Persistent organic pollutants at the synapse: Shared phenotypes and converging mechanisms of developmental neurotoxicity

Latchney, Sarah E.; Majewska, Ania K.

doi:10.1002/dneu.22825

Cited by 17 publications

(8 citation statements)

References 247 publications

(406 reference statements)

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“…To our knowledge, no previous study has investigated the effects of perinatal dioxin exposure on structural brain changes in humans. Although some previous animal studies reported reduced cortical thickness in several brain areas and changes in cortical cell numbers and cell distributions in TCDD-exposed rats [29,30], recent animal studies suggest that dioxins in low doses may lead to neuronal dendritic overgrowth [22,24], which may in turn lead to increases in brain volume.…”

Section: Global and Regional Brain Volume Alterations Associated With...mentioning

confidence: 98%

“…We found that opposing effects were associated with high dioxin levels, observing both volume increases and volume decreases. Previous animal studies suggested that the effects of persistent organic pollutants (POPs), including dioxins, might be nonmonotonic: POPs exert both promoting and suppressing effects on neuronal dendritic growth, depending on their dose and the brain region, which may lead to brain volume increases and decreases, respectively [22][23][24].…”

Section: Regional Brain Volume Changes Associated With Blood Dioxin L...mentioning

confidence: 99%

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Alterations in Regional Brain Regional Volume Associated with Dioxin Exposure in Men Living in the Most Dioxin-Contaminated Area in Vietnam: Magnetic Resonance Imaging (MRI) Analysis Using Voxel-Based Morphometry (VBM)

Pham

Yokawa³

et al. 2021

Toxics

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To clarify the influence of dioxin exposure on brain morphometry, the present study investigated associations between dioxin exposure at high levels and brain structural irregularities in 32 Vietnamese men. Two exposure markers were used: blood dioxin levels, as a marker of exposure in adulthood, and perinatal dioxin exposure, estimated by maternal residency in a dioxin-contaminated area during pregnancy. All subjects underwent brain magnetic resonance imaging (MRI) scans. We analyzed correlations between regional gray matter volumes and blood dioxin levels, and compared regional volumes between men with and without perinatal dioxin exposure using the voxel-based morphometry (VBM) tool from Statistical Parametric Mapping 12 (SPM12). Blood 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was associated with low volume of the medial temporal pole and fusiform gyrus. Toxic equivalency (TEQ)-PCDDs were correlated with low medial temporal pole volume. However, 1,2,3,4,7,8-HxCDD was associated with high middle frontal gyrus and cerebellum volume. In men with perinatal dioxin exposure, the left inferior frontal gyrus pars orbitalis volume was significantly lower than in those without perinatal exposure. These results suggest that dioxin exposure during the perinatal period and in adulthood may alter regional brain volume, which might lead to cognitive deficits and unusual social emotional behavior in Vietnamese men living in dioxin-contaminated areas.

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Section: Global and Regional Brain Volume Alterations Associated With...mentioning

confidence: 98%

Section: Regional Brain Volume Changes Associated With Blood Dioxin L...mentioning

confidence: 99%

Alterations in Regional Brain Regional Volume Associated with Dioxin Exposure in Men Living in the Most Dioxin-Contaminated Area in Vietnam: Magnetic Resonance Imaging (MRI) Analysis Using Voxel-Based Morphometry (VBM)

Pham

Yokawa³

et al. 2021

Toxics

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“…Intracellular and extracellular biomarkers provide useful indicators for detecting cellular abnormality, with limits of detection at the range of micromolar to nanomolar levels [ 17 , 18 ]. However, recent studies have shown that chronic exposure to far lower levels of chemicals can induce cellular phenotypic responses [ 19 ]. Additionally, biomarker-based strategies are generally expensive and require the multi-step processing of cells, limiting their application in high-throughput detection [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Cell-Based Chemical Safety Assessment and Therapeutic Discovery Using Array-Based Sensors

Jiang

Chattopadhyay

Rotello

2022

IJMS

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Synthetic chemicals are widely used in food, agriculture, and medicine, making chemical safety assessments necessary for environmental exposure. In addition, the rapid determination of chemical drug efficacy and safety is a key step in therapeutic discoveries. Cell-based screening methods are non-invasive as compared with animal studies. Cellular phenotypic changes can also provide more sensitive indicators of chemical effects than conventional cell viability. Array-based cell sensors can be engineered to maximize sensitivity to changes in cell phenotypes, lowering the threshold for detecting cellular responses under external stimuli. Overall, array-based sensing can provide a robust strategy for both cell-based chemical risk assessments and therapeutics discovery.

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“…CYPs can also metabolically activate and detoxify several xenobiotics which enter the brain, as well as play important functions in brain homeostasis and disease. Indeed, a feature of most AhR ligands is their lipophilic nature, which allows them to cross the blood-brain barrier and affect brain physiology [ 16 , 17 , 18 , 19 , 20 , 21 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Aryl Hydrocarbon Receptor (AhR)-Mediated Signaling in iPSC-Derived Human Motor Neurons

et al. 2022

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Exposure to environmental pollutants and endogenous metabolites that induce aryl hydrocarbon receptor (AhR) expression has been suggested to affect cognitive development and, particularly in boys, also motor function. As current knowledge is based on epidemiological and animal studies, in vitro models are needed to better understand the effects of these compounds in the human nervous system at the molecular level. Here, we investigated expression of AhR pathway components and how they are regulated by AhR ligands in human motor neurons. Motor neurons generated from human induced pluripotent stem cells (hiPSCs) were characterized at the molecular level and by electrophysiology. mRNA levels of AhR target genes, CYP1A1 and CYP1B1 (cytochromes P450 1A1/1B1), and AhR signaling components were monitored in hiPSCs and in differentiated neurons following treatment with AhR ligands, 2,3,7,8,-tetrachlodibenzo-p-dioxin (TCDD), L-kynurenine (L-Kyn), and kynurenic acid (KA), by RT-qPCR. Changes in AhR cellular localization and CYP1A1 activity in neurons treated with AhR ligands were also assessed. The neurons we generated express motor neuron-specific markers and are functional. Transcript levels of CYP1B1, AhR nuclear translocators (ARNT1 and ARNT2) and the AhR repressor (AhRR) change with neuronal differentiation, being significantly higher in neurons than hiPSCs. In contrast, CYP1A1 and AhR transcript levels are slightly lower in neurons than in hiPSCs. The response to TCDD treatment differs in hiPSCs and neurons, with only the latter showing significant CYP1A1 up-regulation. In contrast, TCDD slightly up-regulates CYP1B1 mRNA in hiPSCs, but downregulates it in neurons. Comparison of the effects of different AhR ligands on AhR and some of its target genes in neurons shows that L-Kyn and KA, but not TCDD, regulate AhR expression and differently affect CYP1A1 and CYP1B1 expression. Finally, although TCDD does not significantly affect AhR transcript levels, it induces AhR protein translocation to the nucleus and increases CYP1A1 activity. This is in contrast to L-Kyn and KA, which either do not affect or reduce, respectively, CYP1A1 activity. Expression of components of the AhR signaling pathway are regulated with neuronal differentiation and are differently affected by TCDD, suggesting that pluripotent stem cells might be less sensitive to this toxin than neurons. Crucially, AhR signaling is affected differently by TCDD and other AhR ligands in human motor neurons, suggesting that they can provide a valuable tool for assessing the impact of environmental pollutants.

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Persistent organic pollutants at the synapse: Shared phenotypes and converging mechanisms of developmental neurotoxicity

Cited by 17 publications

References 247 publications

Alterations in Regional Brain Regional Volume Associated with Dioxin Exposure in Men Living in the Most Dioxin-Contaminated Area in Vietnam: Magnetic Resonance Imaging (MRI) Analysis Using Voxel-Based Morphometry (VBM)

Alterations in Regional Brain Regional Volume Associated with Dioxin Exposure in Men Living in the Most Dioxin-Contaminated Area in Vietnam: Magnetic Resonance Imaging (MRI) Analysis Using Voxel-Based Morphometry (VBM)

Cell-Based Chemical Safety Assessment and Therapeutic Discovery Using Array-Based Sensors

Aryl Hydrocarbon Receptor (AhR)-Mediated Signaling in iPSC-Derived Human Motor Neurons

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