A locust embryo as predictive developmental neurotoxicity testing system for pioneer axon pathway formation
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REPRODUCTIVE TOXICOLOGY
A locust embryo as predictive developmental neurotoxicity testing system for pioneer axon pathway formation Karsten Bode1 · Maja Bohn1 · Jennifer Reitmeier1 · Philine Betker1 · Michael Stern1 · Gerd Bicker1 Received: 16 March 2020 / Accepted: 8 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Exposure to environmental chemicals during in utero and early postnatal development can cause a wide range of neurological defects. Since current guidelines for identifying developmental neurotoxic chemicals depend on the use of large numbers of rodents in animal experiments, it has been proposed to design rapid and cost-efficient in vitro screening test batteries that are mainly based on mixed neuronal/glial cultures. However, cell culture tests do not assay correct wiring of neuronal circuits. The establishment of precise anatomical connectivity is a key event in the development of a functional brain. Here, we expose intact embryos of the locust (Locusta migratoria) in serum-free culture to test chemicals and visualize correct navigation of identified pioneer axons by fluorescence microscopy. We define separate toxicological endpoints for axonal elongation and navigation along a stereotyped pathway. To distinguish developmental neurotoxicity (DNT) from general toxicity, we quantify defects in axonal elongation and navigation in concentration–response curves and compare it to the biochemically determined viability of the embryo. The investigation of a panel of recognized DNT-positive and -negative test compounds supports a rather high predictability of this invertebrate embryo assay. Similar to the semaphorin-mediated guidance of neurites in mammalian cortex, correct axonal navigation of the locust pioneer axons relies on steering cues from members of this family of cell recognition molecules. Due to the evolutionary conserved mechanisms of neurite guidance, we suggest that our pioneer axon paradigm might provide mechanistically relevant information on the DNT potential of chemical agents on the processes of axon elongation, navigation, and fasciculation. Keywords DNT · Semaphorins · Neurite guidance · Fasciculation · Invertebrate model
Introduction Developmental neurotoxicity (DNT) describes any adverse change in the function or structure of the nervous system after exposure to chemicals during in utero or early postnatal period, when the formation of the nervous system is not entirely completed (Mundy et al. 2015). In many cases, these changes in neural development are caused by exposure to industrial chemicals in our environment or by lifestyle habits (Smirnova et al. 2014). Based on epidemiological studies, Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02929-6) contains supplementary material, which is available to authorized users. * Gerd Bicker gerd.bicker@tiho‑hannover.de 1
Institute of Physiology and Cell Biology, University of Veterinary Medicine Hannover, Bischofsholer Damm 15/102, 30173
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