Tissue-specific Nrf2 signaling protects against methylmercury toxicity in Drosophila neuromuscular development
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Tissue‑specific Nrf2 signaling protects against methylmercury toxicity in Drosophila neuromuscular development Jakob T. Gunderson1 · Ashley E. Peppriell1 · Daria Vorojeikina1 · Matthew D. Rand1 Received: 23 May 2020 / Accepted: 12 August 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Methylmercury (MeHg) can elicit cognitive and motor deficits due to its developmental neuro- and myotoxic properties. While previous work has demonstrated that Nrf2 antioxidant signaling protects from MeHg toxicity, in vivo tissue-specific studies are lacking. In Drosophila, MeHg exposure shows greatest developmental toxicity in the pupal stage resulting in failed eclosion (emergence of adults) and an accompanying ‘myosphere’ phenotype in indirect flight muscles (IFMs). To delineate tissue-specific contributions to MeHg-induced motor deficits, we investigated the potential of Nrf2 signaling in either muscles or neurons to moderate MeHg toxicity. Larva were exposed to various concentrations of MeHg (0–20 µM in food) in combination with genetic modulation of the Nrf2 homolog cap-n-collar C (CncC), or its negative regulator Keap1. Eclosion behavior was evaluated in parallel with the morphology of two muscle groups, the thoracic IFMs and the abdominal dorsal internal oblique muscles (DIOMs). CncC signaling activity was reported with an antioxidant response element construct (ARE-GFP). We observed that DIOMs are distinguished by elevated endogenous ARE-GFP expression, which is only transiently seen in the IFMs. Dose-dependent MeHg reductions in eclosion behavior parallel formation of myospheres in the DIOMs and IFMs, while also increasing ARE-GFP expression in the DIOMs. Modulating CncC signaling via muscle-specific Keap1 knockdown and upregulation gives a rescue and exacerbation, respectively, of MeHg effects on eclosion and myospheres. Interestingly, muscle-specific CncC upregulation and knockdown both induce lethality. In contrast, neuron-specific upregulation of CncC, as well as Keap1 knockdown, rescued MeHg effects on eclosion and myospheres. Our findings indicate that enhanced CncC signaling localized to either muscles or neurons is sufficient to rescue muscle development and neuromuscular function from a MeHg insult. Additionally, there may be distinct roles for CncC signaling in myo-morphogenesis. Keywords Methylmercury · Nrf2 signaling · Neuromuscular development · Myotoxicity · Drosophila
Introduction Methylmercury (MeHg) is a pervasive global pollutant that can accumulate in fish and seafood, which may in turn pose risks of toxicity for humans. (Chen et al. 2008; Cunningham et al. 2003; Kim and Zoh 2012). Historical accidental poisonings have shown that the developing fetus is an especially Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00204-020-02879-z) contains supplementary material, which is available to authorized users. * Matthew D. Rand [email protected] 1
Department of Environmental Medicine, Univers
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