Evidence map›Paper›PMID 29428530›Full record

ArticleToxicology and applied pharmacology2018

Rotenone exerts developmental neurotoxicity in a human brain spheroid model.

David Pamies, Katharina Block, Pierre Lau, Laura Gribaldo, Carlos A Pardo, Paula Barreras, Lena Smirnova, Daphne Wiersma, Liang Zhao, Georgina Harris and 2 more

Open access · greenAbstract readComparative Study
PubMed Full text at PMC Publisher
In one paragraph

Article in Toxicology and applied pharmacology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 73 papers.

0numbers the graph read from it
0cells of the map it votes in
73citing papers in PubMed
6.0field-weighted citation impact, top 3% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

73 citing papers in PubMed, 146 citations in OpenAlex.

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  9. Testing Strategies for Metabolite-Mediated Neurotoxicity.International journal of molecular sciences · 2025
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13 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 3 institutions in 3 countries.

David PamiesCenter for Alternative to Animal Testing (CAAT), Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Katharina BlockCenter for Alternative to Animal Testing (CAAT), Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Pierre LauEuropean Commission, Joint Research Centre, European Reference Laboratory - European Centre for the Validation of Alternative Methods (EURL ECVAM), Via Enrico Fermi 2749, Ispra, VA 21027, Italy.
Laura GribaldoEuropean Commission, Joint Research Centre, European Reference Laboratory - European Centre for the Validation of Alternative Methods (EURL ECVAM), Via Enrico Fermi 2749, Ispra, VA 21027, Italy.
Carlos A PardoDepartment of Neurology, Johns Hopkins University, 600 N Wolfe Street, Baltimore, MD 21287, USA.
Paula BarrerasDepartment of Neurology, Johns Hopkins University, 600 N Wolfe Street, Baltimore, MD 21287, USA.
Lena SmirnovaCenter for Alternative to Animal Testing (CAAT), Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Daphne WiersmaCenter for Alternative to Animal Testing (CAAT), Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Liang ZhaoCenter for Alternative to Animal Testing (CAAT), Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA; Bloomberg-Kimmel Institute for Cancer Immunotherapy, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, 650 Orleans Street, CRB1, Rm 464, Baltimore, MD 21287, USA.
Georgina HarrisCenter for Alternative to Animal Testing (CAAT), Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA.
Thomas HartungCenter for Alternative to Animal Testing (CAAT), Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA; University of Konstanz, CAAT-Europe, Universitätsstr. 10, Konstanz 78464, Germany.
Helena T HogbergCenter for Alternative to Animal Testing (CAAT), Johns Hopkins University, 615 North Wolfe Street, Baltimore, MD 21205, USA. Electronic address: hhogberg2@jhu.edu.
Johns Hopkins University · USJoint Research Centre · ITSidney Kimmel Comprehensive Cancer Center · US

Funding

A 3D Model of Human Brain Development for Studying Gene/Environment InteractionsU18TR000547 · NCATS · JOHNS HOPKINS UNIVERSITY · PI HARTUNG, THOMAS · 2012 to 2013
$865k
NCATS NIH HHS U18 TR000547
6 · The paper itself

Abstract

Growing concern suggests that some chemicals exert (developmental) neurotoxicity (DNT and NT) and are linked to the increase in incidence of autism, attention deficit and hyperactivity disorders. The high cost of routine tests for DNT and NT assessment make it difficult to test the high numbers of existing chemicals. Thus, more cost effective neurodevelopmental models are needed. The use of induced pluripotent stem cells (iPSC) in combination with the emerging human 3D tissue culture platforms, present a novel tool to predict and study human toxicity. By combining these technologies, we generated multicellular brain spheroids (BrainSpheres) from human iPSC. The model has previously shown to be reproducible and recapitulates several neurodevelopmental features. Our results indicate, rotenone's toxic potency varies depending on the differentiation status of the cells, showing higher reactive oxygen species (ROS) and higher mitochondrial dysfunction during early than later differentiation stages. Immuno-fluorescence morphology analysis after rotenone exposure indicated dopaminergic-neuron selective toxicity at non-cytotoxic concentrations (1 μM), while astrocytes and other neuronal cell types were affected at (general) cytotoxic concentrations (25 μM). Omics analysis showed changes in key pathways necessary for brain development, indicating rotenone as a developmental neurotoxicant and show a possible link between previously shown effects on neurite outgrowth and presently observed effects on Ca2+ reabsorption, synaptogenesis and PPAR pathway disruption. In conclusion, our BrainSpheres model has shown to be a reproducible and novel tool to study neurotoxicity and developmental neurotoxicity. Results presented here support the idea that rotenone can potentially be a developmental neurotoxicant.

Indexed as

Age FactorsBrainDose-Response Relationship, DrugGene Expression ProfilingGene Expression Regulation, DevelopmentalHumansInduced Pluripotent Stem CellsInsecticidesMetabolomicsMitochondriaNeural Stem CellsNeurogenesisNeurogliaNeurotoxicity SyndromesOxidative StressReactive Oxygen SpeciesInsecticidesReactive Oxygen SpeciesRotenoneDevelopmental neurotoxicityDNTIn VitroOrganoidsRotenoneSpheroids

Identifiers

PMID29428530
PMCPMC6082736
OpenAlexW2794376805

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.