Development of the Adverse Outcome Pathway (AOP): Chronic binding of antagonist to N -methyl- d -aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities of children

Sachana, Magdalini; Rolaki, Alexandra; Bal‐Price, Anna

doi:10.1016/j.taap.2018.02.024

Cited by 50 publications

(27 citation statements)

References 206 publications

(259 reference statements)

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“…Comparing the results of the present study to those assays could serve to help develop putative adverse outcome pathways (AOPs) related to neurotoxicity. Whereas many different mechanisms of neurotoxicity are well-established in the literature, few welldocumented AOPs for neurotoxicity have been described to date (Gong et al 2015;Bal-Price et al 2015Sachana et al 2018;Li et al 2019). These data therefore can serve as a resource to either strengthen existing AOPs or support the development of new ones.…”

Section: Discussionmentioning

confidence: 99%

Concentration–response evaluation of ToxCast compounds for multivariate activity patterns of neural network function

et al. 2019

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The US Environmental Protection Agency's ToxCast program has generated toxicity data for thousands of chemicals but does not adequately assess potential neurotoxicity. Networks of neurons grown on microelectrode arrays (MEAs) offer an efficient approach to screen compounds for neuroactivity and distinguish between compound effects on firing, bursting, and connectivity patterns. Previously, single concentrations of the ToxCast Phase II library were screened for effects on mean firing rate (MFR) in rat primary cortical networks. Here, we expand this approach by retesting 384 of those compounds (including 222 active in the previous screen) in concentration-response across 43 network activity parameters to evaluate neural network function. Using hierarchical clustering and machine learning methods on the full suite of chemicalparameter response data, we identified 15 network activity parameters crucial in characterizing activity of 237 compounds that were response actives ("hits"). Recognized neurotoxic compounds in this network function assay were often more potent compared to other ToxCast assays. Of these chemical-parameter responses, we identified three k-means clusters of chemical-parameter activity (i.e., multivariate MEA response patterns). Next, we evaluated the MEA clusters for enrichment of

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Section: Discussionmentioning

confidence: 99%

Concentration–response evaluation of ToxCast compounds for multivariate activity patterns of neural network function

et al. 2019

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“…Exposure, effects and underlying MoA are comprehensively summarized by . Moreover, AOP13 was developed using lead as a model compound (https://aopwiki.org/aops/13; (Sachana et al, 2018). As lead exerts its DNT properties by interfering with signaling necessary for establishing synapses, the battery, and here especially the MSE NNF reflects well the in vivo situation and thus the specificity of the lead MoA.…”

Section: Figure 47mentioning

confidence: 99%

Establishment of an a priori protocol for the implementation and interpretation of an in‐vitro testing battery for the assessment of developmental neurotoxicity

Masjosthusmann

Blum

Bartmann

et al. 2020

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In this project we set up a human cell-based DNT in vitro testing strategy that is based on test methods with high readiness and data generated therefrom. The methods underwent a fit-for-purpose evaluation that considered four key elements: 1. The test system, 2. the exposure scheme, 3. the assay and analytical endpoint(s) and 4. the classification model. This testing battery was challenged with 119 chemicals for which rich toxicological information was available (for some of them also on their DNT hazard). Testing was performed in 5 test systems measuring 10 DNT-specific endpoints and additional 9 viability/ cytotoxicity-related parameters. For approximately half of the compounds, additional and complementary data from DNT in vitro tests was added by the US-EPA. This extended battery was also evaluated. Testing results revealed that the test methods of this current DNT in vitro battery are reliable and reproducible. The endpoints had to a large extent low redundancy. Battery performance, as assessed with compounds well-characterized for DNT hazard had a sensitivity of 82.7 % and a specificity of 88.2 %. Gap analyses suggested that radial, astro-and microglia as well as myelination endpoints may be added to the battery. Two case studies, one for screening and prioritization of 14 flame retardants, and one on hazard characterization of 2 pesticides, were presented. Hypothetical AOPs were developed based on the latter case study. In conclusion, the DNT testing strategy explored here is a very promising first approach for DNT hazard identification and characterization. The performance is encouraging and may be improved by inclusion of further tests. Some uncertainties in DNT in vitro battery testing outcomes could be reduced by incorporating test data and modelling approaches related to in vitro and in vivo toxicokinetics of test compounds.

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“…These CKEs, linked in a causal manner, as described by key event relationships (KERs) in the AOPs, are essential for inducing learning and memory impairment. The BDNF-ERK-CREB (extracellular signal-regulated kinase / cyclic AMP response element-binding protein) signalling cascade (KE upstream) plays a critical role during brain development including neuronal survival, differentiation (dendrite and neurite formation), synaptogenesis and neuronal network formation [17,18]. Therefore, any change in the BDNF level (increase or decrease) could result in alterations of synaptogenesis, leading to neuronal network dysfunction, as described in the KERs of the AOP ID 12 [13], AOP ID 13 [12], or AOP ID 54 [9], and strongly supported by empirical data [19][20][21][22][23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Assessment of developmental neurotoxicity induced by chemical mixtures using an adverse outcome pathway concept

et al. 2020

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Background: In light of the vulnerability of the developing brain, mixture risk assessment (MRA) for the evaluation of developmental neurotoxicity (DNT) should be implemented, since infants and children are co-exposed to more than one chemical at a time. One possible approach to tackle MRA could be to cluster DNT chemicals in a mixture on the basis of their mode of action (MoA) into 'similar' and 'dissimilar', but still contributing to the same adverse outcome, and anchor DNT assays to common key events (CKEs) identified in DNT-specific adverse outcome pathways (AOPs). Moreover, the use of human in vitro models, such as induced pluripotent stem cell (hiPSC)derived neuronal and glial cultures would enable mechanistic understanding of chemically-induced adverse effects, avoiding species extrapolation. Methods: HiPSC-derived neural progenitors differentiated into mixed cultures of neurons and astrocytes were used to assess the effects of acute (3 days) and repeated dose (14 days) treatments with single chemicals and in mixtures belonging to different classes (i.e., lead(II) chloride and methylmercury chloride (heavy metals), chlorpyrifos (pesticide), bisphenol A (organic compound and endocrine disrupter), valproic acid (drug), and PCB138 (persistent organic pollutant and endocrine disrupter), which are associated with cognitive deficits, including learning and memory impairment in children. Selected chemicals were grouped based on their mode of action (MoA) into 'similar' and 'dissimilar' MoA compounds and their effects on synaptogenesis, neurite outgrowth, and brain derived neurotrophic factor (BDNF) protein levels, identified as CKEs in currently available AOPs relevant to DNT, were evaluated by immunocytochemistry and high content imaging analysis. Results: Chemicals working through similar MoA (i.e., alterations of BDNF levels), at non-cytotoxic (IC 20 /100), very low toxic (IC 5), or moderately toxic (IC 20) concentrations, induce DNT effects in mixtures, as shown by increased number of neurons, impairment of neurite outgrowth and synaptogenesis (the most sensitive endpoint as confirmed by mathematical modelling) and increase of BDNF levels, to a certain extent reproducing autism-like cellular changes observed in the brain of autistic children. Conclusions: Our findings suggest that the use of human iPSC-derived mixed neuronal/glial cultures applied to a battery of assays anchored to key events of an AOP network represents a valuable approach to identify mixtures of chemicals with potential to cause learning and memory impairment in children.

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Development of the Adverse Outcome Pathway (AOP): Chronic binding of antagonist to N -methyl- d -aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities of children

Cited by 50 publications

References 206 publications

Concentration–response evaluation of ToxCast compounds for multivariate activity patterns of neural network function

Concentration–response evaluation of ToxCast compounds for multivariate activity patterns of neural network function

Establishment of an a priori protocol for the implementation and interpretation of an in‐vitro testing battery for the assessment of developmental neurotoxicity

Assessment of developmental neurotoxicity induced by chemical mixtures using an adverse outcome pathway concept

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