Tissue-specific Nrf2 signaling protects against methylmercury toxicity in Drosophila neuromuscular development

Gunderson, Jakob; Peppriell, Ashley E.; Vorojeikina, Daria; Rand, Matthew D.

doi:10.1007/s00204-020-02879-z

Cited by 14 publications

(9 citation statements)

References 71 publications

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“…Developmental MeHg exposures not only retard tissue development [ 41 , 42 ], but they also trigger long-lasting effects secondary to altered neuronal differentiation and neurogenesis [ 19 , 43 ]. Studies in in vitro cell cultures, including primary cell culture, immortalized neuronal cell lines, and human iPSC derived neurons, as well as animal models, suggest that exposure to low-level MeHg at the early developmental stage or parental lines induced long-last effects at the mature stage or even in future generations [ 17 , 18 , 19 , 44 ].…”

Section: Mehg and Neurogenesismentioning

confidence: 99%

Epigenetics and Methylmercury-Induced Neurotoxicity, Evidence from Experimental Studies

Tao

Tinkov

Skalny

et al. 2023

Toxics

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MeHg is an environmental neurotoxin that can adversely affect the development of the nervous system. The molecular integrity of chromatin in the nucleus is an important target of MeHg. Low levels of MeHg trigger epigenetic mechanisms that may be involved in long-lasting and transgenerational neurotoxicity after exposure. Emerging evidence has shown that these mechanisms include histone modification, siRNA, and DNA methylation. The MeHg-induced inhibition of neurodifferentiation and neurogenesis are mechanistically associated with epigenetic alterations in critical genes, such as neurotrophin brain-derived neurotrophic factor (BDNF). Further, MeHg exposure has been shown to alter the activity and/or expression of the upstream regulators of chromatin structure, including histone deacetylases (HDACs) and DNA methyltransferase (DNMTs), which may trigger permanent alterations in histone modifications and DNA methylation. MeHg-exposure also alters several species of miRNA that are associated with neurodevelopment. Genetic studies in the C. elegans model of MeHg-induced toxicity proposes a potential interplay between exogenous RNAi and antioxidant defense. In this review, we discuss the molecular basis for MeHg exposure-induced alterations in chromatin structure and the roles of histone modifications, siRNA, and DNA methylation in MeHg-induced neurotoxic effects.

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Section: Mehg and Neurogenesismentioning

confidence: 99%

Epigenetics and Methylmercury-Induced Neurotoxicity, Evidence from Experimental Studies

Tao

Tinkov

Skalny

et al. 2023

Toxics

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“…Flies carrying reporter transgenes can be used for a toxicity readout. For example, flies engineered to express the antioxidant response element fused to GFP are effective as a reporter of Nrf2 transcription factor activation in response to specific oxidants, metals, and drugs (Gunderson et al., 2020; Sykiotis & Bohmann, 2008). Other strategies have used the promoter of heat shock protein 70 (HSP70) linked to reporter genes (e.g., lacZ or GFP) to report a toxic response to even crude mixtures of toxicants (Siddique et al., 2008).…”

Section: Measuring Toxic Exposure In the Flymentioning

confidence: 99%

“…Other strategies have used the promoter of heat shock protein 70 (HSP70) linked to reporter genes (e.g., lacZ or GFP) to report a toxic response to even crude mixtures of toxicants (Siddique et al., 2008). Such a reporter gene strategy can be used not only to reveal global toxicity across the fly but also to localize toxicity to specific organs and cells through microscopy (Gunderson et al., 2020; Siddique et al., 2007).…”

Section: Measuring Toxic Exposure In the Flymentioning

confidence: 99%

Perspectives on the Drosophila melanogaster Model for Advances in Toxicological Science

Rand,

Tennessen,

Mackay

et al. 2023

Current Protocols

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The use of Drosophila melanogaster for studies of toxicology has grown considerably in the last decade. The Drosophila model has long been appreciated as a versatile and powerful model for developmental biology and genetics because of its ease of handling, short life cycle, low cost of maintenance, molecular genetic accessibility, and availability of a wide range of publicly available strains and data resources. These features, together with recent unique developments in genomics and metabolomics, make the fly model especially relevant and timely for the development of new approach methodologies and movements toward precision toxicology. Here, we offer a perspective on how flies can be leveraged to identify risk factors relevant to environmental exposures and human health. First, we review and discuss fundamental toxicologic principles for experimental design with Drosophila. Next, we describe quantitative and systems genetics approaches to resolve the genetic architecture and candidate pathways controlling susceptibility to toxicants. Finally, we summarize the current state and future promise of the emerging field of Drosophila metabolomics for elaborating toxic mechanisms. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC.

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“…It is difficult to dissect the mechanisms of methyl-mercury-induced developmental toxicity due to a wide variety of adverse effects in humans. Larval exposure in Drosophila resulted in morphological muscle defects which correlated with failed adult eclosion [42]. Methyl mercury exposure caused enhanced expression of an antioxidant reporter construct in the muscles.…”

Section: Dnt Studies In Drosophilamentioning

confidence: 99%

“…To characterize antioxidant signaling by the Drosophila orthologue of Nrf2 transcription factor as protective measure, adult eclosion behavior was recorded in parallel with morphology of two muscle groups. Muscle-and neuron-specific genetic manipulation showed tissue-specific, but independent protective functions of the Nrf2 signaling pathway against developmental toxicity [42].…”

Section: Dnt Studies In Drosophilamentioning

confidence: 99%

Looking at Developmental Neurotoxicity Testing from the Perspective of an Invertebrate Embryo

Bicker¹

2022

IJMS

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Developmental neurotoxicity (DNT) of chemical compounds disrupts the formation of a normal brain. There is impressive progress in the development of alternative testing methods for DNT potential in chemicals, some of which also incorporate invertebrate animals. This review briefly touches upon studies on the genetically tractable model organisms of Caenorhabditis elegans and Drosophila melanogaster about the action of specific developmental neurotoxicants. The formation of a functional nervous system requires precisely timed axonal pathfinding to the correct cellular targets. To address this complex key event, our lab developed an alternative assay using a serum-free culture of intact locust embryos. The first neural pathways in the leg of embryonic locusts are established by a pair of afferent pioneer neurons which use guidance cues from membrane-bound and diffusible semaphorin proteins. In a systematic approach according to recommendations for alternative testing, the embryo assay quantifies defects in pioneer navigation after exposure to a panel of recognized test compounds for DNT. The outcome indicates a high predictability for test-compound classification. Since the pyramidal neurons of the mammalian cortex also use a semaphorin gradient for neurite guidance, the assay is based on evolutionary conserved cellular mechanisms, supporting its relevance for cortical development.

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Tissue-specific Nrf2 signaling protects against methylmercury toxicity in Drosophila neuromuscular development

Cited by 14 publications

References 71 publications

Epigenetics and Methylmercury-Induced Neurotoxicity, Evidence from Experimental Studies

Epigenetics and Methylmercury-Induced Neurotoxicity, Evidence from Experimental Studies

Perspectives on the Drosophila melanogaster Model for Advances in Toxicological Science

Looking at Developmental Neurotoxicity Testing from the Perspective of an Invertebrate Embryo

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