Developmental neurotoxicity of environmentally relevant pharmaceuticals and mixtures thereof in a zebrafish embryo behavioural test

Humans are exposed daily to complex mixtures of chemical substances via food intake, inhalation, and dermal contact. Developmental neurotoxicity is an understudied area and entails one of the most complex areas in toxicology. Animal studies for developmental neurotoxicity (DNT) are hardly performed in the context of regular hazard studies, as they are costly and time consuming and provide only limited information as to human relevance. There is a need for a combination of in vitro and in silico tests for the assessment of chemically induced DNT in humans. The zebrafish (Danio rerio) embryo (ZFE) provides a powerful model to study DNT because it shows fast neurodevelopment with a large resemblance to the higher vertebrate, including the human system. One of the suitable readouts for DNT testing in the zebrafish is neurobehaviour (stimulus-provoked locomotion) since this provides integrated information on the functionality and status of the entire nervous system of the embryo. In the current study, environmentally relevant pharmaceuticals and their mixtures were investigated using the zebrafish light-dark transition test. Zebrafish embryos were exposed to three neuroactive compounds of concern, carbamazepine (CBZ), fluoxetine (FLX), and venlafaxine (VNX), as well as their main metabolites, carbamazepine 10,11-epoxide (CBZ 10,11E), norfluoxetine (norFLX), and desvenlafaxine (desVNX). All the studied compounds, except CBZ 10,11E, dose-dependently inhibited zebrafish locomotor activity, providing a distinct behavioural phenotype. Mixture experiments with these pharmaceuticals identified that dose addition was confirmed for all the studied binary mixtures (CBZ-FLX, CBZ-VNX, and VNX-FLX), thereby supporting the zebrafish embryo as a model for studying the cumulative effect of chemical mixtures in DNT. This study shows that pharmaceuticals and a mixture thereof affect locomotor activity in zebrafish. The test is directly applicable in environmental risk assessment; however, further studies are required to assess the relevance of these findings for developmental neurotoxicity in humans

Results of the Cooperative Uniform Soybean Tests, 1947 Part I. North Central States

United States Department of Agriculture, Agricultural Research Administration; Bureau of Plant Industry, Soils, and Agricultural Engineering, Division of Forage Crops and Diseases Cooperating with State Agricultural Experiment Station

Results of the Cooperative Uniform Soybean Tests, 1946 Part I. North Central States

United States Department of Agriculture, Agricultural Research Administration; Bureau of Plant Industry, Soils, and Agricultural Engineering, Division of Forage Crops and Diseases Cooperating with State Agricultural Experiment Station

Results of the Cooperative Uniform Soybean Tests Part I. North Central States 1949

United States Department of Agriculture, Agricultural Research Administration; Bureau of Plant Industry, Soils, and Agricultural Engineering, Division of Forage Crops and Diseases Cooperating with State Agricultural Experiment Station

Results of the Cooperative Uniform Soybean Tests, 1945. Part I. North Central States

United States Department of Agriculture Agricultural Research Administration Bureau of Plant Industry, Soils, and Agricultural Engineering, Division of Forage Crops and Diseases Cooperating with State Agricultural Experiment Station

Local and systemic immunomodulatory mechanisms triggered by Human Papillomavirus transformed cells: a potential role for G-CSF and neutrophils

Cervical cancer is the last stage of a series of molecular and cellular alterations initiated with Human Papillomavirus (HPV) infection. The process involves immune responses and evasion mechanisms, which culminates with tolerance toward tumor antigens. Our objective was to understand local and systemic changes in the interactions between HPV associated cervical lesions and the immune system as lesions progress to cancer. Locally, we observed higher cervical leukocyte infiltrate, reflected by the increase in the frequency of T lymphocytes, neutrophils and M2 macrophages, in cancer patients. We observed a strong negative correlation between the frequency of neutrophils and T cells in precursor and cancer samples, but not cervicitis. In 3D tumor cell cultures, neutrophils inhibited T cell activity, displayed longer viability and longer CD16 expression half-life than neat neutrophil cultures. Systemically, we observed higher plasma G-CSF concentration, higher frequency of immature low density neutrophils, and tolerogenic monocyte derived dendritic cells, MoDCs, also in cancer patients. Interestingly, there was a negative correlation between T cell activation by MoDCs and G-CSF concentration in the plasma. Our results indicate that neutrophils and G-CSF may be part of the immune escape mechanisms triggered by cervical cancer cells, locally and systemically, respectively.Tis study was supported by Sao Paulo Research foundation: grants 2008/57889-1, 2010/20010-4, 2014/19326-6, by the Brazilian National Counsel of Technological and Scientifc Development: grant 573799/2008-3. KLFA and RAMR had PhD fellowships by Sao Paulo Research Foundation, CRSF has a Coordination for the Improvement of Higher Education Personnel PhD fellowship. We thank the Pathology Department of the School of Medicine, coordinated by Prof. Venâncio Avancini Ferreira Alves, Universidade de São Paulo for the slides containing histological samples from the biopsies used in this study. We thank Sandra Alexandre Alves for her technical support.info:eu-repo/semantics/publishedVersio

Copper treatment during storage reduces <i>Phytophthora</i> and <i>Halophytophthora</i> infection of <i>Zostera marina</i> seeds used for restoration

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