Mitochondrial Stress Response in Neural Stem Cells Exposed to Electronic Cigarettes

Zahedi, Atena; Phandthong, Rattapol; Chaili, Angela; Leung, Sara W.; Omaiye, Esther E; Talbot, Prue

doi:10.1016/j.isci.2019.05.034

Cited by 51 publications

(44 citation statements)

References 91 publications

(120 reference statements)

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“…While the brain is formed, GABA does not only serve short-term communication, but it also triggers synaptogenesis (Oh et al 2016), synapse pruning (Wu et al 2012), neuronal migration (Li et al 2018), stem cell fate (Song et al 2012) and neurogenesis (Kriegstein 2005;Tozuka et al 2005). Other neurotransmitters take similar roles, such as spine growth triggered by glutamate (Kwon and Sabatini 2011), and various neurogenic processes affected by serotonin (Schaefer et al 2013;Migliarini et al 2013;Agrawal et al 2019), or nicotine (Slikker Jr et al 2005;Dwyer et al 2009;Slotkin et al 2016;Zahedi et al 2019). The toxicological consequence is that disturbance of neurotransmitter signaling during development can result in an altered brain connectivity in later life.…”

Section: Introductionmentioning

confidence: 99%

Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons

et al. 2021

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Neonicotinoid pesticides, originally developed to target the insect nervous system, have been reported to interact with human receptors and to activate rodent neurons. Therefore, we evaluated in how far these compounds may trigger signaling in human neurons, and thus, affect the human adult or developing nervous system. We used SH-SY5Y neuroblastoma cells as established model of nicotinic acetylcholine receptor (nAChR) signaling. In parallel, we profiled dopaminergic neurons, generated from LUHMES neuronal precursor cells, as novel system to study nAChR activation in human post-mitotic neurons. Changes of the free intracellular Ca2+ concentration ([Ca2+]i) were used as readout, and key findings were confirmed by patch clamp recordings. Nicotine triggered typical neuronal signaling responses that were blocked by antagonists, such as tubocurarine and mecamylamine. Pharmacological approaches suggested a functional expression of α7 and non-α7 nAChRs on LUHMES cells. In this novel test system, the neonicotinoids acetamiprid, imidacloprid, clothianidin and thiacloprid, but not thiamethoxam and dinotefuran, triggered [Ca2+]i signaling at 10–100 µM. Strong synergy of the active neonicotinoids (at low micromolar concentrations) with the α7 nAChR-positive allosteric modulator PNU-120596 was observed in LUHMES and SH-SY5Y cells, and specific antagonists fully inhibited such signaling. To provide a third line of evidence for neonicotinoid signaling via nAChR, we studied cross-desensitization: pretreatment of LUHMES and SH-SY5Y cells with active neonicotinoids (at 1–10 µM) blunted the signaling response of nicotine. The pesticides (at 3–30 µM) also blunted the response to the non-α7 agonist ABT 594 in LUHMES cells. These data show that human neuronal cells are functionally affected by low micromolar concentrations of several neonicotinoids. An effect of such signals on nervous system development is a toxicological concern.

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Section: Introductionmentioning

confidence: 99%

Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons

et al. 2021

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“…With growing appreciation for toxicity of flavoring chemicals [30,32,39,40,41,42] and a specific concern for the consequences of exposure on the vulnerable developing lung, we sought to determine the relative toxicity and the impact on physiologic responses in immature lungs cells and tissue exposed to popular nicotine-free e-cigarette flavored solutions [34,43]. Unique access to fetal, newborn, and adult ovine pulmonary cells lines as well isolated neonatal and adult ovine lung tissue allowed evaluation of developmental susceptibility.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Consequences of Electronic-Cigarette Flavoring Exposure on the Immature Lung

Berkelhamer

Helman

Gugino

et al. 2019

IJERPH

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Background: The developing lung is uniquely susceptible and may be at increased risk of injury with exposure to e-cigarette constituents. We hypothesize that cellular toxicity and airway and vascular responses with exposure to flavored refill solutions may be altered in the immature lung. Methods: Fetal, neonatal, and adult ovine pulmonary artery smooth muscle cells (PASMC) were exposed to popular flavored nicotine-free e-cigarette refill solutions (menthol, strawberry, tobacco, and vanilla) and unflavored solvents: propylene glycol (PG) or vegetable glycerin (VG). Viability was assessed by lactate dehydrogenase assay. Brochodilation and vasoreactivity were determined on isolated ovine bronchial rings (BR) and pulmonary arteries (PA). Results: Neither PG or VG impacted viability of immature or adult cells; however, exposure to menthol and strawberry flavored solutions increased cell death. Neonatal cells were uniquely susceptible to menthol flavoring-induced toxicity, and all four flavorings demonstrated lower lethal doses (LD50) in immature PASMC. Exposure to flavored solutions induced bronchodilation of neonatal BR, while only menthol induced airway relaxation in adults. In contrast, PG/VG and flavored solutions did not impact vasoreactivity with the exception of menthol-induced relaxation of adult PAs. Conclusion: The immature lung is uniquely susceptible to cellular toxicity and altered airway responses with exposure to common flavored e-cigarette solutions.

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“…By stimulating nAChRs, nicotine was shown to affect mitochondrial function and induce a mitochondrial stress response ( Gergalova et al., 2012 ; Lykhmus et al., 2014 ; Zahedi et al., 2019 ). To examine whether chronic nicotine exposure impacts mitochondrial stress in C. elegans , we used an established transcriptional reporter for mitochondrial stress, hsp-6 ::GFP ( Yoneda et al., 2004 ).…”

Section: Resultsmentioning

confidence: 99%

Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress

et al. 2021

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Summary Tobacco smoking is a risk factor for several human diseases. Conversely, smoking also reduces the prevalence of Parkinson’s disease, whose hallmark is degeneration of substantia nigra dopaminergic neurons (DNs). We use C. elegans as a model to investigate whether tobacco-derived nicotine activates nicotinic acetylcholine receptors (nAChRs) to selectively protect DNs. Using this model, we demonstrate conserved functions of DN-expressed nAChRs. We find that DOP-2, a D3-receptor homolog; MCU-1, a mitochondrial calcium uniporter; PINK-1 (PTEN-induced kinase 1); and PDR-1 (Parkin) are required for nicotine-mediated protection of DNs. Together, our results support involvement of a calcium-modulated, mitochondrial stress-activated PINK1/Parkin-dependent pathway in nicotine-induced neuroprotection. This suggests that nicotine-selective protection of substantia nigra DNs is due to the confluence of two factors: first, their unique vulnerability to mitochondrial stress, which is mitigated by increased mitochondrial quality control due to PINK1 activation, and second, their specific expression of D3-receptors.

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Mitochondrial Stress Response in Neural Stem Cells Exposed to Electronic Cigarettes

Cited by 51 publications

References 91 publications

Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons

Functional alterations by a subgroup of neonicotinoid pesticides in human dopaminergic neurons

In Vitro Consequences of Electronic-Cigarette Flavoring Exposure on the Immature Lung

Conserved nicotine-activated neuroprotective pathways involve mitochondrial stress

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