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Hazel leaf, a by-product of hazelnuts, is commonly used in traditional folk medicine in Portugal, Sweden, Iran and other regions for properties such as vascular protection, anti-bleeding, anti-edema, anti-infection, and pain relief. Based on our previous studies, the polyphenol extract from hazel leaf was identified and quantified via HPLC fingerprint. The contents of nine compounds including kaempferol, chlorogenic acid, myricetin, caffeic acid, p-coumaric acid, resveratrol, luteolin, gallic acid and ellagic acid in hazel leaf polyphenol extract (ZP) were preliminary calculated, among which kaempferol was the highest with 221.99 mg/g, followed by chlorogenic acid with 8.23 mg/g. The inhibition of ZP on α-glucosidase and xanthine oxidase activities was determined via the chemical method, and the inhibition on xanthine oxidase was better. Then, the effect of ZP on hyperuricemia zebrafish was investigated. It was found that ZP obviously reduced the levels of uric acid, xanthine oxidase, urea nitrogen and creatinine, and up-regulated the expression ofOAT1 and HPRT genes in hyperuricemia zebrafish. Finally, the targeted network pharmacological analysis and molecular docking of nine polyphenol compounds were performed to search for relevant mechanisms for alleviating hyperuricemia. These results will provide a valuable basis for the development and application of hazel leaf polyphenols as functional ingredients. [ABSTRACT FROM AUTHOR]

Abstract: Qualitative and quantitative approaches were tested to assess zebrafish liver effects after sub-acute exposures of certain pharmaceuticals. Carbamazepine, fenofibric acid, propranolol, sulfamethoxazole and trimethoprim were tested individually and in mixtures, including low environmental levels. Overall, data showed sex specific reactions in liver, with the major alterations being observed in males. Males treated with propranolol, fenofibric acid and with mixtures, showed an increase of vitellogenin immunostaining, compared with the control. Males also evidenced a tendency for an increased hepatic mass, after individual and mixture exposures. The volume-weighted nuclear volume of hepatocytes was high in males after exposures to either mixture, which together with the greater cytoplasmic eosinophilia and changes in cytochrome P450 1A immunoreactivity, point to an increase in metabolic/detoxification activity. These investigations revealed distinct impacts depending on the exposure type, and strengthened the importance of studying non-steroidal compounds in mixtures, including environmental levels and both sexes. [Copyright &y& Elsevier]

In natural environments fish are exposed to endocrine disrupting compounds (EDCs) present at low concentrations and with different modes of actions. Here, adult zebrafish of both sexes were exposed for 21 days to an estrogenic mixture (Mix) of eleven EDCs previously quantified in Douro River estuary (Portugal) and to 100 ng/L 17α-ethinylestradiol (EE2) as positive control. Vitellogenin mRNA and HSI in males confirmed both exposure regimes as physiologically active. Potential candidates for estrogenic disturbance of steroidogenesis were identified (StAR, 17β-HSD1, cyp19a1), but Mix only affected cyp19a1 in females. Significant differences in the response of FSHβ, cypa19a2, 20β-HSD were observed between EE2 and Mix. Mtf-1 and tfap2c transcription factor binding sites were discovered in the putative promoter regions and corresponding transcription factors were found to be differentially expressed in response to Mix and EE2. The results suggest that “non-classical effects” of estrogenic EDC in fish are mediated via transcription factors. [Copyright &y& Elsevier]

Abstract: Concerns associated with pharmaceuticals in aquatic systems demand the establishment of links between xenobiotics and their respective concentrations and impacts on aquatic organisms. Herein, effects of non-steroidal pharmaceuticals in the gonadal maturation of zebrafish (Danio rerio) were evaluated by histopathological and stereological analyses after 21 days of exposure. Carbamazepine, fenofibric acid, propranolol, sulfamethoxazole and trimethoprim were selected, considering their detection in the Douro estuary (Portugal). Exposures were performed with single compounds and mixtures, the exposure concentrations including environmental levels. Overall, quantitative analyses showed a decreasing trend for late maturation stages in male and female gametogenesis with parallel increases in immature gametes. In females, and at the highest concentration mixture, a significant switch between the volume densities of late/mature oocytes versus primary oocytes was observed. On the verge of statistical significance, oocyte atresia was higher in both mixtures (5.75±4.02% for MXA and 5.65±5.27% for MXB) versus control (2.21±1.88%), in accordance with the histological identification of large atretic areas in some fish. Unlike females, males showed significant effects with single exposures. Spermatozoa in controls totalled 53.25±7.13% of the testis volume, decreasing with carbamazepine (47.19±5.30%), fenofibric acid (46.36±4.30%), propranolol (37.22±2.38%) and sulfametoxazole (39.37±5.15%). An increase in spermatocyte percentage was noted with propranolol (40.13±7.36%) and sulfametoxazole (40.84±1.66%) versus control (30.93±6.53%). The changes in maturation dynamics did not impact the gonadosomatic index. The results show that pharmaceuticals from various therapeutic classes can disrupt the maturation dynamics of fish ovaries and testes. Further studies are justified to tackle the underlying mechanisms and to gauge the full extent of effects/risks. [Copyright &y& Elsevier]

Abstract: Fish embryos are a particularly vulnerable stage of development, so they represent optimal targets for screening toxicological effects of waterborne xenobiotics. Herein, the toxicity potential of two mixtures of pharmaceuticals was evaluated using a zebrafish embryo test. One of the mixtures corresponds to an environmentally realistic scenario and both have carbamazepine, fenofibric acid, propranolol, trimethoprim and sulfamethoxazole. The results evidenced morphological alterations, such as spinal deformities and yolk-sac oedemas. Moreover, heart rates decreased after both mixture exposures, e.g., at 48hpf, highest mixture versus blank control (47.8±4.9 and 55.8±3.7 beats/30s, respectively). The tail lengths also diminished significantly from 3208±145μm in blank control to 3130±126μm in highest mixture. The toxicological effects were concentration dependent. Mortality, hatching rate and the number of spontaneous movements were not affected. However, the low levels of pharmaceuticals did interfere with the normal development of zebrafish, which indicates risks for wild organisms. [Copyright &y& Elsevier]

• Simvastatin exposure in zebrafish affected behaviour through hiperactivity. • Simvastatin's antioxidant properties caused a decrease in biochemical biomarkers. • This antihyperlipidemic drug did not act as a reproductive disruptor. Due to their wide use, pharmaceuticals can be discarded, metabolized and excreted into the environment, potentially affecting aquatic organisms. Lipid-regulating drugs are among the most prescribed medications around the world, to control human cholesterol levels, in more than 20 million patients. Despite this massive use of lipid-regulating drugs, particularly simvastatin, the role of these drugs is not fully characterized and understood in terms of its potential toxicological effects at the environmental level. This work intended to characterize the toxicity of an acute (120 h post-fertilization) and chronic (60 days) exposure to the antihyperlipidemic drug simvastatin (in concentrations of 92.45, 184.9, 369.8, 739.6 and 1479.2 ng L−1), in the freshwater species zebrafish (Danio rerio). The concentrations hereby mentioned were implemented in both exposures, and were based on levels found in wastewater treatment plant influents (11.7 ± 3.2 μg L−1), effluents (2.65 ± 0.8 μg L−1) and Apies River (1.585 ± 0.3 μg L−1), located in Pretoria, South Africa and, particularly in the maximum levels found in effluents from wastewater treatment plants in Portugal (369.8 ng L−1). The acute effects were analysed focusing on behavioural endpoints (erratic and purposeful swimming), total distance travelled and swimming time), biomarkers of oxidative stress (the activities of the enzymes superoxide dismutase, catalase, glutathione peroxidase), biotransformation (the activity of glutathione S-transferases) and lipid peroxidation (levels of thiobarbituric acid reactive substances). Animals chronically exposed were also histologically analysed for sex determination and gonadal developmental stages identification. In terms of acute exposure, significant alterations were reported in terms of behavioural alterations (hyperactivity), followed by a general reduction in all tested biomarkers. Also, the analysis of chronically exposed fish evidenced no alterations in sex ratio and maturation stages. In addition, the analysis of chronically exposed fish evidenced no alterations in terms of sexual characteristics, suggesting that the chronic exposure of Danio rerio to simvastatin does not alter the sex ratio and maturation stages of individuals. This assumption suggests that simvastatin did not act as an endocrine disruptor. Moreover, the metabolism, neuronal interactions and the antioxidant properties of SIM seem to have modulated the hereby-mentioned results of toxicity. Results from this assay allow inferring that simvastatin can have an ecologically relevant impact in living organisms. [ABSTRACT FROM AUTHOR]