorophyll content and chlorophyll a fluorescence in P. vulgaris. It was observed that both fungicides were phytotoxic and cytotoxic, reducing root growth and the mitotic index, cytogenotoxic, increasing the occurrence of chromosomal alterations, as well as inducing oxidative stress and an increase in chlorophyll fluorescence emission and altered energy absorption in the plants used as a test system. In view of this, studies such as the one presented here indicate that the use of pesticides, even in small quantities, can lead to damage to the metabolism of plant organisms.

Biological effects of a copper-based fungicide on the fruit fly, Drosophila melanogaster.

The increased consumption of pesticides can have a negative environmental impact by increasing the essential metals to toxic levels. Bordasul® is a commonly used fungicide in Brazil and it is composed of 20% Cu, 10% sulfur, and 3.0% calcium. The study of fungicides in vivo in non-target model organisms can predict their environmental impact more broadly. The Drosophila melanogaster is a unique model due to its ease of handling and maintenance. Here, the potential toxicity of Bordasul® was investigated by assessing the development, survival, and behavior of exposed flies. Exposure to Bordasul® impaired the development (p < 0.01) and caused a significant reduction in memory retention (p < 0.05) and locomotor ability (p < 0.001). Fungicides are needed to assure the world's food demand; however, Bordasul® was highly toxic to D. melanogaster. Therefore, Bordasul® may be potentially toxic to non-target invertebrates and new environmentally-safe biofertilizers have to be developed to preserve the biota.

Investigation on the mancozeb toxicity in adult zebrafish (Danio rerio).

Agriculture has gained increasing importance in response to the continuous growth of the world population and constant need for food. To avoid production losses, farmers commonly use pesticides. Mancozeb is a fungicide used in agriculture as this compound is effective in combating fungi that harm crops. However, this fungicide may also produce damage to non-target organisms present in soil and water. Therefore, this study aimed to investigate the influence of exposure to mancozeb on survival rate, locomotor activity, behavior, and oxidative status utilizing adult zebrafish (Danio rerio) as a model following exposure to environmentally relevant concentrations of this pesticide. The experimental groups were negative control, positive control, and mancozeb (0.3; 1.02; 3.47; 11.8 or 40 µg/L). Zebrafish were exposed to the respective treatments for 96 hr. Exposure to mancozeb did not markedly alter survival rate and oxidative status of Danio rerio. At a concentration of 11.8 µg/L, the fungicide initiated changes in locomotor pattern of the animals. The results obtained suggest that the presence of mancozeb in the environment might produce locomotor alterations in adult zebrafish, which subsequently disrupt the animals' innate defense mechanisms. In nature, this effect attributed to mancozeb on non-target organisms might result in adverse population impacts and ecological imbalance.

Genotoxic effects induced by iprodione and tebuconazole in meristematic cells of Allium cepa: responses dependent on concentration and exposure time.

The present work explores the genotoxicity of the fungicides iprodione (IP) and tebuconazole (TB) using the Allium cepa assay as an in vivo biological model. Both short-term and long-term exposures were studied, revealing concentration- and time-dependent cytological and genotoxic effects. IP exhibited genotoxicity over a wider concentration range (5-50 µg/ml) and required 30 h of exposure, while TB showed genotoxicity at higher concentrations (10 and 30 µg/ml) within a 4-h exposure period. The study highlights the importance of assessing potential risks associated with fungicide exposure, including handling, disposal practices, and concerns regarding food residue. Moreover, the research underscores the genotoxic effects of IP and TB on plant cells and provides valuable insights into their concentration and time-response patterns.

Toxicological impact of strobilurin fungicides on human and environmental health: a literature review.

Fungicides are specifically used for controlling fungal infections. Strobilurins, a class of fungicides originating from the mushroom Strobilurus tenacellus, act on the fungal mitochondrial respiratory chain, interrupting the ATP cycle and causing oxidative stress. Although strobilurins are little soluble in water, they have been detected in water samples (such as rainwater and drinking water), indoor dust, and sediments, and they can bioaccumulate in aquatic organisms. Strobilurins are usually absorbed orally and are mainly eliminated via the bile/fecal route and urine, but information about their metabolites is lacking. Strobilurins have low mammalian toxicity; however, they exert severe toxic effects on aquatic organisms. Mitochondrial dysfunction and oxidative stress are the main mechanisms related to the genotoxic damage elicited by toxic compounds, such as strobilurins. These mechanisms alter genes and cause other dysfunctions, including hormonal, cardiac, neurological, and immunological impairment. Despite limitations, we have been able to compile literature information about strobilurins. Many studies have dealt with their toxic effects, but further investigations are needed to clarify their cellular and underlying mechanisms, which will help to find ways to minimize the harmful effects of these compounds.

Fungicides as a risk factor for the development of neurological diseases and disorders in humans: a systematic review.

Although studies show that pesticides, especially insecticides, may be toxic to humans, publications on the neurological effects of fungicides are scarce. As fungicides are used widely in Brazil, it is necessary to gather evidence to support actions aimed at safely using of these chemicals. We investigated through a systematic review of publications on the use of fungicides and consequences of exposure related to nervous system diseases or neurological disorders in humans. The protocol review was registered on PROSPERO and followed the guidelines of the PRISMA-Statement. As far as it is known, there is no apparent systematic review in the literature on this topic. The search was comprised of the following databases: PubMed; Web of Science; Scopus and EMBASE, using groups of Mesh terms and strategies specific to each database. Thirteen articles were selected for this review. Regarding the substances analyzed in the studies, some reported the use of fungicides in general, without separating them by type, while others summarized the categories of all pesticides by their function (insecticides, herbicides, fungicides, etc.) or chemical class (dithiocarbamate, dicarboximide, inorganic, etc.). However, most of the articles referred to fungicides that contain the metal manganese (Mn) in their composition. As for neurological disorders, articles addressed Parkinson's disease (PD), neurodevelopmental outcomes, extrapyramidal syndrome resembling PD, cognitive disorders, depression, neural tube defects, motor neurone disease, and amyotrophic lateral sclerosis. Most investigations pointed to exposure to fungicides, mainly maneb and mancozeb, leading to the development of at least one neurological disease, which suggests the need for further multicentric clinical trials and prospective studies for greater clarity of the research problem.

Toxicity assessment of a tebuconazole-based fungicide on the embryo-larval development of the common south American toad Rhinella arenarum.

Agrochemicals cause diverse effects on aquatic communities, and amphibian species are particularly threatened due the high susceptibility to contamination. Present study evaluates the toxicity of a widely used fungicide tebuconazole (Trigal®) by the assessment of mortality and developmental alterations at acute, subchronic, and chronic exposure during the embryo-larval development of the South American toad Rhinella arenarum. Also, the sensitivity of the different embryonic stages was evaluated with 24-h pulse exposure treatments. The results demonstrated that larvae were more sensitive than embryos at acute exposure (LC50-24 and 96 h = 74.62, 31.92 mg/L and 24.27, 16.81 mg/L for embryos and larvae, respectively). Nevertheless, embryos toxicity increased significantly achieving a sensitivity very similar to larvae at chronic exposure (LC50-168 and 504 h = 13.31, 4.35 mg/L and 14.47, 6.83 mg/L for embryos and larvae, respectively). Embryos exhibited several sublethal effects from 5 mg/L at 96 h onwards, such as delayed development, reduce body size, edemas, tail/axial flexures, weakness, and absence of movements. The teratogenic index at 96 h was 10.13, indicating the severe teratogenic potential of the fungicide. 24-h pulse exposure treatments showed an increased sensitivity in intermediate stages as S.11, S.18, S20, and S.23 (NOEC-96 h = 100, 200, 75, and 20 mg/L, respectively), while stage S.25 was the most sensitive to the fungicide (NOEC-96 h = 5 mg/L). About metamorphic process, tebuconazole caused an acceleration of metamorphosis at the lowest concentration (0.001 mg/L), but also an increase in mortality and in addition, significant differences in the weight in all treatments. The results obtained throughout this work indicate that tebuconazole cause several adverse effects in Rhinella arenarum embryo-larval development.

Fungicides from rice cultivation (tebuconazole and azoxystrobin) alters biochemical and histological markers of hammertoad tadpoles (Boanafaber).

Tebuconazole (TBZ) and azoxystrobin (AZX) are fungicides frequently used in rice cultivation. Despite protecting crops against fungal diseases, these compounds can contaminate the natural environments close to the crops, exerting negative effects on non-target organisms, the present study aimed to characterize the contamination by fungicides of a river that flows in an area dominated by rice cultivation in the north of the state of Santa Catarina, SC, Brazil. Concentrations of TBZ and AZX found in the field were used to evaluate their negative effects on development, biochemical biomarkers and histopatology of the liver of a native tadpole species, the hammerfrog (Boana faber). Tadpoles were exposed for 16 days to the lowest (1.20 µg/L) and highest (2.60 µg/L) concentration of TBZ, lowest (0.70 µg/L) and highest (1.60 µg/L) concentration of AZX, and the mix of both fungicides at lowest and highest concentration of each found in field analyses. Exposure to the lower TBZ concentration and both concentrations of the Mix accelerated the development of tadpoles. AZX caused an increase in the activities of glutathione S-transferase (GST), carboxylesterase (CbE) and glucose-6-phosphate dehydrogenase (G6PDH) in the liver, an increase in the levels of protein carbonyls (PC) in the liver and an increase in the activity of acetylcholinesterase (AChE) in muscle of tadpoles. TBZ, on the other hand, generated an increase in GST, G6PDH, PC and histopathological severity scores in liver and in muscle AChE activity. The effects were more intense in the groups exposed to the Mix of contaminants. No treatment altered brain AChE. The data showed that the fungicides from in rice cultivation found in natural aquatic environments around the crops pose risks to the health of the animals, compromising their metabolism and development.

Identification of metabolites generated in the biotransformation process by the Danio rerio (zebrafish) exposed to the fungicide tebuconazole.

Tebuconazole is a triazole fungicide widely used in agricultural crops for control of multiple fungal, mainly foliar and soil-borne diseases. Due to its intense use, this pesticide has been detected on aquatic matrices in different countries, which makes it necessary to identify metabolites capable to be used in its exposure monitoring. The aim of this work was to evaluate tebuconazole metabolites in zebrafish water tanks using liquid chromatography coupled to a high-resolution mass spectrometer (LCHRMS) to highlight analytical targets to monitor tebuconazole exposure in aquatic environments. Two Phase I metabolites, TEB-OH and TEB-COOH, and one Phase II metabolite, TEB-S, were identified. Target metabolomics pointed TEB-S as the most important metabolite for discrimination between treatment and negative control group and potential surrogate for detection and monitoring of tebuconazole exposure in aquatic environments. To the best of our knowledge, this is the first study to suggest the sulphation of tebuconazole (TEB-S) by zebrafish metabolism. Moreover, the use of water samples proved to be a promising approach when compared to the usual biological matrices (e.g. plasma) for evaluating the exposure of aquatic animals to tebuconazole because it is a clean and easy to obtain matrix. Water samples presented a higher concentration of metabolites when compared to plasma samples. The results suggest the applicability of this assay model for the identification of potential biomarkers for monitoring the presence of xenobiotics in water.

Evaluation of the acute and sublethal toxicity of Mancozeb in Pacamã (Lophiosilurus alexandri).

The toxic potential of dithiocarbamates fungicides widely used in world agriculture is well known, among which Mancozeb is one of the most used. This study aimed to evaluate the toxicity of Mancozeb, determining the LC50% of the product and the behavioral and histological changes observed in fish of the Pacamã species through acute and sublethal toxicity tests. The first experiment was carried out on Pacamã fingerlings exposed to dosages of 0.5, 1, 2, 4, and 8mg/L of Mancozeb under the form ManzateWG®, for a total period of 96 hours in the acute experiment, and in the second experiment, fish were subjected to concentrations of 1/10 of those used in the acute experiment (0.05, 0.1, 0.2, 0.4 and 0.8mg/L, respectively), for 15 days in total. The 50% lethal concentration of ManzateWG® was calculated at the end of the acute experiment, presenting a value of 2.29mg/L at 96h for Pacamã fingerlings. A behavioral assessment was carried out through daily observation of the fish during both experiments, and an increase in mucus production was observed, as well as atypical social behavior in those exposed to the toxic agent. Histopathological evaluation was performed on livers collected after the end of the sublethal experiment, and the main hepatic alterations observed were cytoplasmic vacuolization, inflammatory infiltrate, and necrosis. Mancozeb has toxic potential and is capable of generating behavioral changes, as well as increasing the risk of liver damage in Pacamãs exposed to this compound.

Neurobehavioral effects of fungicides in zebrafish: a systematic review and meta-analysis.

Pesticides are widely used in global agriculture to achieve high productivity levels. Among them, fungicides are specifically designed to inhibit fungal growth in crops and seeds. However, their application often results in environmental contamination, as these chemicals can persistently be detected in surface waters. This poses a potential threat to non-target organisms, including humans, that inhabit the affected ecosystems. In toxicologic research, the zebrafish (Danio rerio) is the most commonly used fish species to assess the potential effects of fungicide exposure, and numerous and sometimes conflicting findings have been reported. To address this, we conducted a systematic review and meta-analysis focusing on the neurobehavioral effects of fungicides in zebrafish. Our search encompassed three databases (PubMed, Scopus, and Web of Science), and the screening process followed predefined inclusion/exclusion criteria. We extracted qualitative and quantitative data, as well as assessed reporting quality, from 60 included studies. Meta-analyses were performed for the outcomes of distance traveled in larvae and adults and spontaneous movements in embryos. The results revealed a significant overall effect of fungicide exposure on distance, with a lower distance traveled in the exposed versus control group. No significant effect was observed for spontaneous movements. The overall heterogeneity was high for distance and moderate for spontaneous movements. The poor reporting practices in the field hindered a critical evaluation of the studies. Nevertheless, a sensitivity analysis did not identify any studies skewing the meta-analyses. This review underscores the necessity for better-designed and reported experiments in this field.

Assessment of cellular damage with cytome assay among environmental/occupational triazole.

The use of triazole fungicides is common in Minas Gerais, Brazil. However, the risk arising from excessive and often unprotected exposure can be harmful to farmers. Therefore, we evaluated volunteers, exposed to triazole fungicides for cellular damage caused by this pesticide. In the buccal micronucleus cytome assay (BMCyt), cells were analyzed. Urinary triazoles were analyzed by the Liquid-Liquid Extraction coupled with Gas-chromatography/mass-spectrometry (LLE-GC/MS). Statistical differences were found for all cell types evaluated in residents of rural areas (n = 145). Analysis of variance showed statistical difference in kariolytic and pyknotic cells, between the groups of men and women living in rural areas, with higher incidence in the male group. Likewise, higher concentrations triazoles in urine samples in the male group were observed. Greater cellular damage suggests increases in DNA damage, chromossomal instability and cell deaths. The results showed the urgency of the public management with the implementation of measures to minimize the pesticides exposure.

Contamination and mortality of leaf-cutting ant workers by the quinone inside inhibitor fungicide after social interactions.

Leaf-cutting ants of the genera Atta and Acromyrmex (Hymenoptera: Formicidae) are the most important pests in forest and agricultural plantations and livestock. Toxic baits are the main method to manage these insects. The objective was to determine whether the behavior of allogrooming, touch, and self-grooming among Atta sexdens rubropilosa Forel, 1908 (Hymenoptera: Formicidae) workers disperse the fungicide quinone inside inhibitor and whether this product is toxic to them. This fungicide was applied, topically, in groups of workers and the social interactions between them and their mortality with and without the fungicide were evaluated. The interactions and the quinone inside inhibitor fungicide contamination increased with the number of leaf-cutting ant workers per group. Excessive touches, with subsequent allogrooming, and self-grooming among the ant workers dispersed the quinone inside the inhibitor fungicide causing 100% mortality and indicating its toxicity to this insect. The hypothesis that social interactions contaminated ant colony mates and the toxicity of the fungicide quinone inside inhibitor to workers of the leaf-cutting ant A. sexdens rubropilosa was proven.

The fungicide azoxystrobin causes histopathological and cytotoxic changes in the midgut of the honey bee Apis mellifera (Hymenoptera: Apidae).

Apis mellifera is an important bee pollinating native and crop plants but its recent population decline has been linked to the use of pesticides, including fungicides that have been commonly classified as safe for bees. However, many pesticides, in addition to direct mortality cause sublethal effects, including damage to target selective honey bee organs. The midgut is the organ responsible for the digestion and absorption of nutrients and the detoxification of ingested substances, such as pesticides. This study evaluated the histopathological and cytotoxic changes in the midgut of A. mellifera workers caused by the pesticide azoxystrobin. The limit-test was performed, and a 100 µg a.i./bee dose was administered orally and midgut analyzed with light and transmission electron microscopies after 24 h and 48 h of pesticide exposure. The midgut of the control bees has a single layer of digestive cells, with spherical nuclei, nests of regenerative cells, and the lumen coated with the peritrophic matrix. The bees fed on azoxystrobin showed morphological changes, including intense cytoplasm vacuolization and cell fragments released into the gut lumen. The protein detection test showed greater staining intensity in the nests of regenerative cells after 24 h of exposure to azoxystrobin. The occurrence of damage to the midgut in A. mellifera exposed to azoxystrobin indicates that although this fungicide has been classified as low toxicity for bees, it has sublethal effects in the midgut, and effects in other organs should be investigated.

Effects of fungicides on the ultrastructure of the hypopharyngeal glands and the strength of the hives of Apis mellifera Linnaeus, 1758 (Hymenoptera: Apidae).

Several crops of agronomic interest depend on bees' pollination, and Apis mellifera L (Hymanoptera: Apidae) is the most studied direct pollinator. Nevertheless, the use of pesticides in agricultural environments is common, including fungicides. Studies that seek to evaluate the effects of fungicides on the hypopharyngeal glands of bees, the site of royal jelly synthesis, are lacking. Thus, this work aimed to evaluate the effect of field doses of fungicides (Captan SC® and Zignal®), alone or in mixture, on the hypopharyngeal glands and their subsequent effect on the strength of hives. The evaluations were carried out under field conditions in three hives per treatment. For a period of one month, bee hives received feed containing sugar syrup, pollen and 1.2 mL of Zignal® and 3 mL of Captan SC® in the isolated treatments and 4.2 mL in the mixture. The action of fungicides on the hypopharyngeal glands was determined by transmission electron microscopy analysis in bees 7 and 15 days old, collected in the hives one month after exposure to fungicides. The strength of the hives was evaluated for six months based on the number of frames with adult bees, open and closed brood, and stored food. The results indicate that fungicides promote early degeneration of the rough endoplasmic reticulum and morphological and structural changes in mitochondria. In addition, a reduction in adult population, open and closed breeding and food stock was observed. More pronounced damage occurred when bees were exposed to the mixture of fungicides. Overall, it can be concluded that the presence of fungicides in bee diets promotes harm accentuated over time and compromises the survival of hives. It will be worth estimating the fungicide effects of the queen development and on the colony heath.

Analytical and toxicological aspects of dithiocarbamates: an overview of the last 10 years.

Compilation studies related to toxicological aspects and also biological monitoring and analysis methods for specific fungicides and, mainly, those that belong to the class of the dithiocarbamates (DTCs) have not been carried out at least in the last ten years. DTCs - dimethyldithiocarbamates, ethylenebisditiocarbamates, propylenebisditiocarbamates - are organosulfur compounds that form complexes due to the presence of different chemical elements, which bind strongly and inhibit enzymes that are essential to the functioning of the organism, causing a serious proven adverse effect on biological systems, such as alteration of thyroid hormones, teratogenesis and neurotoxicity. It is still evident, as shown by world data, that the growing consumption of fungicides has increasingly exposed the population in general and, in particular, workers who deal with these substances. There is a scarcity of studies in the literature discussing the toxicological and analytical aspects that are important for understanding the real effects of DTCs and monitoring human exposure to them. Therefore, the aim of this work was to expose, in a comprehensive way and through a narrative review, gaps in research related to the fungicides of the DTCs class, their metabolites, as well as the toxicological and analytical aspects involved. The review is divided into two parts: (1) Toxicological aspects, including toxicokinetics, toxicodynamics and toxidromes; and (2) Analytical Toxicology, which comprises biomarkers, sample preparation and identification/quantification methods.

The fungicide Tebuconazole induces electromechanical cardiotoxicity in murine heart and human cardiomyocytes derived from induced pluripotent stem cells.

Tebuconazole (TEB) is an important fungicide that belongs to the triazole family. It is widely used in agriculture and its use has experienced a tremendous increase in the last decade. The long-term exposure of humans to this pesticide is a real threat because it is stable in water and soil. The association between long-term exposure to TEB and damage of several biological systems, including hepatotoxicity and cardiotoxicity is evident, however, acute toxicological studies to reveal the toxicity of TEB are limited. This research paper addressed the acute exposure of TEB in murine hearts, cardiomyocytes, and human cardiomyocytes derived from an induced pluripotent stem cell (hiPSC-CMs), spelling out TEB's impact on electromechanical properties of the cardiac tissue. In ex vivo experiments, TEB dose dependently, caused significant electrocardiogram (ECG) remodeling with prolonged PR and QTc interval duration. The TEB was also able to change the action potential waveform in murine cardiomyocytes and hiPSC-CMs. These effects were associated with the ability of the compound to block the L-type calcium current (IC50 = 33.2 ± 7.4 µmol.l-1) and total outward potassium current (IC50 = 5.7 ± 1.5 µmol.l-1). TEB also increased the sodium/calcium exchanger current in its forward and reverse modes. Additionally, sarcomere shortening and calcium transient in isolated cardiomyocytes were enhanced when cells were exposed to TEB at 30 µmol.l-1. Combined, our results demonstrated that acute TEB exposure affects the cardiomyocyte's electro-contractile properties and triggers the appearance of ECG abnormalities.