peer reviewed | Metconazole (MEZ), a chiral triazole fungicide, produces enantioselective adverse effects in non-target organisms. Among MEZ's isomers, cis-MEZ displays robust antimicrobial properties. Evaluating MEZ and cis-MEZ's toxicity may mitigate fungicide usage and safeguard non-target organisms. Our study evaluated the toxicity of MEZ and its cis-isomers at concentrations of 0.02, 0.2, 2, and 4 mg L−1. We report stereoselectivity and severe cardiovascular defects in zebrafish, including pericardial oedema, decreased heart rate, increased sinus venous and bulbous arteries distances, intersegmental vessel defects, and altered cardiovascular development genes (hand2, gata4, nkx2.5, tbx5, vmhc, amhc, dll4, vegfaa, and vegfc). Further, MEZ significantly increased oxidative stress and apoptosis in zebrafish, primarily in the cardiac region. Isoquercetin, an antioxidant found in plants, partially mitigates MEZ-induced cardiac defects. Furthermore, MEZ upregulated the Wnt/β-catenin pathway genes (wnt3, β-catenin, axin2, and gsk-3β) and β-catenin protein expression. Inhibitor of Wnt Response-1 (IWR-1) rescued MEZ-induced cardiotoxicity. Our findings highlight oxidative stress, altered cardiovascular development genes, and upregulated Wnt/β-catenin signaling as contributors to cardiovascular toxicity in response to MEZ and cis-MEZ treatments. Importantly, 1R,5S-MEZ exhibited greater cardiotoxicity than 1S,5R-MEZ. Thus, our study provides a comprehensive understanding of cis-MEZ's cardiovascular toxicity in aquatic life. © 2024 Elsevier Ltd

An increasing number of epidemiological studies have examined the association between ultrafine particles (UFP) and imbalanced autonomic control of the heart, a potential mechanism linking particulate matter air pollution to cardiovascular disease. This study systematically reviews and meta-analyzes studies on short-term effects of UFP on autonomic function, as assessed by heart rate variability (HRV). We searched PubMed and Web of Science for articles published until June 30, 2022. We extracted quantitative measures of UFP effects on HRV with a maximum lag of 15 days from single-pollutant models. We assessed the risk of bias in the included studies regarding confounding, selection bias, exposure assessment, outcome measurement, missing data, and selective reporting. Random-effects models were applied to synthesize effect estimates on HRV of various time courses. Twelve studies with altogether 1,337 subjects were included in the meta-analysis. For an increase of 10,000 particles/cm³ in UFP assessed by central outdoor measurements, our meta-analysis showed immediate decreases in the standard deviation of the normal-to-normal intervals (SDNN) by 4.0% [95% confidence interval (CI): 7.1%, −0.9%] and root mean square of successive R-R interval differences (RMSSD) by 4.7% (95% CI: 9.1%, 0.0%) within 6 h after exposure. The immediate decreases in SDNN and RMSSD associated with UFP assessed by personal measurements were smaller and borderline significant. Elevated UFP were also associated with decreases in SDNN, low-frequency power, and the ratio of low-frequency to high-frequency power when pooling estimates of lags across hours to days. We did not find associations between HRV and concurrent-day UFP exposure (daily average of at least 18 h) or exposure at lags ≥ one day. Our study indicates that short-term exposure to ambient UFP is associated with decreased HRV, predominantly as an immediate response within hours. This finding highlights that UFP may contribute to the onset of cardiovascular events through autonomic dysregulation.

Azoxystrobin (AZ) and pyraclostrobin (PY) are strobilurin fungicides that inhibit fungal mitochondrial respiration. In this study, a representative model, zebrafish (Danio rerio), was used as a test species for acute and developmental toxicity. Survival and malformation rates were observed only PY-treated embryos, with an LC₅₀ value of 77.75 ppb accompanied by a dramatic decrease in hatching rate, while AZ did not show great mortality. Morphological changes were observed in PY-treated embryos with the occurrence of pericadial edema at 25 ppb. A delay in growth was observed after treatment with pyraclostrobin at 50 ppb. Use of genetically engineered Tg(cmlc:EGFP) allowed fluorescence observation during heart development. PY interfered with normal heart development via upregulation of the nppa gene responsible for the expression of natriuretic peptides. Heart function was dramatically reduced as indicated by reduced heart rates. Increased expression of the nppa gene was also seen in AZ-treated embryos. The expression level of cyp24a1 was also up-regulated, while ugt1a1 and sult1st6 were down-regulated after treatment of zebrafish embryos with AZ or PY. Overall, strobilurin fungicides might inhibit normal heart formation and function within the range of concentrations tested.

Fluoxetine is frequently detected in aquatic environment, and chronic FLX exposure exhibits adverse effects on aquatic communities. Its chirality makes the adverse effects more complicated. This study aimed at the enantioselective cardiotoxicity in developmental zebrafish induced by racemic (rac-)/S-/R-fluoxetine. The accumulation profiles demonstrated that biotransformation of fluoxetine to norfluoxetine occurred during rac-fluoxetine exposure, with a higher enrichment of S-norfluoxetine than R-norfluoxetine. Heart malformations including pericardial edema, circulation abnormalities, and thrombosis were observed, and enantioselective changes also occurred. According to H&E staining and Masson’s trichrome staining, the loose severity of cardiac structure and cardiac fibrosis in rac-norfluoxetine treated group was worse than that in fluoxetine treated groups. Results of toxicity-associated parameters in our homochiral enantiomers’ exposure also indicated that the toxicity induced by S-fluoxetine was more severe than R-fluoxetine. Enantioselective arrhythmia in developmental zebrafish after chiral fluoxetine exposure could be caused by myocardial fibrosis, abnormal developmental processes, and the biotransformation of fluoxetine to norfluoxetine could make that worse. Our findings can be used to assess the environmental risk of the two enantiomers of fluoxetine that induce cardiotoxicity in aquatic organisms.

Bifenazate is a novel acaricide for selective foliar spraying and is widely used to control mites in agricultural production. However, its toxicity to aquatic organisms is unknown. Here, a zebrafish model was used to study bifenazate toxicity to aquatic organisms. Exposure to bifenazate was found to cause severe cardiotoxicity in zebrafish embryos, along with disorders in the gene expression related to heart development. Bifenazate also caused oxidative stress. Cardiotoxicity caused by bifenazate was partially rescued by astaxanthin (an antioxidant), accompanied by cardiac genes and oxidative stress-related indicators becoming normalized. Our results showed that exposure to bifenazate can significantly change the ATPase activity and gene expression levels of the calcium signaling pathway. These led to heart failure, in which the blood accumulated outside the heart without entering it, eventually leading to death. The results indicated that bifenazate exposure caused cardiotoxicity in zebrafish embryos through the induction of oxidative stress and inhibition of the calcium signaling pathway.

Diesel exhaust (DE) had been associated with cardiopulmonary toxicity and developmental toxicity. However, neonatal very early-in-life exposure had not been extensively studied previously. To investigate the potential effects of neonatal very early-in-life exposure to DE, a brand-new chicken embryo in ovo exposure model had been established, with which the cardiopulmonary effects of DE exposure via air cell infusion at embryonic day 18/19 (ED18/19) were assessed in hatchling chicks post-hatch 0-, 1-, or 2-weeks. Heart rates were assessed with electrocardiography. Cardiac and pulmonary morphologies were investigated with histopathological methods. Cardiopulmonary effects were explored with immunohistochemistry for alpha smooth muscle actin (alpha-SMA). In further investigations, the expression levels of phosphorylated AhR, serum levels of TGF-β1, phosphorylated SMAD2/3 and phosphorylated p38MAPK were assessed in the lung tissues. Significantly elevated heart rates, increased right ventricular wall thickness and cardiac collagen deposition were observed in the hearts of exposed hatchling chicks. Significantly increased collagen deposition as well as increased vascular alpha-SMA layer thickness/decreased cavity area were observed in exposed animal lungs. These effects persisted up to two weeks post-hatch. Mechanistic studies revealed elevated phosphorylated AhR expression levels in 0-week and 1-week chicken lungs, while phosphorylated SMAD2/3 levels significantly increased in 0-week chicken lungs but decreased in 2-week chicken lungs following DE exposure. Phosphorylation of p38MAPK did not remarkably increase until 2-week post-hatch. In summary, the novel chicken neonatal very early-in-life exposure model effectively exposed the chicken embryos during the neonatal initial breathing, resulting in cardiopulmonary toxicity, which is associated with AHR, TGF-β1 and MAPK signaling.

The phenylpyrazole insecticide, fipronil, isused for the eradication of insects in agriculture, which also exposes various non-target groups such as birds and animals. Our aim was to assess the cardiac and pulmonary consequences of sub-acute administration of fipronil (¹∕₅ LD₅₀; 2.26 mg/kg) in the Japanese quail for fifteen days and to determine the tissue recovery over a period of 60 days. Fipronil exposure led to a significant decrease in the body weight of the treated birds. Its exposure also induced cardiac and pulmonary damage of varying degrees. Fipronil increased the lipid peroxide (LPO) and nitric oxide (NO) contents as well as indices of tissue injury in the serum of exposed birds. Furthermore, it decreased the antioxidant indices in both the organs. Most of these changes gradually reversed and the histological changes, particularly of the heart, reversed completely by day-60 of recovery. Furthermore, alterations in the mRNA gene expressions of Nuclear factor kappa B (NF-κB), Interleukin 6 (IL-6), and Tumor necrosis factor-alpha (TNF-α) were monitored by quantitative polymerase chain reaction (RT-PCR). In both the tissues, a significant up-regulation of the transcripts was recorded after fipronil administration, which was reversed during the recovery period in the heart tissue except for TNF-α, while the transcripts in the lung tissue declined non-significantly. This study showed that the exposure of Japanese quail to fipronil has a profound negative impact on heart and lung including oxidative injury and tissue inflammation. Fipronil can induce the activity of NF-κB inflammatory -signaling pathway that play a role in the associated tissue inflammation. Although most of the cardiac changes could be reversed after a recovery period of sixty days, the pulmonary changes did not reverse much.

Drugs are excreted from the human body as both original substances and as metabolites and enter aquatic environment through waste water. The aim of this study was to widen the current knowledge considering the effects of waterborne antidepressants with different modes of action—amitriptyline, venlafaxine, sertraline—on embryos of non-target aquatic biota—fish (represented by Danio rerio) and amphibians (represented by Xenopus tropicalis). The tested concentrations were 0.3; 3; 30; 300 and 3000 μg/L in case of amitriptyline and venlafaxine and 0.1; 1; 10; 100 and 1000 μg/L for sertraline. Test on zebrafish embryos was carried out until 144 h post fertilization, while test on Xenopus embryos was terminated after 48 h. Lethal and sublethal effects as well as swimming alterations were observed at higher tested concentrations that are not present in the environment. In contrast, mRNA expression of genes related to heart, eye, brain and bone development (nkx2.5, otx 2, bmp4 and pax 6) seems to be impacted also at environmentally relevant concentrations. In a wider context, this study reveals several indications on the ability of antidepressants to affect non target animals occupying environments which may be contaminated by such compounds.

There is a growing conservation concern about the possible consequences of environmental contamination in the health of bat communities. Most studies on the effects of contaminants in bats have been focused on organic contaminants, and the consequences of bat exposure to metals and metalloids remain largely unknown. The aim of this study was to evaluate the suitability of external biological matrices (fur and wing membrane) for the assessment of exposure and bioaccumulation of metals in bats. The concentration of arsenic, cadmium, cobalt, chromium, copper, manganese, nickel, lead, selenium and zinc was measured in internal organs (liver, heart, brain), internal (bone) and external tissues (wing membrane, fur) collected from bat carcasses of four species (Hypsugo savii, Nyctalus leisleri, Pipistrellus pipistrellus, Pipistrellus pygmaeus) obtained in windfarm mortality searches. With the exception of zinc (P = 0.223), the results showed significant differences between the concentrations of metals in the analyzed tissues for all metals (P < 0.05). Significant differences were also found between organs/tissues (P < 0.001), metals (P < 0.001) and a significant interaction between organs/tissues and metals was found (P < 0.001). Despite these results, the patterns in terms of metal accumulation were similar for all samples. Depending on the metal, the organ/tissue that showed the highest concentrations varied, but fur and wing had the highest concentrations for most metals. The variability obtained in terms of metal concentrations in different tissues highlights the need to define standardized methods capable of being applied in monitoring bat populations worldwide. The results indicate that wing membrane and fur, biological matrices that may be collected from living bats, yield reliable results and may be useful for studies on bats ecotoxicology, coupled to a standardized protocol for large-scale investigation of metal accumulation.

Silver nanoparticles (nAg), due to their biocidal properties, are common in medical applications and are used in more consumer products than any other engineered nanomaterial. This growing abundance, combined with their ability to translocate across the epithelium and bioaccumulate, suggests that internalized nAg may present a risk of toxicity to many organisms in the future. However, little experimentation has been devoted to cardiac responses to acute nAg exposure, even though nAg is known to disrupt ion channels even when ionic Ag+ does not. In this study, we examined the cardiac response to nAg exposure relative to a sham and an ionic AgNO3 control across cardiomyocyte survival and homeostasis, ventricular contractility, and intrinsic pacing rates of whole hearts. Our results suggest that nAg, but not Ag+ alone, inhibits force production by the myocardium, that Ag in any form disrupts normal pacing of cardiac contractions, and that these responses are likely not due to cytotoxicity. This evidence of nanoparticle-specific effects on physiology should encourage further research into nAg cardiotoxicity and other potential sublethal effects.