An in vitro model to study brain tissue recovery

Gourov, Andrei V.; Curran, Bridget Mary

doi:10.1016/j.mehy.2014.03.001

Cited by 1 publication

(1 citation statement)

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“…The present work does not inform us on the specificity of rotenone in inducing resilience, since no other cell types or chemicals were tested yet, but as, with an AOP approach, demonstrates how events which can lead to adversity and their reversibility can be addressed. Some have studied repeated-dose chronic effects in vitro (Borland et al 2008; Shaikh and Nicholson 2009; Gourov and Currran 2014), but not with a focus on recovery, adaptation, and resilience in dopaminergic neurons. Gene–environment interactions play an important role in neurodegeneration, e.g., in PD, and an altered genetic/epigenetic response to toxicants is thought to primarily drive sporadic PD (Miranda-Morales et al 2017).…”

Section: Discussionmentioning

confidence: 99%

Toxicity, recovery, and resilience in a 3D dopaminergic neuronal in vitro model exposed to rotenone

et al. 2018

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To date, most in vitro toxicity testing has focused on acute effects of compounds at high concentrations. This testing strategy does not reflect real-life exposures, which might contribute to long-term disease outcome. We used a 3D-human dopaminergic in vitro LUHMES cell line model to determine whether effects of short-term rotenone exposure (100 nM, 24 h) are permanent or reversible. A decrease in complex I activity, ATP, mitochondrial diameter, and neurite outgrowth were observed acutely. After compound removal, complex I activity was still inhibited; however, ATP levels were increased, cells were electrically active and aggregates restored neurite outgrowth integrity and mitochondrial morphology. We identified significant transcriptomic changes after 24 h which were not present 7 days after wash-out. Our results suggest that testing short-term exposures in vitro may capture many acute effects which cells can overcome, missing adaptive processes, and long-term mechanisms. In addition, to study cellular resilience, cells were re-exposed to rotenone after wash-out and recovery period. Pre-exposed cells maintained higher metabolic activity than controls and presented a different expression pattern in genes previously shown to be altered by rotenone. NEF2L2, ATF4, and EAAC1 were downregulated upon single hit on day 14, but unchanged in pre-exposed aggregates. DAT and CASP3 were only altered after re-exposure to rotenone, while TYMS and MLF1IP were downregulated in both single-exposed and pre-exposed aggregates. In summary, our study shows that a human cell-based 3D model can be used to assess cellular adaptation, resilience, and long-term mechanisms relevant to neurodegenerative research.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2250-8) contains supplementary material, which is available to authorized users.

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