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- Bal-Price, Anna, et al.
(författare)
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Putative adverse outcome pathways relevant to neurotoxicity
- 2015
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Ingår i: Critical reviews in toxicology. - : Informa UK Limited. - 1040-8444 .- 1547-6898. ; 45:1, s. 83-91
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Forskningsöversikt (refereegranskat)abstract
- The Adverse Outcome Pathway (AOP) framework provides a template that facilitates understanding of complex biological systems and the pathways of toxicity that result in adverse outcomes (AOs). The AOP starts with an molecular initiating event (MIE) in which a chemical interacts with a biological target(s), followed by a sequential series of KEs, which are cellular, anatomical, and/or functional changes in biological processes, that ultimately result in an AO manifest in individual organisms and populations. It has been developed as a tool for a knowledge-based safety assessment that relies on understanding mechanisms of toxicity, rather than simply observing its adverse outcome. A large number of cellular and molecular processes are known to be crucial to proper development and function of the central (CNS) and peripheral nervous systems (PNS). However, there are relatively few examples of well-documented pathways that include causally linked MIEs and KEs that result in adverse outcomes in the CNS or PNS. As a first step in applying the AOP framework to adverse health outcomes associated with exposure to exogenous neurotoxic substances, the EU Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) organized a workshop (March 2013, Ispra, Italy) to identify potential AOPs relevant to neurotoxic and developmental neurotoxic outcomes. Although the AOPs outlined during the workshop are not fully described, they could serve as a basis for further, more detailed AOP development and evaluation that could be useful to support human health risk assessment in a variety of ways.
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| 2. |
- Högberg, Helena T., 1975-, et al.
(författare)
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Application of micro electrode arrays (MEAs) as an emerging technology for domoic acid- induced developmental neurotoxicity evaluation in primary cultures of rat cortical neurons
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Due to lack of knowledge only a few industrial chemicals have been identified as developmental neurotoxicants. Current developmental neurotoxicity (DNT) guidelines (OECD TG 426 and EPA712-C-98-239) are based entirely on in vivo studies that are both time consuming and costly. Consequently, there is a high demand to develop alternative in vitro methods for initial screening to prioritise chemicals for further DNT testing. One of the most promising tools for neurotoxicity assessment is the measurement of electrical activity using micro electrode arrays (MEA) that provides a functional and neuronal specific endpoint that until now mainly has been used to detect acute neurotoxicity. Here, electrical activity measurements were evaluated to be a suitable endpoint for the detection of potential developmental neurotoxicants. Initially, primary cortical neurons grown on MEA were characterized for different cell markers (neural precursor cells, neurons and astrocytes) over time using immunocytochemistry to evaluate if the model could be suitable for DNT testing. Indeed, our results show that primary cortical neurons could be a promising in vitro model for DNT testing since some of the most critical neurodevelopment processes such as progenitor cell commitment, proliferation and differentiation of astrocytes and maturation of neurons are present. To evaluate if electrical activity could be a suitable endpoint to detect chemicals with DNT effects primary cortical neurons grown on MEA were exposed to domoic acid (DA), a potential developmental neurotoxicant for up to 4 weeks. Long term exposure to a low concentration (50 nM) of DA increased the basal spontaneous electrical activity as measured by spike and burst rates, as compared to the control cultures. Moreover, the effect induced by the GABAA receptor antagonist bicuculline was significantly lower in the DA treated cultures than in the untreated ones. Obtained data indicates that electrical activity measurements can be used as a tool to detect chemicals with DNT potential. However, more DNT chemicals as well as non-neurotoxic chemicals (negative controls) should be tested to confirm the use of electrical activity measurements for initial DNT screening purposes.
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