Anti-androgens act jointly in suppressing spiggin concentrations in androgen-primed female three-spined sticklebacks - Prediction of combined effects by concentration addition

This is the post-print version of the final paper published in Aquatic Toxicology. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2013 Elsevier B.V.Increasing attention is being directed at the role played by anti-androgenic chemicals in endocrine disruption of wildlife within the aquatic environment. The co-occurrence of multiple contaminants with anti-androgenic activity highlights a need for the predictive assessment of combined effects, but information about anti-androgen mixture effects on wildlife is lacking. This study evaluated the suitability of the androgenised female stickleback screen (AFSS), in which inhibition of androgen-induced spiggin production provides a quantitative assessment of anti-androgenic activity, for predicting the effect of a four component mixture of anti-androgens. The anti-androgenic activity of four known anti-androgens (vinclozolin, fenitrothion, flutamide, linuron) was evaluated from individual concentration-response data and used to design a mixture containing each chemical at equipotent concentrations. Across a 100-fold concentration range, a concentration addition approach was used to predict the response of fish to the mixture. Two studies were conducted independently at each of two laboratories. By using a novel method to adjust for differences between nominal and measured concentrations, good agreement was obtained between the actual outcome of the mixture exposure and the predicted outcome. This demonstrated for the first time that androgen receptor antagonists act in concert in an additive fashion in fish and that existing mixture methodology is effective in predicting the outcome, based on concentration-response data for individual chemicals. The sensitivity range of the AFSS assay lies within the range of anti-androgenicity reported in rivers across many locations internationally. The approach taken in our study lays the foundations for understanding how androgen receptor antagonists work together in fish and is essential in informing risk assessment methods for complex anti-androgenic mixtures in the aquatic environment.European Commission and Natural Environment Research Council

Plasticity of boldness in rainbow trout, Oncorhynchus mykiss: do hunger and predation influence risk-taking behaviour?

Boldness, a measure of an individual's propensity for taking risks, is an important determinant of fitness but is not necessarily a fixed trait. Dependent upon an individual's state, and given certain contexts or challenges, individuals may be able to alter their inclination to be bold or shy in response. Furthermore, the degree to which individuals can modulate their behaviour has been linked with physiological responses to stress. Here we attempted to determine whether bold and shy rainbow trout, Oncorhynchus mykiss, can exhibit behavioural plasticity in response to changes in state (nutritional availability) and context (predation threat). Individual trout were initially assessed for boldness using a standard novel object paradigm; subsequently, each day for one week fish experienced either predictable, unpredictable, or no simulated predator threat in combination with a high (2% body weight) or low (0.15%) food ration, before being reassessed for boldness. Bold trout were generally more plastic, altering levels of neophobia and activity relevant to the challenge, whereas shy trout were more fixed and remained shy. Increased predation risk generally resulted in an increase in the expression of three candidate genes linked to boldness, appetite regulation and physiological stress responses – ependymin, corticotrophin releasing factor and GABAA – but did not produce a significant increase in plasma cortisol. The results suggest a divergence in the ability of bold and shy trout to alter their behavioural profiles in response to internal and exogenous factors, and have important implications for our understanding of the maintenance of different behavioural phenotypes in natural populations

Myocarditis Concurrent with Sweet Syndrome: A Presentation of Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the most common acute leukemia in American adults and portends a poor prognosis if untreated. Commonly, AML presents with symptoms related to concurrent leukopenia, anemia, or thrombocytopenia; however, due to its ability to affect many organ systems in the body, AML can have a highly varied clinical presentation. One such presentation is myocarditis, which is a rarely reported manifestation of AML. Myocarditis can have a varied clinical picture and often requires exclusion of other causes of cardiac dysfunction. Sweet syndrome, also known as acute febrile neutrophilic dermatosis, is another presentation of AML; however, it is more commonly associated with AML than cardiac involvement. Sweet syndrome can occur in patients with an already established malignancy or can occur de novo in a patient with previously undiagnosed cancer and, interestingly, can also be accompanied by extracutaneous manifestations, one of which is myocarditis. Herein, we report a case of a 45-year-old male with a history of obesity and depression who presented with chest pain, a tender and diffuse rash, and pancytopenia. Heart catheterization performed at outside institution was negative for coronary artery disease. Cardiac MRI images were compatible with myocarditis. Dermal biopsy of the rash was consistent with sweet syndrome. Peripheral blood flow cytometry and bone marrow biopsy confirmed the diagnosis of AML. He was treated with an induction chemotherapy regimen of 7 days of cytarabine and 3 days of daunorubicin with resolution of his chest pain and skin lesions. The patient had persistent leukemia cells on day 14 postinduction bone marrow biopsy and was treated with high-dose cytarabine reinduction treatment. Bone marrow biopsy with count recovery after reinduction therapy revealed complete response (CR)

Electrically Mediated Plasmid DNA Delivery to Hepatocellular Carcinomas in Vivo

Gene therapy by direct delivery of plasmid DNA has several advantages over viral gene transfer, but plasmid delivery is less efficient. In vivo electroporation has been used to enhance delivery of chemotherapeutic agents to tumors in both animal and human studies. Recently, this delivery technique has been extended to large molecules such as plasmid DNA. Here, the successful delivery of plasmids encoding reporter genes to rat hepatocellular carcinomas by in vivo electroporation is demonstrated

Does environmental enrichment promote recovery from stress in rainbow trout?

The EC Directive on animal experimentation suggests that animals should have enrichment to improve welfare yet relatively little research has been conducted on the impact of enrichment in fish. Studies on zebrafish have been contradictory and other fish species may require species specific enrichments. Salmonids are important experimental models given their relevance to aquaculture and natural ecosystems. This study sought to establish how an enriched environment may promote better welfare in rainbow trout (Oncorhynchus mykiss) enhancing their recovery from invasive procedures. Trout were held individually in either barren or enriched (gravel, plants and an area of cover) conditions and recovery rates after a potentially painful event and a standard stressor were investigated by recording parameters such as behaviour, opercular beat rate and plasma cortisol concentrations. Fish were randomly assigned to one of four treatment groups: Control where the fish were left undisturbed; Sham where fish were anaesthetised but no invasive procedure; Pain where a subcutaneous injection of acetic acid was administered to the frontal lips during anaesthesia; and Stress where fish were subject to one minute of air emersion. Video recordings were made prior to treatment then at 30 minute intervals afterwards to determine whether fish in enriched conditions recovered more rapidly than those in barren tanks. Preliminary analyses suggest that enriched fish may be less stressed thus these findings have important implications for the husbandry and welfare of captive rainbow trout but may also affect the outcome of experimental studies dependent upon whether enrichment was adopted