Translating neurobehavioural endpoints of developmental neurotoxicity tests into in vitro assays and readouts

Abstract

The developing nervous system is particularly vulnerable to chemical insults. Exposure to chemicals can results in neurobehavioural alterations, and these have been be used as sensitive readouts to assess neurotoxicity in animals and man. Deconstructing neurobehaviour into relevant cellular and molecular components may allow for detection of specific neurotoxic effects in cell-based systems, which in turn may allow an easier examination of neurotoxic pathways and modes of actions and eventually inform the regulatory assessment of chemicals with potential developmental neurotoxicity. Here, current developments towards these goals are reviewed. Imaging genetics (CB) provides new insights into the neurobiological correlates of cognitive function that are being used to delineate neurotoxic mechanisms. The gaps between in vivo neurobehaviour and real-time in vitro measurements of neuronal function are being bridged by ex vivo measurements of synaptic plasticity (RW). An example of solvent neurotoxicity demonstrates how an in vivo neurological defect can be linked via the N-methyl-D-aspartate (NMDA)-glutamate receptor as a common target to in vitro readouts (AB). Axonal and dendritic morphology in vitro proved to be good correlates of neuronal connectivity and neurobehaviour in animals exposed to polychlorinated biphenyls and organophosphorus pesticides (PJL). Similarly, chemically-induced changes in neuronal morphology affected the formation of neuronal networks on structured surfaces. Such network formation may become an important readout for developmental neurotoxicity in vitro (CvT), especially when combined with human neurons derived from embryonic stem cells (ML). We envision that future in vitro test systems for developmental neurotoxicity will combine the above approaches with exposure information, and we suggest a strategy for test system development and cell-based risk assessment.

Reply on ‘Prerequisites for a reliable introduction of in vitro neurotoxicity testing within the REACH framework’

“…Doing so will aid in implementing the use of in vitro data for REACH and other legislative frameworks (Bal-Price et al, 2008, 2010Llorens et al, 2012;van Thriel et al, 2012). Combined with validation of the (biological) relevance of the in vitro observed effects in alternative species (Levin et al, 2009;Peterson et al, 2008), the increase in in vitro data will ultimately pave the way for further implementation of in silico data in legislative frameworks as suggested by Dr. Zarros.…”

“…Solving this challenge will require translational research to bridge the gap between in vitro and in vivo (Llorens et al, 2012;van Thriel et al, 2012), but will be a big step from a legislative perspective. To do so, we may need to know the biological relevance of the hundreds of endpoints studied in in vitro assays, including pathological endpoints.…”

Design of a high-throughput human neural crest cell migration assay to indicate potential developmental toxicants_suppl

“…Modern in vitro DNT assays are designed to model a specific biological key event (Leist et al, 2010;Crofton et al, 2011) at defined developmental stages (Stummann et al, 2009;van Dartel et al, 2009;Zimmer et al, 2011;van Thriel et al, 2012). For instance, assays have been developed that assess changes in early neural differentiation Pennings et al, 2012;Theunissen et al, 2012Theunissen et al, , 2013Krug et al, 2013b;Balmer et al, 2014;Waldmann et al, 2014;Rempel et al, 2015;Shinde et al, 2015), neurite outgrowth (Stiegler et al, 2011;Krug et al, 2013a), synaptogenesis (Harrill et al, 2011), gliogenesis (Fritsche et al, 2005) or myelination (Zurich et al, 2000(Zurich et al, , 2002.…”

“…This approach has a low sensitivity and specificity with respect to human hazard prediction Leist et al, 2008;van Thriel et al, 2012;Smirnova et al, 2014). The evaluation of in vivo developmental toxicity testing data indicates a high percentage of false positive (~40%) (Hartung, 2009) and of false negative (~55%) classifications (Bremer and Hartung, 2004).…”

On the necessity of translational cognitive-neurotoxicological research in methamphetamine abuse and addiction

“…Doing so would allow to examine the same (or at least corresponding) neurobiochemical, neurophysiological/electrophysiological, behavioral, or cognitive processes in both humans and animal models to overcome some of the limitations of each group and provide a more causal, mechanistic insight into the effects of METH toxicity and its consequences. This necessitates closely coordinated collaborations, which, despite the anticipated effort of consultation and coordination, may provide fruitful new insights and help further integrate the findings made in both fields (van Thriel et al 2012(van Thriel et al , 2017. As part of these efforts particular attention must be paid to examine the neurobiological and neurophysiological mechanisms underlying possible dysfunctions in cognitive processes relevant to the above-mentioned fields of school readiness, school success, job success, public safety, physical and mental health (Diamond 2013).…”