<i>In Vitro</i>
            Effects of Lead on Gene Expression in Neural Stem Cells and Associations between Up-regulated Genes and Cognitive Scores in Children

Wagner, Peter J.; Park, Hae-Ryung; Wang, Zhaoxi; Kirchner, Rory; Wei, Yongyue; Li, Su; Stanfield, Kirstie; Guilarte, Tomás R.; Wright, Robert O.; Christiani, David C.; Lu, Quan

doi:10.1289/ehp265

Cited by 35 publications

(21 citation statements)

References 69 publications

(73 reference statements)

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“…Oxidative stress plays a fundamental role in the pathogenesis and development of Pb-induced neurotoxicity. Pb exposure induced the generation of reactive oxygen species (ROS), which further cause cellular structure damage and the peroxidation of cell membrane lipids [ 1 , 29 ]. Previous studies showed that Pb exposure could cause transcriptomic changes in human neural stem cells stimulating oxidative stress, which could associate with neurodevelopment in children [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Gastrodin against Lead-Induced Brain Injury in Mice Associated with the Wnt/Nrf2 Pathway

et al. 2020

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Gastrodin (GAS), the main phenolic glycoside extracted from Gastrodia elata Blume, exhibited potential neuroprotective properties. Here we examined the protective effects of GAS against lead(Pb)-induced nerve injury in mice, and explores its underlying mechanisms. Our research findings revealed that GAS improved behavioral deficits in Pb-exposed mice. GAS reduced the accumulation of p-tau and amyloid-beta (Aβ). GAS inhibited Pb-induced inflammation in the brain, as indicated by the decreased levels of pro-inflammatory cytokines, including tumor necrosis factor-a (TNF-α), cyclooxygenase-2 (COX-2). GAS increased the expression levels of NR2A and neurotrophin brain-derived neurotrophic factor (BDNF). GAS inhibited Pb-induced apoptosis of neurons in hippocampus tissue, as indicated by the decreased levels of pro-apoptotic proteins Bax and cleaved caspase-3. Furthermore, the neuroprotective effects of GAS were associated with inhibiting oxidative stress by modulating nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated antioxidant signaling. GAS supplement activated the Wnt/β-catenin signaling pathway and reduced the expression of Wnt inhibitor Dickkopf-1 (Dkk-1). Collectively, this study clarified that GAS exhibited neuroprotective property by anti-oxidant, anti-inflammatory and anti-apoptosis effects and its ability to regulate the Wnt/Nrf2 pathway.

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Section: Discussionmentioning

confidence: 99%

Effects of Gastrodin against Lead-Induced Brain Injury in Mice Associated with the Wnt/Nrf2 Pathway

et al. 2020

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“…Another study, which was cited by Wagner et al 1 , showed that measurable effects in stem cells in vitro could occur at doses as low as 0.4 µM; this dose would represent a blood lead level of 800 µg/dL by our calculations 5 . In a study by Chan et al, the lowest dose of 1 µM lead used in a study of newborn rat neuronal stem cells would represent 1000 µg/L in serum and a massive systemic blood lead level of about 10,000 µg/dL 6 .…”

Section: V1mentioning

confidence: 66%

Matching target dose to target organ

Bannon

Williams

2016

F1000Res

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In vitro assays have become a mainstay of modern approaches to toxicology with the promise of replacing or reducing the number of in vivo tests required to establish benchmark doses, as well as increasing mechanistic understanding. However, matching target dose to target organ is an often overlooked aspect of in vitro assays, and the calibration of in vitro exposure against in vivo benchmark doses is often ignored, inadvertently or otherwise. An example of this was recently published in Environmental Health Perspectives by Wagner et al., where neural stems cells were used to model the molecular toxicity of lead. On closer examination of the in vitro work, the doses used in media reflected in vivo lead doses that would be at the highest end of lead toxicity, perhaps even lethal. Here we discuss the doses used and suggest more realistic doses for future work with stem cells or other neuronal cell lines.

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“…In the study by Wagner et al 1 , much of this may have been considered by the authors, and key assumptions may have been made; however, the question still remains whether the upregulation of genes in the Nrf2-mediated anti-oxidative stress pathway would have been observed if a more physiologically relevant dose of 0.2 µg/dL (0.1 µM) in the media (i.e., representing a blood lead level of 20 µg/dL) had been used.…”

mentioning

confidence: 96%

“…Another study, which was cited by Wagner et al 1 , showed that measurable effects in stem cells in vitro could occur at doses as low as 0.4 µM 5 ; this dose would represent a blood lead level of 829 µg/dL, using the same assumptions as above. In a study by Chan et al, the lowest dose of 1 µM lead used in a study of newborn rat neuronal stem cells would represent 20.73 µg/L in serum and a systemic blood lead level of about 2073 µg/dL 6 .…”

mentioning

confidence: 97%

“…A recent article by Wagner et al reported the involvement of the anti-oxidant Nrf2 transcription factor signaling pathway in the toxicity of lead using neural stem cells in an in vitro model of neuronal differentiation 1 . While this work was completed in a similar way to other studies involving in vitro lead exposure, the work avoids a critical, often neglected issue of what constitutes a relevant physiological dose in vitro .…”

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confidence: 99%

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