Evaluation of Chemical Effects on Network Formation in Cortical Neurons Grown on Microelectrode Arrays

Shafer, Timothy J.; Brown, Jasmine P.; Lynch, Brittany; Dávila-Montero, Sylmarie; Wallace, Kathleen; Friedman, Katie Paul

doi:10.1093/toxsci/kfz052

Cited by 42 publications

(45 citation statements)

References 61 publications

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“…1&2) allowed us to directly test the first hypothesis. While some recent studies have begun to employ MEAs to study PBDE developmental neurotoxicity as part of larger screens (80)(81)(82), the data presented here are, to our knowledge, the first example of such evidence for hydroxylated PBDE metaboliteinduced effects. They demonstrate that chronic nanomolar 6-OH exposures suppress both spontaneous and evoked electrical activity and suggest that the exposures may specifically impact pre-synapses, including synapsin-related signaling and function.…”

Section: Discussionmentioning

confidence: 87%

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

Poston

Rejepova

Ghaninejad-Esfahani

et al. 2020

Journal of Biological Chemistry

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The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH–BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) (MEK) biology and our observation that 6-OH–BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK–ERK axis of MAPK signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand–protein docking suggested that 6-OH–BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH–BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH–BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom-body β–lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK–ERK signaling, and axonal guidance.

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Section: Discussionmentioning

confidence: 87%

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

Poston

Rejepova

Ghaninejad-Esfahani

et al. 2020

Journal of Biological Chemistry

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“…FR MSE including the 3-fold MSE limit and CI for the MSE. The endpoint NNF does not provide CIs (Shafer et al, 2019;Frank et al, 2017). A MSE using hits regardless of DNT-specificity, i.e.…”

Section: Figure 65mentioning

confidence: 95%

“…Gene expression data for these test systems with regards to electrophysiologically-relevant molecules are collected in Annex A6. For properly representing the overall state-of-the-art concerning DNT in vitro testing for regulatory purposes, we added results from test methods established and performed by Tim Shafer, US-Environmental Protection Agency (US-EPA; Figure 4; (Frank et al, 2017;Shafer et al, 2019;Harrill et al, 2011) as well as from a recently developed and yet unpublished test method (IUF) sponsored by the Danish EPA (DK-EPA, grant number DK-EPA, grant number MST-667-00205). These test methods use test systems suitable for assessing neuronal network formation and activity.…”

Section: Dnt Test Methods Assembled Into An In Vitro Dnt Testing Batterymentioning

confidence: 99%

“…Flufenacet was not tested in these assays. Data for deltamethrin assessed in the rat neuronal network formation assay was taken from Frank et al (2017) and flufenacet data from Shafer et al (2019). hNNF values originate from unpublished data generated at the IUF.…”

Section: Figure 67mentioning

confidence: 99%

“…Here, all endpoints, including vi-ability/cytotoxicity are shown. The CI for the NNF were not provided in the publications (Shafer et al, 2019;Frank et al, 2017) and thus were not plotted. BDE-47, TDCPP and TBBPA were the three compounds with the lowest BMC < 1µM for unspecific hits, thus candidates for priorisation according to the MSE (TBBPA, BDE-99, BDP according to ToxPi).…”

Section: Table 19mentioning

confidence: 99%

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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

EFS3

156

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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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Community‐Engaged Research and the Use of Open Access ToxVal/ToxRef In Vivo Databases and New Approach Methodologies (NAM) to Address Human Health Risks From Environmental Contaminants

Silva,

Capps,

London

2024

Birth Defects Research

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BackgroundThe paper analyzes opportunities for integrating Open access resources (Abstract Sifter, US EPA and NTP Toxicity Value and Toxicity Reference [ToxVal/ToxRefDB]) and New Approach Methodologies (NAM) integration into Community Engaged Research (CEnR).MethodsCompTox Chemicals Dashboard and Integrated Chemical Environment with in vivo ToxVal/ToxRef and NAMs (in vitro) databases are presented in three case studies to show how these resources could be used in Pilot Projects involving Community Engaged Research (CEnR) from the University of California, Davis, Environmental Health Sciences Center.ResultsCase #1 developed a novel assay methodology for testing pesticide toxicity. Case #2 involved detection of water contaminants from wildfire ash and Case #3 involved contaminants on Tribal Lands. Abstract Sifter/ToxVal/ToxRefDB regulatory data and NAMs could be used to screen/prioritize risks from exposure to metals, PAHs and PFAS from wildfire ash leached into water and to investigate activities of environmental toxins (e.g., pesticides) on Tribal lands. Open access NAMs and computational tools can apply to detection of sensitive biological activities in potential or known adverse outcome pathways to predict points of departure (POD) for comparison with regulatory values for hazard identification. Open access Systematic Empirical Evaluation of Models or biomonitoring exposures are available for human subpopulations and can be used to determine bioactivity (POD) to exposure ratio to facilitate mitigation.ConclusionsThese resources help prioritize chemical toxicity and facilitate regulatory decisions and health protective policies that can aid stakeholders in deciding on needed research. Insights into exposure risks can aid environmental justice and health equity advocates.

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Evaluation of Chemical Effects on Network Formation in Cortical Neurons Grown on Microelectrode Arrays

Cited by 42 publications

References 61 publications

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

Certain ortho-hydroxylated brominated ethers are promiscuous kinase inhibitors that impair neuronal signaling and neurodevelopmental processes

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

Community‐Engaged Research and the Use of Open Access ToxVal/ToxRef In Vivo Databases and New Approach Methodologies (NAM) to Address Human Health Risks From Environmental Contaminants

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