Expanding the test set: Chemicals with potential to disrupt mammalian brain development

Mundy, William R.; Padilla, Stephanie; Breier, Joseph M.; Crofton, Kevin M.; Gilbert, Mary E.; Herr, David W.; Jensen, Karl F.; Radio, Nicholas M.; Raffaele, Kathleen C.; Schumacher, Kelly; Shafer, Timothy J.; Cowden, John

doi:10.1016/j.ntt.2015.10.001

Cited by 78 publications

(78 citation statements)

References 214 publications

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“…Of the 33 compounds listed, the majority (n = 29) overlap with the more extensive list assembled by scientists from the EPA (Mundy et al, 2015). The non-overlapping references suggested here are the pesticide lindane, the recreational drug 3,4-methylenedioxy-N-methamphetamine, and the groups of perfluorinated aliphatic compounds comprising perfluoro-octanoic acid (PFOA) and perfluoroactane-sulfonic acid (PFOS).…”

Section: Selection Of High-quality Dnt Reference Compoundsmentioning

confidence: 99%

“…Developmental neurotoxicity (DNT) may be broadly defined as an adverse change in the structure or function of the nervous system that manifests after exposure to a chemical during the prenatal or gestational period (Mundy et al, 2015). Notably, the adverse change canmanifest well after the toxicant exposure has ended, a phenomenon referred to as ‘delayed consequence of early life exposure’.…”

Section: Introductionmentioning

confidence: 99%

“…This list has been complemented with additional background information (e.g. reference to the respective animal studies) and re-published to support the development of high-throughput screening systems (Mundy et al, 2015). This extensive list contains both direct- and indirect-acting compounds, and the quality of the underlying publications shows a large variability.…”

Section: Introductionmentioning

confidence: 99%

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Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use

Aschner

Ceccatelli

Daneshian

et al. 2016

ALTEX

127

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SummaryThere is a paucity of information concerning the developmental neurotoxicity (DNT) hazard posed by industrial and environmental chemicals. New testing approaches will most likely be based on batteries of alternative and complementary (non-animal) tests. As DNT is assumed to result from the modulation of fundamental neurodevelopmental processes (such as neuronal differentiation, precursor cell migration or neuronal network formation) by chemicals, the first generation of alternative DNT tests target these processes. The advantage of such types of assays is that they capture toxicants with multiple targets and modes-of-action. Moreover, the processes modelled by the assays can be linked to toxicity endophenotypes, i.e. alterations in neural connectivity that form the basis for neurofunctional deficits in man. The authors of this review convened in a workshop to define criteria for the selection of positive/negative controls, to prepare recommendations on their use, and to initiate the setup of a directory of reference chemicals. For initial technical optimization of tests, a set of >50 endpoint-specific control compounds was identified. For further test development, an additional “test” set of 33 chemicals considered to act directly as bona fide DNT toxicants is proposed, and each chemical is annotated to the extent it fulfills these criteria. A tabular compilation of the original literature used to select the test set chemicals provides information on statistical procedures, and toxic/non-toxic doses (both for pups and dams). Suggestions are provided on how to use the >100 compounds (including negative controls) compiled here to address specificity, adversity and use of alternative test systems.

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Section: Selection Of High-quality Dnt Reference Compoundsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use

Aschner

Ceccatelli

Daneshian

et al. 2016

ALTEX

127

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“…Neurotoxins can affect human neural progenitor (hNP) cell to neuron differentiation, survival, proliferation and cellular functions during neurogenesis (such as neurite outgrowth), resulting in profound functional and behavioral deficits in an exposed developing human central nervous system (CNS) [1]. The concept of an embryonic and fetal basis for adult disease has emerged from these findings and has received considerable attention in the scientific community [2, 3].…”

Section: Introductionmentioning

confidence: 99%

High content imaging quantification of multiple in vitro human neurogenesis events after neurotoxin exposure

Wang

Majumder

Webb

et al. 2016

BMC Pharmacol Toxicol

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BackgroundOur objective was to test neural active compounds in a human developmental neurotoxicity (DNT) model that represents neural tube stages of vulnerability. Previously we showed that 14 days in vitro (DIV 14) was sufficient to generate cryopreserved neuronal cells for post thaw neurite recovery assays. However, short exposure and assessment may not detect toxicants that affect an early neurogenesis continuum, from a mitotic human neural progenitor (hNP) cell population through the course of neurite outgrowth in differentiating neurons. Therefore, we continuously exposed differentiating hNP cells from DIV 0 through DIV 14 to known toxicants and endocrine active compounds in order to assess at DIV 14 effects of these compounds in a human DNT maturation model for neurogenesis.MethodsThe Human DNT continuum (DIV 0 to DIV 14) was determined using immunocytochemistry for SOX1+ (proliferating hNP) and HuC/D+ (post mitotic neurons). The cumulative effects of five compounds was observed on neurite outgrowth in (βIII-tubulin+) and (HuC/D+) cells using high content imaging. All data were analyzed using a one-way ANOVA with a significance threshold of p < 0.05.ResultsDuring maturation in vitro, the neural cultures transitioned from uniform hNP cells (DIV 0) to predominantly mature post mitotic neuronal neurons (HuC/D+, 65%; DIV14) but also maintained a smaller population of hNP cells (SOX1+). Using this DNT maturation model system, Bis-1, testosterone, and β-estradiol inhibited neuronal maturation at micromolar levels but were unaffected by acetaminophen. β-estradiol also disrupted neurite extension at 10 μM. Treating cells in this window with Bisphenol A (BPA) significantly inhibited neurite outgrowth and branching in these continuum cultures but only at the highest concentrations tested (10 μM).ConclusionsCumulative effects of neurotoxicant exposure during a maturation continuum altered human neurogenesis at lower exposure levels than observed in acute exposure of static cryopreserved neurite recovery neurons cultures. Unlike prior acute studies, β-estradiol was highly toxic when present throughout the continuum and cytotoxicity was manifested starting early in the continuum via a non-estrogen receptor α (ER α) mechanism. Therefore, the effect of neural developmental neurotoxins can and should be determined during the dynamic process of human neural maturation.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-016-0107-4) contains supplementary material, which is available to authorized users.

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“…Many of these human cell-based assays have been used to study small numbers of chemicals (n < 15; e.g., Harrill et al, 2011;He et al, 2012;Rempel et al, 2015;Baumann et al, 2016;Brown et al, 2016) or to derive mechanistic information for limited numbers of chemicals (e.g., Gassmann et al, 2010;Balmer et al, 2012;Balmer and Leist, 2014;Barenys et al, 2016). Only a few have been utilized to screen larger numbers (n > 15) of compounds (e.g., Stiegler et al, 2011;Zimmer et al, 2012;Culbreth et al, 2012;McConnell et al, 2012;Krug et al, 2013;Valdivia et al, 2014;Mundy et al, 2015;Hoelting et al, 2016;Nyffeler et al, 2016).…”

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confidence: 99%

OECD/EFSA workshop on developmental neurotoxicity (DNT): The use of non-animal test methods for regulatory purposes

Fritsche

Crofton

Hernández

et al. 2017

ALTEX

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Expanding the test set: Chemicals with potential to disrupt mammalian brain development

Cited by 78 publications

References 214 publications

Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use

Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use

High content imaging quantification of multiple in vitro human neurogenesis events after neurotoxin exposure

OECD/EFSA workshop on developmental neurotoxicity (DNT): The use of non-animal test methods for regulatory purposes

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