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Estrogen plays fundamental roles in a range of developmental processes and exposure to estrogen mimicking chemicals has been associated with various adverse health effects in both wildlife and human populations. Estrogenic chemicals are found commonly as mixtures in the environment and can have additive effects, however risk analysis is typically conducted for single-chemicals with little, or no, consideration given for an animal’s exposure history. Here we developed a transgenic zebrafish with a photoconvertable fluorophore (Kaede, green to red on UV light exposure) in a skin pigment-free mutant element (ERE)-Kaede-Casper model and applied it to quantify tissue-specific fluorescence biosensor responses for combinations of estrogen exposures during early life using fluorescence microscopy and image analysis. We identify windows of tissue-specific sensitivity to ethinylestradiol (EE2) for exposure during early-life (0–5 dpf) and illustrate that exposure to estrogen (EE2) during 0–48 hpf enhances responsiveness (sensitivity) to different environmental estrogens (EE2, genistein and bisphenol A) for subsequent exposures during development. Our findings illustrate the importance of an organism’s stage of development and estrogen exposure history for assessments on, and possible health risks associated with, estrogen exposure.

Compared to two-dimensional (2D) cell culture, cellular aggregates or spheroids (3D) offer a more appropriate alternative system where individual cell-cell communication and micro-environment more closely represent the organ; yet we understand little of the physiological conditions at this scale. The relationship between spheroid size and oxygen microenvironment, an important factor influencing the metabolic capacity of cells, was first established using the fish intestine derived RTgutGC cell line. Subsequently, pharmaceutical metabolism (Propranolol), as determined by high performance liquid chromatography, in this intestinal model was examined as a function of spheroid size. Co-efficient of variation between spheroid size was below 12% using the gyratory platform method, with the least variation observed in the highest cell seeding density. The viable, high oxygen micro-environment of the outer rim of the spheroid, as determined by electron paramagnetic resonance (EPR) oximetry, decreased over time, and the hypoxic zone increased as a function of spheroid size. Despite a trend of higher metabolism in smaller spheroids, the formation of micro-environments (quiescent, hypoxic or anoxic) did not significantly affect metabolism or function of an environmentally relevant pharmaceutical in this spheroid model.

Rationale Synthetic opioids pose a significant public health risk due to their rapid synthesis and potentially lethal potency. New compounds are emerging continuously, meaning current testing platforms struggle to keep pace. Objectives Consequently, there is a critical need for simple, rapid, translatable models to provide a scalable screening platform to identify and hazard-assess emerging synthetic opioids, and test potential intervention strategies. Methods Here, we exposed 4 days post-fertilization (dpf) larval zebrafish to a range of concentrations of the prototypical class representative, fentanyl, to investigate behavioral and neural responses. Results Fentanyl caused low concentration hyperactivity, and high concentration hypolocomotion (sedation) which was reversed by the opioid antagonist naloxone. We confirmed predictive validity by replicating the behavioral responses with other class representatives (diacetylmorphine [heroin] and remifentanil). We also confirmed, pharmacologically, that low concentration hyperlocomotion was mediated by dopamine D2 receptors, replicating effects observed in mammals. Further mechanistic investigation using whole-brain in vivo imaging revealed disrupted connectivity in opioid-related circuits, such as the habenulae and dorsal thalamus, alongside novel pathways, including circuits associated with the pineal gland, torus semicircularis and eminentia granularis, potentially highlighting previously uncharacterized sensory and cerebellar neuronal networks. Conclusions These findings support the use of the larval zebrafish as a scalable model for assessment of synthetic opioids to provide novel insights into opioid-induced behaviors and mechanisms of action that may aid strategies in the growing challenge of interventive treatments for synthetic opioid intoxication. Larval zebrafish reveal neurobehavioral pathways affected by synthetic opioids, offering a valuable tool for rapid hazard assessment.

Establishing anaesthesia for ensuring both animal welfare and compatibility with protocols required for different areas of scientific research is vital. Zebrafish (Danio rerio) are one of the most used animal models in research; however, little is known about the appropriateness of anaesthetic used for this species, especially for embryo-larval life stages. Using a combination of whole-brain functional imaging, quantification of cardiovascular performance, and behaviour, we explore the efficacy and tolerability of six widely used fish anaesthetics (2-phenoxyethanol, benzocaine, etomidate, MS222, isoeugenol and quinaldine sulfate) in larval zebrafish. We show that MS222 and quinaldine sulfate are the most suitable for achieving deep anaesthesia, while etomidate is better suited for studies focused on the cardiovascular system. Only quinaldine sulfate was found to be aversive. Our findings aid researchers for selecting the most suitable anaesthetic compounds and concentrations for their specific research goals, and the refinement of studies using anaesthesia in larval zebrafish.

Aims/Introduction Little is known about the impact of sleep duration and late‐night snacking on glycemic control in patients with type 1 diabetes using insulin pumps. The aim of the present study was to examine whether late‐night eating habits and short sleep duration are associated with glycemic control in continuous subcutaneous insulin infusion‐treated type 1 diabetic patients. Materials and Methods We included 148 consecutive adult type 1 diabetic subjects using an insulin pump (100 women and 48 men). Participants completed a questionnaire regarding sleep duration (classified as short if ≤6 h) and late‐night snacking. Other sources of information included medical records and data from blood glucose meters. Glycemic control was assessed by glycated hemoglobin (HbA1c) levels and mean self‐monitoring of blood glucose (SMBG) readings. Results The mean age of patients was 26 years, mean type 1 diabetes duration was 13.4 years and mean HbA1c level was 7.2%. In a univariate regression analysis, sleep duration was a predictor of both HbA1c (β = 0.51, P = 0.01) and SMBG levels (β = 11.4, P = 0.02). Additionally, an association was found between frequent late‐night snacking and higher SMBG readings (often snacking β = 18.1, P = 0.05), but not with increased HbA1c levels. In the multivariate linear regression, independent predictors for HbA1c and SMBG were sleep duration and patient age. In a univariate logistic regression, sleep duration and frequency of late‐night snacking were not predictors of whether HbA1c target levels were achieved. Conclusions Short sleep duration, but not late‐night snacking, seems to be associated with poorer glycemic control in type 1 diabetic patients treated with continuous subcutaneous insulin infusion. In this study we evaluate a potential association of sleep duration and late night snacking with glycemic control in type 1 diabetes patients treated with insulin pumps.