Abstract
Developmental neurotoxicity (DNT) of chemical compounds disrupts the formation of a normal brain. There is impressive progress in the development of alternative testing methods for DNT potential in chemicals, some of which also incorporate invertebrate animals. This review briefly touches upon studies on the genetically tractable model organisms of Caenorhabditis elegans and Drosophila melanogaster about the action of specific developmental neurotoxicants. The formation of a functional nervous system requires precisely timed axonal pathfinding to the correct cellular targets. To address this complex key event, our lab developed an alternative assay using a serum-free culture of intact locust embryos. The first neural pathways in the leg of embryonic locusts are established by a pair of afferent pioneer neurons which use guidance cues from membrane-bound and diffusible semaphorin proteins. In a systematic approach according to recommendations for alternative testing, the embryo assay quantifies defects in pioneer navigation after exposure to a panel of recognized test compounds for DNT. The outcome indicates a high predictability for test-compound classification. Since the pyramidal neurons of the mammalian cortex also use a semaphorin gradient for neurite guidance, the assay is based on evolutionary conserved cellular mechanisms, supporting its relevance for cortical development.
Highlights
The formation of a functional nervous system requires precisely timed axonal pathfinding to the correct cellular targets
In a systematic approach according to recommendations for alternative testing, the embryo assay quantifies defects in pioneer navigation after exposure to a panel of recognized test compounds for Developmental neurotoxicity (DNT)
While neurotoxicity has been defined as “any adverse effect on the chemistry, structure or function of the nervous system during development or at maturity, induced by chemical or physical influences” [1], developmental neurotoxicity (DNT) especially addresses the problem that, during its growth, the human brain is more sensitive to chemical exposure than during adulthood [2–4]
Summary
Growing concerns about chemical compounds that potentially cause an increase in neurodevelopmental disorders has stimulated research in developmental neurotoxicity This is a rather challenging field within applied and basic science, requiring epidemiological studies, neuropsychological investigations, biomedical brain imaging, and toxicological data, including modern omics-based and in silico approaches about the effects of neurotoxicants on the developing nervous system. This in vitro battery has been devised for the analysis of key neurodevelopmental events, including neuroprogenitor proliferation, cell migration, and differentiation into neuronal and glial cell types, neurite outgrowth, synaptogenesis, and formation of an electrically active network It will improve DNT testing by taking adverse outcome pathways (AOPs) into account. Main parts describe in more details a recent approach to design a DNT-assay for correct anatomical wiring, using another classical model system of developmental neurobiology This approach follows the recommendations for the selection of reference compounds and appropriate use in alternative DNT assays [7]. Results from a panel of established DNT-positive and DNT-negative test compounds support a rather high level of human predictability for this assay
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