Developmental neurotoxicity of the harmful algal bloom toxin domoic acid: Cellular and molecular mechanisms underlying altered behavior in the zebrafish model

This paper is not subject to U.S. copyright. The definitive version was published in Environmental Health Perspectives 128(11), (2020): 117002, doi:10.1289/EHP6652.Background: Harmful algal blooms (HABs) produce potent neurotoxins that threaten human health, but current regulations may not be protective of sensitive populations. Early life exposure to low levels of the HAB toxin domoic acid (DomA) produces long-lasting behavioral deficits in rodent and primate models; however, the mechanisms involved are unknown. The zebrafish is a powerful in vivo vertebrate model system for exploring cellular processes during development and thus may help to elucidate mechanisms of DomA developmental neurotoxicity. Objectives: We used the zebrafish model to investigate how low doses of DomA affect the developing nervous system, including windows of susceptibility to DomA exposure, structural and molecular changes in the nervous system, and the link to behavioral alterations. Methods: To identify potential windows of susceptibility, DomA (0.09–0.18 ng) was delivered to zebrafish through caudal vein microinjection during distinct periods in early neurodevelopment. Following exposure, structural and molecular targets were identified using live imaging of transgenic fish and RNA sequencing. To assess the functional consequences of exposures, we quantified startle behavior in response to acoustic/vibrational stimuli. Results: Larvae exposed to DomA at 2 d postfertilization (dpf), but not at 1 or 4 dpf, showed consistent deficits in startle behavior at 7 dpf, including lower responsiveness and altered kinematics. Similarly, myelination in the spinal cord was disorganized after exposure at 2 dpf but not 1 or 4 dpf. Time-lapse imaging revealed disruption of the initial stages of myelination. DomA exposure at 2 dpf down-regulated genes required for maintaining myelin structure and the axonal cytoskeleton. Discussion: These results in zebrafish reveal a developmental window of susceptibility to DomA-induced behavioral deficits and identify altered gene expression and disrupted myelin structure as possible mechanisms. The results establish a zebrafish model for investigating the mechanisms of developmental DomA toxicity, including effects with potential relevance to exposed sensitive human populations. https://doi.org/10.1289/EHP6652This research was supported by the Oceans Venture Fund, the Von Damm Fellowship, the Ocean Ridge Initiative Fellowship, and Woods Hole Sea grant (NA14OAR4170074) (all to J.M.P.), and by the Woods Hole Center for Oceans and Human Health (NIH: P01ES021923 and P01ES028938; NSF: OCE-1314642 and OCE-1840381; Center PI: John Stegeman, Project PI: M.E.H.)

Bisphenol A in oocytes leads to growth suppression and altered stress performance in juvenile rainbow trout

© The Authors, 2010. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS ONE 5 (2010): e10741, doi:10.1371/journal.pone.0010741.Bisphenol A (BPA), used in the manufacture of plastics, is ubiquitously distributed in the aquatic environment. However, the effect of maternal transfer of these xenobiotics on embryonic development and growth is poorly understood in fish. We tested the hypothesis that BPA in eggs, mimicking maternal transfer, impact development, growth and stress performance in juveniles of rainbow trout (Oncorhynchus mykiss). Trout oocytes were exposed to 0, 30 and 100 µg.mL−1 BPA for 3 h in ovarian fluid, followed by fertilization. The embryos were maintained in clean water and sampled temporally over 156-days post-fertilization (dpf), and juveniles were sampled at 400-dpf. The egg BPA levels declined steadily after exposure and were undetectable after 21- dpf. Oocyte exposure to BPA led to a delay in hatching and yolk absorption and a consistently lower body mass over 152-dpf. The growth impairment, especially in the high BPA group, correlated with higher growth hormone (GH) content and lower GH receptors gene expression. Also, mRNA abundances of insulin-like growth factors (IGF-1 and IGF-2) and their receptors were suppressed in the BPA treated groups. The juvenile fish grown from the BPA-enriched eggs had lower body mass and showed perturbations in plasma cortisol and glucose response to an acute stressor. BPA accumulation in eggs, prior to fertilization, leads to hatching delays, growth suppression and altered stress response in juvenile trout. The somatotropic axis appears to be a key target for BPA impact during early embryogenesis, leading to long term growth and stress performance defects in fish.This work was supported by funds from the Natural Science and Engineering Research Council (NSERC) of Canada Discovery grant and the Ontario Ministry of Agriculture and Food

Generative Design in Minecraft (GDMC), Settlement Generation Competition

This paper introduces the settlement generation competition for Minecraft, the first part of the Generative Design in Minecraft challenge. The settlement generation competition is about creating Artificial Intelligence (AI) agents that can produce functional, aesthetically appealing and believable settlements adapted to a given Minecraft map - ideally at a level that can compete with human created designs. The aim of the competition is to advance procedural content generation for games, especially in overcoming the challenges of adaptive and holistic PCG. The paper introduces the technical details of the challenge, but mostly focuses on what challenges this competition provides and why they are scientifically relevant.Comment: 10 pages, 5 figures, Part of the Foundations of Digital Games 2018 proceedings, as part of the workshop on Procedural Content Generatio

Gene expression and epigenetic responses of the marine Cladoceran, Evadne nordmanni, and the copepod, Acartia clausi, to elevated CO2

Characterizing the capacity of marine organisms to adapt to climate change related drivers (e.g., pCO2 and temperature), and the possible rate of this adaptation, is required to assess their resilience (or lack thereof) to these drivers. Several studies have hypothesized that epigenetic markers such as DNA methylation, histone modifications and noncoding RNAs, act as drivers of adaptation in marine organisms, especially corals. However, this hypothesis has not been tested in zooplankton, a keystone organism in marine food webs. The objective of this study is to test the hypothesis that acute ocean acidification (OA) exposure alters DNA methylation in two zooplanktonic species—copepods (Acartia clausii) and cladocerans (Evadne nordmanii). We exposed these two species to near-future OA conditions (400 and 900 ppm pCO2) for 24 h and assessed transcriptional and DNA methylation patterns using RNA sequencing and Reduced Representation Bisulfite Sequencing (RRBS). OA exposure caused differential expression of genes associated with energy metabolism, cytoskeletal and extracellular matrix functions, hypoxia and one-carbon metabolism. Similarly, OA exposure also caused altered DNA methylation patterns in both species but the effect of these changes on gene expression and physiological effects remains to be determined. The results from this study form the basis for studies investigating the potential role of epigenetic mechanisms in OA induced phenotypic plasticity and/or adaptive responses in zooplanktonic organisms.publishedVersio

Genetic diversity and population structure of Leishmania infantum from Southeastern France : evaluation using Multi-Locus Microsatellite Typing

In the south of France, Leishmania infantum is responsible for numerous cases of canine leishmaniasis (CanL), sporadic cases of human visceral leishmaniasis (VL) and rare cases of cutaneous and muco-cutaneous leishmaniasis (CL and MCL, respectively). Several endemic areas have been clearly identified in the south of France including the Pyrenees-Orientales, Cevennes (CE), Provence (P), Alpes-Maritimes (AM) and Corsica (CO). Within these endemic areas, the two cities of Nice (AM) and Marseille (P), which are located 150 km apart, and their surroundings, concentrate the greatest number of French autochthonous leishmaniasis cases. In this study, 270 L. infantum isolates from an extended time period (1978-2011) from four endemic areas, AM, P, CE and CO, were assessed using Multi-Locus Microsatellite Typing (MLMT). MLMT revealed a total of 121 different genotypes with 91 unique genotypes and 30 repeated genotypes. Substantial genetic diversity was found with a strong genetic differentiation between the Leishmania populations from AM and P. However, exchanges were observed between these two endemic areas in which it seems that strains spread from AM to P. The genetic differentiations in these areas suggest strong epidemiological structuring. A model-based analysis using STRUCTURE revealed two main populations: population A (consisting of samples primarily from the P and AM endemic areas with MON-1 and non-MON-1 strains) and population B consisting of only MON-1 strains essentially from the AM endemic area. For four patients, we observed several isolates from different biological samples which provided insight into disease relapse and re-infection. These findings shed light on the transmission dynamics of parasites in humans. However, further data are required to confirm this hypothesis based on a limited sample set. This study represents the most extensive population analysis of L. infantum strains using MLMT conducted in France

Thermal Phase Mixing During First Order Phase Transitions

The dynamics of first order phase transitions are studied in the context of (3+1)-dimensional scalar field theories. Particular attention is paid to the question of quantifying the strength of the transition, and how `weak' and `strong' transitions have different dynamics. We propose a model with two available low temperature phases separated by an energy barrier so that one of them becomes metastable below the critical temperature $T_c$. The system is initially prepared in this phase and is coupled to a thermal bath. Investigating the system at its critical temperature, we find that `strong' transitions are characterized by the system remaining localized within its initial phase, while `weak' transitions are characterized by considerable phase mixing. Always at $T_c$, we argue that the two regimes are themselves separated by a (second order) phase transition, with an order parameter given by the fractional population difference between the two phases and a control parameter given by the strength of the scalar field's quartic self-coupling constant. We obtain a Ginzburg-like criterion to distinguish between `weak' and `strong' transitions, in agreement with previous results in (2+1)-dimensions.Comment: 28 pages RevTeX, 9 postscript figures, IMPERIAL/TP/93-94/58, DART-HEP-94/0

Imaging the real space structure of the spin fluctuations in an iron-based superconductor

Spin fluctuations are a leading candidate for the pairing mechanism in high temperature superconductors, supported by the common appearance of a distinct resonance in the spin susceptibility across the cuprates, iron-based superconductors and many heavy fermion materials1. The information we have about the spin resonance comes almost exclusively from neutron scattering. Here we demonstrate that by using low-temperature scanning tunneling microscopy and spectroscopy we can characterize the spin resonance in real space. We establish that inelastic tunneling leads to the characteristic "dip-hump" feature seen in tunneling spectra in high temperature superconductors and that this feature arises from excitations of the spin fluctuations. Spatial mapping of this feature near defects allows us to probe non-local properties of the spin susceptibility and to image its real space structure.Publisher PDFPeer reviewe

Adrenocorticotropic Hormone Suppresses Gonadotropin-Stimulated Estradiol Release from Zebrafish Ovarian Follicles

While stress is known to impact reproductive performance, the pathways involved are not entirely understood. Corticosteroid effects on the functioning of the hypothalamus-pituitary-gonadal axis are thought to be a key aspect of stress-mediated reproductive dysfunction. A vital component of the stress response is the pituitary secretion of adrenocorticotropic hormone (ACTH), which binds to the melanocortin 2 receptor (MC2R) in the adrenal glands and activates cortisol biosynthesis. We recently reported MC2R mRNA abundance in fish gonads leading to the hypothesis that ACTH may be directly involved in gonadal steroid modulation. Using zebrafish (Danio rerio) ovarian follicles, we tested the hypothesis that acute ACTH stimulation modulates cortisol and estradiol (E2) secretion. ACTH neither affected cortisol nor unstimulated E2 release from ovarian follicles. However, ACTH suppressed human chorionic gonadotropin (hCG)-stimulated E2 secretion in a dose-related manner, with a maximum decrease of 62% observed at 1 I.U. ACTH mL−1. This effect of ACTH on E2 release was not observed in the presence of either 8-bromo-cAMP or forskolin, suggesting that the mechanism(s) involved in steroid attenuation was upstream of adenylyl cyclase activation. Overall, our results suggest that a stress-induced rise in plasma ACTH levels may initiate a rapid down-regulation of acute stimulated E2 biosynthesis in the zebrafish ovary, underscoring a novel physiological role for this pituitary peptide in modulating reproductive activity

Impact of Iron-site defects on Superconductivity in LiFeAs

PW acknowledges funding from the MPG-UBC center and financial support from EPSRC (EP/I031014/1).In conventional s-wave superconductors, only magnetic impurities exhibit impurity bound states, whereas for an s order parameter they can occur for both magnetic and non-magnetic impurities. Impurity bound states in superconductors can thus provide important insight into the order parameter. Here, we present a combined experimental and theoretical study of native and engineered iron-site defects in LiFeAs. Detailed comparison of tunneling spectra measured on impurities with spin fluctuation theory reveals a continuous evolution from negligible impurity bound state features for weaker scattering potential to clearly detectable states for somewhat stronger scattering potentials. All bound states for these intermediate strength potentials are pinned at or close to the gap edge of the smaller gap, a phenomenon that we explain and ascribe to multi-orbital physics.PostprintPeer reviewe