Fipronil Affects Craniofacial and Heart Development in Zebrafish Embryos (Danio rerio).

Fipronil is a broad-spectrum insecticide that has off-target effects in developing vertebrate embryos. In this study, we investigate treatment of zebrafish embryos with fipronil over the course of 5 days and examine the effects on body length, the cardiovascular system, and craniofacial morphology. We found the insecticide caused shorter body length and a decrease in eye size. By examining specific heart chamber morphology, as well as jaw angle and length, we quantified defects including enlargement of the heart and increases in jaw length and width. Further studies are needed to assess the mechanisms of fipronil's effect on vertebrate development for both environmental and human health concerns.

Fomepizole use reported to United States Poison Centers from 2010 to 2021.

BACKGROUND: The diagnosis of toxic alcohol poisoning is often based on clinical presentation and nonspecific surrogate laboratory studies due to limited testing availability. Fomepizole is the recommended antidote and often administered empirically. The objective of this study is to identify substances that mimic toxic alcohols and compare key clinical factors between toxic alcohol and non-toxic alcohol exposures when fomepizole was administered. METHODS: This study was a retrospective evaluation using the National Poison Data System from January 1, 2010 through December 31, 2021. Exposures were included if fomepizole was administered. Toxic alcohol exposures had ethylene glycol or methanol as a coded substance. For exposures not coded as a toxic alcohol, the first substance was described. Paracetamol (acetaminophen) exposures from 2020 and 2021 were excluded. RESULTS: Fomepizole was reportedly used 25,110 times over 12 years. Use increased from 1,955 in 2010 to 2,710 in 2021. Most administrations were for reported toxic alcohol poisoning (60 percent) but use in reported non-toxic alcohol poisoning was greater starting in 2020. Toxic alcohol exposures were older (43.3 versus 39.8 years; P < 0.001) and more likely male (65.7 percent versus 58.2 percent). Level of care was mostly a critical care unit (67.7 percent), which was less common in toxic alcohol (63.3 percent) than non-toxic alcohol exposures (74.2 percent). The most common non-toxic alcohol substances were ethanol (24.9 percent) or an unknown drug (17.5 percent). Acidosis, increased creatinine concentration, anion gap, and osmolal gap, and kidney failure were coded in a lower proportion of toxic alcohol exposures than non-toxic alcohol exposures (P < 0.001). DISCUSSION: The inability to provide rapid clinical confirmation of toxic alcohol poisoning results in the empiric administration of fomepizole to many patients who will ultimately have other diagnoses. Although fomepizole is relative well tolerated we estimated that this practice costs between $1.5 to $2.5 million. The major limitations of this work include the biases associated with retrospective record review, and the inability to confirm the exposures which may have resulted in allocation error. CONCLUSION: Most fomepizole use was for a presumed toxic alcohol. This recently shifted to greater use in likely non-toxic alcohol poisoning. Key difference between the groups suggest fomepizole administration was likely due to the difficulty in diagnosis of toxic alcohol poisoning along with the efficacy and safety of fomepizole. Increased toxic alcohol laboratory testing availability could improve timely diagnosis, reserving fomepizole use for toxic alcohol poisoning.

Ecological consequences when organisms avoid a contaminated environment: A study evaluating the toxicity of fipronil.

The ability of aquatic organisms to sense the surrounding environment chemically and interpret these signals correctly is crucial to their survival and ecological niche. This study applied the Heterogenous Multi-Habitat Assay System - HeMHAS to evaluate the avoidance potential of Daphnia magna to detect fipronil-contaminated habitats in a connected landscape after a short (48 h), previous, forced exposure to an environmentally relevant concentration of the same insecticide. The swimming of daphnids was also analyzed by recording the total distance covered. D. magna preferred areas with less contamination, although the effect of fipronil on their swimming ability (a decrease) was observed for all the concentrations tested. The application of non-forced multi-compartment exposure methodologies is a recent trend and is ecologically relevant as it is based on how contamination can really produce changes in an organism's habitat selection. Finally, we consider the importance of more non-forced exposure approaches where Stress Ecology can be aggregated to improve systemic understanding of the risk that contaminants pose to aquatic ecosystems from a broader landscape perspective.

Toxicity assessment of carvacrol and its acetylated derivative in early staged zebrafish (Danio rerio): Safer alternatives to fipronil-based pesticides?

Fipronil is a broad-spectrum pesticide presenting high acute toxicity to non-target organisms, particularly to aquatic species. Natural compounds stand out as promising alternatives to the use of synthetic pesticides such as fipronil. Thus, our study aimed to compare the toxicity of carvacrol (natural), acetylcarvacrol (semisynthetic), and fipronil (synthetic) to early staged zebrafish. We conducted a series of toxicity assays at concentrations ranging from 0.01 µM to 25 µM for fipronil and 0.01 µM to 200 µM for carvacrol and acetylcarvacrol, depending on the assay, after 7-days post-fertilization (dpf). The potency (EC50) of fipronil was ∼1 µM for both deformities and mortality at 7 dpf, whereas EC50 was >50 µM for carvacrol and >70 µM for acetylcarvacrol. Fipronil at 0.1 and 1 µM caused a decrease in body length and swim bladder area of larvae at 7dpf, but no difference was observed for either carvacrol or acetylcarvacrol. Based upon the visual motor response test, fipronil induced hypoactivity in larval zebrafish at 1 µM and acetylcarvacrol induced hyperactivity at 0.1 µM. Anxiolytic-type behaviors were not affected by any of these chemicals. All chemicals increased the production of reactive oxygen species at 7 dpf, but not at 2 dpf. Genes related to swim bladder inflation, oxidative stress, lipid metabolism, and mitochondrial activity were measured; only fipronil induced upregulation of atp5f1c. There were no changes were observed in oxygen consumption rates of fish and apoptosis. Taken together, our data suggest that carvacrol and its derivative may be safer replacements for fipronil due to their lower acute toxicity.

Design, Synthesis, Antiproliferative Actions, and DFT Studies of New Bis-Pyrazoline Derivatives as Dual EGFR/BRAFV600E Inhibitors.

Some new Bis-pyrazoline hybrids 8-17 with dual EGFR and BRAFV600E inhibitors have been developed. The target compounds were synthesized and tested in vitro against four cancer cell lines. Compounds 12, 15, and 17 demonstrated strong antiproliferative activity with GI50 values of 1.05 µM, 1.50 µM, and 1.20 µM, respectively. Hybrids showed dual inhibition of EGFR and BRAFV600E. Compounds 12, 15, and 17 inhibited EGFR-like erlotinib and exhibited promising anticancer activity. Compound 12 is the most potent inhibitor of cancer cell proliferation and BRAFV600E. Compounds 12 and 17 induced apoptosis by increasing caspase 3, 8, and Bax levels, and resulted in the downregulation of the antiapoptotic Bcl2. The molecular docking studies verified that compounds 12, 15, and 17 have the potential to be dual EGFR/BRAFV600E inhibitors. Additionally, in silico ADMET prediction revealed that most synthesized bis-pyrazoline hybrids have low toxicity and adverse effects. DFT studies for the two most active compounds, 12 and 15, were also carried out. The values of the HOMO and LUMO energies, as well as softness and hardness, were computationally investigated using the DFT method. These findings agreed well with those of the in vitro research and molecular docking study.

Acute exposure of Isopyrazam damages the developed cardiovascular system of zebrafish (Danio rerio).

Isopyrazam (IPZ) is one of the broad-spectrum succinate dehydrogenase inhibitor fungicides (SDHIs). Although the potential bio-toxicity of SDHIs has been reported hourly, the specific effects focused on the cardiovascular system have remained unclear and piecemeal. Thus, we chose IPZ as a representative to observe the cardiovascular toxicity of SDHIs in zebrafish. Two types of transgenic zebrafish, Tg (cmlc2:GFP) and Tg (flk1:GFP) were used in this study. Healthy embryos at 6 hpf were exposed to IPZ solutions. The statistical data including survival rate, hatching rate, malformed rate, and morphological and functional parameters of the cardiovascular system at 48 hpf and 72 hpf demonstrated that IPZ could cause abnormalities and cardiovascular defects such as spinal curvature, dysmotility, pericardial edema, pericardial hemorrhage, and slowed heart rate, etc. At the same time, the activity of enzymes related to oxidative stress was altered with IPZ. Our results revealed that IPZ-induced cardiovascular toxicity and oxidative stress might be one of the underlying toxic mechanisms.

Assessment of Biological Activities and Genomic Changes on Microorganisms, Wheat, and Wilding Arise from Poly(pyrazole).

The rapidly growing human population has led to duplicate food production and also reduced product loss. Although the negative effects of synthetic chemicals were recorded, they are still used as agrochemical. The production of non-toxic synthetics makes their use particularly safe. The goal of our research is to evaluate antimicrobial activity of previously synthesized Poly(p-phenylene-1-(2,5-dimethylphenyl)-5-phenyl-1H-pyrazole-3,4-dicarboxy amide) (poly(PDPPD)) against selected Gram-negative, Gram-positive bacteria, and fungus. In addition, the possible genotoxic effects of the poly(PDPPD) were searched on Triticum vulgare and Amaranthus retroflexus seedlings using Random Amplified Polymorphic DNA (RAPD) marker. The binding affinity and binding energies of the synthesized chemical to B-DNA were simulated with AutoDock Vina. It was observed that the poly(PDPPD) affected most of the organisms in a dose-dependent manner. Pseudomonas aeruginosa was the most affected species in tested bacteria at 500 ppm with 21.5 mm diameters. Similarly, a prominent activity was observed for tested fungi. The poly(PDPPD) decreased root and stem length of the Triticum vulgare and Amaranthus retroflexus seedlings and also reduced the genomic template stability (GTS) value of Triticum vulgare more than Amaranthus retroflexus. The binding energy of poly(PDPPD) was found in range of -9.1 and -8.3 kcal/mol for nine residues of B-DNA.

Phytotoxicity of 2,4-D and fipronil mixtures to three green manure species.

Sugarcane expansion has been associated with soil contamination by agrochemicals. Pesticides can affect plant growth, and their mixture might have potentiated effects on exposed species. This research aimed to evaluate the influence of fipronil on the phytotoxicity of 2,4-D on three green manure plant species: Canavalia ensiformis, Dolichos lablab, and Lupinus albus. Plants were exposed (for 21 days, at 25 °C) to a control soil and five concentrations of each pesticide and their combinations (36 treatments, considering a full-factorial approach). Effect concentrations of 50% growth inhibition (EC50) were estimated. No phytotoxicity effects were identified when plants were exposed to different fipronil concentrations (up to 0.12 mg kg-1). All species exposed to 2,4-D showed a decrease in shoot and root length and fresh/dry biomass. L. albus and D. lablab roots showed the highest sensitivity when exposed to 2,4-D among the endpoints (EC50 = 0.02 and 0.05 mg kg-1, respectively), while C. ensiformis roots were the most tolerant (EC50 = 0.98 mg kg-1). However, the interference of fipronil on the toxicity of 2,4-D was not detected in different mixture proportions, indicating no interaction between pesticides. Residues of 2,4-D might also impair other crops' growth, compromise productivity, and limit phytotechnologies for soil recovery.

Effects of exposure to sediment-associated fipronil on cardiac function of Neotropical armored catfish Hypostomus regani.

Fipronil is widely used as a broad-spectrum insecticide in agriculture, urban environments, and veterinary medicine. Fipronil can enter aquatic ecosystems and spread to sediment and organic matter, representing a risk to non-target species. This study aimed to evaluate the effects of short-term (96 h) exposure to a low and realistic concentration of sediment-associated fipronil (4.2 µg.kg-1 of Regent® 800 WG) on myocardial contractility of armored catfish Hypostomus regain, a benthic fish species. Fipronil exposure induced increased inotropism and acceleration of contractile kinetics, although no alterations in the relative ventricular mass were observed. This better cardiac function was associated with an elevated expression and/or function of the Na+/Ca2+ exchanger and its marked contribution to contraction and relaxation, probably due to a stress-induced adrenergic stimulation. Ventricle strips of exposed fish also exhibited a faster relaxation and a higher cardiac pumping capacity, indicating that armored catfish were able to perform cardiac adjustments to face the exposure. However, a high energetic cost to maintain an increased cardiac performance can make fish more susceptible to other stressors, impairing developmental processes and/or survival. These findings highlight the need for regulations of emerging contaminants, such as fipronil, to ensure adequate protection of the aquatic system.

Tebufenpyrad induces cell cycle arrest and disruption of calcium homeostasis in porcine trophectoderm and luminal epithelial cells.

Tebufenpyrad is classified as a pyrazole acaricide and insecticide. It is widely used for several crops, especially in greenhouses, in several countries. While its unfavorable effects on non-target organisms have already been established, relatively little is known about its reproductive toxicity. Therefore, we demonstrated the biochemical effects of tebufenpyrad using porcine trophectoderm and porcine luminal epithelial cells, which are involved in implantation. We found that tebufenpyrad had antiproliferative effects and reduced cell viability. Tebufenpyrad also triggered apoptosis and excessive reactive oxygen species production. Furthermore, it induced cell cycle arrest in the G1 phase and disrupted calcium homeostasis in the cytosol and mitochondria. MAPK signaling pathways and the crosstalk among them were altered following tebufenpyrad treatment. In addition, the migration ability of cells was reduced after treatment with tebufenpyrad. Lastly, tebufenpyrad influenced the expression of genes related to pregnancy. Collectively, these results reveal the mechanism of the biochemical and physiological effects of tebufenpyrad to both trophectoderm and uterine cells and suggest that tebufenpyrad reduces the potential of successful implantation.

Insights into the toxicity and biodegradation of fipronil in contaminated environment.

Fipronil is a phenylpyrazole insecticide used in various agricultural, horticulture, and veterinary practices. Besides its wide range of applications, it also causes severe health hazards to the non-targeted organisms especially in developing countries. Fipronil showed hepatotoxic, nephrotoxic, neurotoxic, and altered reproductive development and endocrine system in humans and animals. Several methods have been already introduced for the removal of toxic fipronil including physicochemical and by the implementation of microorganisms. The microbial methods of fipronil degradation are the most promising and environmentally sustainable. The remediation of fipronil from the environment is an emerging task due to its enhanced residual concentration. Herein, we discuss the bioremediation potential of microbial strains in contaminated soil and water. It is shown that fipronil can be remediated from the environment using combined ecotechnologies. This review discusses the toxicity, different physico-chemical and biological methods, and sustainable developments in fipronil-contaminated agriculture and aquatic environments.

Exposure to pyrazosulfuron-ethyl induces immunotoxicity and behavioral abnormalities in zebrafish embryos.

Pyrazosulfuron-ethyl is one of the most widely used herbicides in agriculture and can be widely detected in aquatic ecosystems. However, its biosafety, including its potential toxic effects on aquatic organisms and its mechanism, is still poorly understood. As an ideal vertebrate model, zebrafish, the effect of pyrazosulfuron-ethyl on early embryonic development and immunotoxicity of zebrafish can be well evaluated. From 10 to 72 h post fertilization (hpf), zebrafish embryos were exposed to 1, 5, and 9 mg/L pyrazosulfuron-ethyl which led in a substantial reduction in survival, total length, and heart rate, as well as a range of behavioral impairments. In zebrafish larvae, the number of neutrophils and macrophages was considerably decreased and oxidative stress levels increased in a dose-dependent way after pyrazosulfuron-ethyl exposure. And the expression of immune-related genes, such as TLR-4, MyD88 and IL-1ß, were downregulated by pyrazosulfuron-ethyl exposure. Moreover, pyrazosulfuron-ethyl exposure also inhibited motor behavior. Notch signaling was upregulated after exposure to pyrazosulfuron-ethyl, while inhibition of Notch signaling pathway could rescue immunotoxicity. Therefore, our findings suggest that pyrazosulfuron-ethyl has the potential to induce immunotoxicity and neurobehavioral changes in zebrafish larvae.

Structure-Based Bioisosterism Design, Synthesis, Biological Activity and Toxicity of 1,2,4-Oxadiazole Substituted Benzamides Analogues Containing Pyrazole Rings.

In order to discover pesticidal lead compounds with high activity and low toxicity, a series of novel benzamides substituted with pyrazole-linked 1,2,4-oxadiazole were designed via bioisosterism. The chemical structures of the target compounds were confirmed via 1H NMR, 13C NMR and HRMS analysis. The preliminary bioassay showed that most compounds exhibited good lethal activities against Mythimna separate, Helicoverpa armigera, Ostrinia nubilalis and Spodoptera frugiperda at 500 mg/L. Particularly in the case of Mythimna separate, compound 14q (70%) exhibited obvious insecticidal activity. In addition, compound 14h demonstrated good fungicidal activity against Pyricularia oryae with an inhibition rate of 77.8%, and compounds 14e, 14k, 14n and 14r also showed certain antifungal activities (55.6-66.7%). The zebrafish toxicity test showed that the LC50 of compound 14h was 14.01 mg/L, which indicated that it may be used as a potential leading compound for further structural optimization.

Sensitivity of the stripe-faced dunnart, Sminthopsis macroura (Gould 1845), to the insecticide, fipronil; implications for pesticide risk assessments in Australia.

A lack of toxicity data quantifying responses of Australian native mammals to agricultural pesticides prompted an investigation into the sensitivity of the stripe-faced dunnart, Sminthopsis macroura (Gould 1845) to the insecticide, fipronil (5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinyl pyrazole, CAS No. 120068-37-3). Using the Up-And-Down method for determining acute oral toxicity in mammals (OECD) median lethal dose estimates of 990 mg kg-1 (95% confidence interval (CI) = 580.7-4770.0 mg kg-1) and 270.4 mg kg-1 (95% CI = 0.0->20,000.0 mg kg-1) were resolved for male and female S. macroura, respectively. The difference between median lethal dose estimates for males and females may have been influenced by the older ages of two female dunnarts. Consequently, further modelling of female responses to fipronil doses used the following assumptions: (a) death at 2000 mg kg-1, (b) survival at 500 mg kg-1 and (c) a differential response (both survival and death) at 990 mg kg-1. This modelling revealed median lethal dose estimates for female S. macroura of 669.1 mg kg-1 (95% CI = 550-990 mg kg-1; assuming death at 990 mg kg-1) and 990 mg kg-1 (95% CI = 544.7-1470 mg kg-1; assuming survival at 990 mg kg-1). These median lethal dose estimates are 3-10-fold higher than available LD50 values of 94 mg kg-1 for a similarly sized eutherian mammal, Mus musculus (L. 1758) and 97 mg kg-1 for Rattus norvegicus (Birkenhout 1769). Implications for pesticide risk assessments in Australia are discussed.

Lung-restricted ALK5 inhibition avoids systemic toxicities associated with TGFß pathway inhibition.

Systemic therapies targeting transforming growth factor beta (TGFß) or TGFßR1 kinase (ALK5) have been plagued by toxicities including cardiac valvulopathy and bone physeal dysplasia in animals, posing a significant challenge for clinical development in pulmonary indications. The current work aims to demonstrate that systemic ALK5-associated toxicities can be mitigated through localized lung delivery. Lung-selective (THRX-144644) and systemically bioavailable (galunisertib) ALK5 inhibitors were compared to determine whether lung selectivity is sufficient to maintain local tissue concentrations while mitigating systemic exposure and consequent pathway-related findings. Both molecules demonstrated potent ALK5 activity in rat precision cut lung slices (PCLS; p-SMAD3 half-maximal inhibitory concentration [IC50], 141 nM and 1070 nM for THRX-144644 and galunisertib, respectively). In 14-day repeat-dose studies in rats, dose-related cardiac valvulopathy was recapitulated with oral galunisertib at doses ≥150 mg/kg/day. In contrast, inhaled nebulized THRX-144644 did not cause similar systemic findings up to the maximally tolerated doses in rats or dogs (10 and 1.5 mg/kg/day, respectively). THRX-144644 lung-to-plasma ratios ranged from 100- to 1200-fold in rats and dogs across dose levels. THRX-144644 lung trough (24 h) concentrations in rats and dogs ranged from 3- to 17-fold above the PCLS IC50 across tolerated doses. At a dose level exceeding tolerability (60 mg/kg/day; 76-fold above PCLS IC50) minimal heart and bone changes were observed when systemic drug concentrations reached pharmacologic levels. In conclusion, the current preclinical work demonstrates that localized pulmonary delivery of an ALK5 inhibitor leads to favorable TGFß pathway pharmacodynamic inhibition in lung while minimizing key systemic toxicities.

Identification of a Potent Cytotoxic Pyrazole with Anti-Breast Cancer Activity That Alters Multiple Pathways.

In this study, we identified a novel pyrazole-based derivative (P3C) that displayed potent cytotoxicity against 27 human cancer cell lines derived from different tissue origins with 50% cytotoxic concentrations (CC50) in the low micromolar and nanomolar range, particularly in two triple-negative breast cancer (TNBC) cell lines (from 0.25 to 0.49 µM). In vitro assays revealed that P3C induces reactive oxygen species (ROS) accumulation leading to mitochondrial depolarization and caspase-3/7 and -8 activation, suggesting the participation of both the intrinsic and extrinsic apoptotic pathways. P3C caused microtubule disruption, phosphatidylserine externalization, PARP cleavage, DNA fragmentation, and cell cycle arrest on TNBC cells. In addition, P3C triggered dephosphorylation of CREB, p38, ERK, STAT3, and Fyn, and hyperphosphorylation of JNK and NF-kB in TNBC cells, indicating the inactivation of both p38MAPK/STAT3 and ERK1/2/CREB signaling pathways. In support of our in vitro assays, transcriptome analyses of two distinct TNBC cell lines (MDA-MB-231 and MDA-MB-468 cells) treated with P3C revealed 28 genes similarly affected by the treatment implicated in apoptosis, oxidative stress, protein kinase modulation, and microtubule stability.

Cyantraniliprole impairs reproductive parameters by inducing oxidative stress in adult female wistar rats.

Cyantraniliprole is a synthetic insecticide used to control pests of up to 23 different types of crops. It is able to modulate ryanodine-like calcium channels, which are widely found in the organism of insects and mammals. The objective of this research was to verify the possible reproductive effects of adult female Wistar rats exposure to cyantraniliprole. Animals (67 days old) were exposed to the chemical at doses of 10 or 150 mg/kg/day, orally, for 28 consecutive days (control animals received only the vehicle). Vaginal secretions were collected during the exposure period to assess the regularity of the estrous cycle; the liver, kidneys, pituitary gland, adrenal gland, uterus, and ovaries were collected and weighed; reproductive organs were assessed for histopathological evaluation and for biochemical markers of oxidative stress and progesterone plasma level was measured. Both doses caused negative changes in the morphology and redox system of the uterus and ovaries. Animals exposed to 10 mg/kg also exhibited higher level of plasma progesterone, elevated levels of lipid peroxidation in reproductive organs, increased superoxide dismutase activity in the uterus and glutathione peroxidase activity on the ovary, while the 150 mg/kg group exhibited an increment in estrous cycle length and diminished uterine glandular epithelium. Based on these results, we conclude that cyantraniliprole may have acted as an endocrine disruptor, and its effects are mediated by oxidative stress.

Human Exposure of Fipronil Insecticide and the Associated Health Risk.

Fipronil, as an emerging phenylpyrazole insecticide, is ubiquitous in the environment and food due to its broad spectrum and persistent characteristics, but the research on pathways of human exposure to fipronil and the associated health risk is relatively unclear. In this regard, we summarize potential human exposures to fipronil through ingestion and inhalation, as well as results of human biomonitoring studies. This scientific information will contribute to future assessment of fipronil exposure and subsequent characterization of human health risks. Additionally, this Perspective highlights the lack of epidemiological studies and total diet studies for the general population on fipronil.

Oxidative stress, apoptosis and histopathological alterations in brain stem and diencephalon induced by subacute exposure to fipronil in albino rats.

Fipronil (FIP) is a highly effective insecticide that has been used in agriculture and veterinary medicine. Its neurotoxic effect to insects and to non-target organisms, after nonintentional exposure, was reported. Many studies were conducted to evaluate FIP effects on mammals. However, slight is known about its effect on the brain stem and diencephalon. The current study was designed to investigate the ability of FIP to induce oxidative stress as a molecular mechanism of FIP neurotoxicity that resulted in apoptosis and neural tissue reactivity in these regions. Ten adult male rats received 10 mg/kg of FIP technical grade by oral gavage, daily for 45 days. Brain stem and diencephalon were processed to examine oxidative stress-induced macromolecular alteration (MDA, PCC and DNA fragmentation). Also, the histopathological assessment and immunoreactivity for caspase-3 (active form), iNOS and GFAP were performed on the thalamus, hypothalamus and medulla oblongata. Our results revealed that FIP significantly raised MDA, PCC and DNA fragmentation (p ≤ 0.05). In addition, significantly increased immunoreactivity to GFAP, iNOS and caspase-3 (active form) in the FIP-treated group was noticed (p ≤ 0.05). Moreover, alterations in the histoarchitecture of the neural tissue of these regions were observed. We conclude that FIP can induce oxidative stress, leading to apoptosis and tissue reaction in brain stem and diencephalon.

SDHI Fungicide Toxicity and Associated Adverse Outcome Pathways: What Can Zebrafish Tell Us?

Succinate dehydrogenase inhibitor (SDHI) fungicides are increasingly used in agriculture to combat molds and fungi, two major threats to both food supply and public health. However, the essential requirement for the succinate dehydrogenase (SDH) complex-the molecular target of SDHIs-in energy metabolism for almost all extant eukaryotes and the lack of species specificity of these fungicides raise concerns about their toxicity toward off-target organisms and, more generally, toward the environment. Herein we review the current knowledge on the toxicity toward zebrafish (Brachydanio rerio) of nine commonly used SDHI fungicides: bixafen, boscalid, fluxapyroxad, flutolanil, isoflucypram, isopyrazam, penthiopyrad, sedaxane, and thifluzamide. The results indicate that these SDHIs cause multiple adverse effects in embryos, larvae/juveniles, and/or adults, sometimes at developmentally relevant concentrations. Adverse effects include developmental toxicity, cardiovascular abnormalities, liver and kidney damage, oxidative stress, energy deficits, changes in metabolism, microcephaly, axon growth defects, apoptosis, and transcriptome changes, suggesting that glycometabolism deficit, oxidative stress, and apoptosis are critical in the toxicity of most of these SDHIs. However, other adverse outcome pathways, possibly involving unsuspected molecular targets, are also suggested. Lastly, we note that because of their recent arrival on the market, the number of studies addressing the toxicity of these compounds is still scant, emphasizing the need to further investigate the toxicity of all SDHIs currently used and to identify their adverse effects and associated modes of action, both alone and in combination with other pesticides.