@article{RuszkiewiczdeMacedoMirandaVizueteetal.2019,
  author    = {Ruszkiewicz, Joanna and de Macedo, Gabriel Teixeira and Miranda-Vizuete, Antonio and Bowman, Aaron B. and Bornhorst, Julia and Schwerdtle, Tanja and Antunes Soares, Felix A. and Aschner, Michael},
  title     = {Sex-Specific response of caenorhabditis elegans to Methylmercury Toxicity},
  series = {Neurotoxicity Research},
  volume    = {35},
  journal   = {Neurotoxicity Research},
  number    = {1},
  publisher = {Springer},
  address   = {New York},
  issn      = {1029-8428},
  doi       = {10.1007/s12640-018-9949-4},
  pages     = {208 -- 216},
  year      = {2019},
  abstract  = {Methylmercury (MeHg), an abundant environmental pollutant, has long been known to adversely affect neurodevelopment in both animals and humans. Several reports from epidemiological studies, as well as experimental data indicate sex-specific susceptibility to this neurotoxicant; however, the molecular bases of this process are still not clear. In the present study, we used Caenorhabditis elegans (C. elegans), to investigate sex differences in response to MeHg toxicity during development. Worms at different developmental stage (L1, L4, and adult) were treated with MeHg for 1h. Lethality assays revealed that male worms exhibited significantly higher resistance to MeHg than hermaphrodites, when at L4 stage or adults. However, the number of worms with degenerated neurons was unaffected by MeHg, both in males and hermaphrodites. Lower susceptibility of males was not related to changes in mercury (Hg) accumulation, which was analogous for both wild-type (wt) and male-rich him-8 strain. Total glutathione (GSH) levels decreased upon MeHg in him-8, but not in wt. Moreover, the sex-dependent response of the cytoplasmic thioredoxin system was observedmales exhibited significantly higher expression of thioredoxin TRX-1, and thioredoxin reductase TRXR-1 expression was downregulated upon MeHg treatment only in hermaphrodites. These outcomes indicate that the redox status is an important contributor to sex-specific sensitivity to MeHg in C. elegans.},
  language  = {en}
}
@article{RuszkiewiczEndigGueveretal.2023,
  author    = {Ruszkiewicz, Joanna and Endig, Lisa and G{\"u}ver, Ebru and B{\"u}rkle, Alexander and Mangerich, Aswin},
  title     = {Life-cycle-dependent toxicities of mono- and bifunctional alkylating agents in the 3R-compliant model organism C. elegans},
  series = {Cells : open access journal},
  volume    = {12},
  journal   = {Cells : open access journal},
  number    = {23},
  publisher = {MDPI},
  address   = {Basel},
  issn      = {2073-4409},
  doi       = {10.3390/cells12232728},
  pages     = {16},
  year      = {2023},
  abstract  = {Caenorhabditis elegans (C. elegans) is gaining recognition and importance as an organismic model for toxicity testing in line with the 3Rs principle (replace, reduce, refine). In this study, we explored the use of C. elegans to examine the toxicities of alkylating sulphur mustard analogues, specifically the monofunctional agent 2-chloroethyl-ethyl sulphide (CEES) and the bifunctional, crosslinking agent mechlorethamine (HN2). We exposed wild-type worms at different life cycle stages (from larvae L1 to adulthood day 10) to CEES or HN2 and scored their viability 24 h later. The susceptibility of C. elegans to CEES and HN2 paralleled that of human cells, with HN2 exhibiting higher toxicity than CEES, reflected in LC50 values in the high µM to low mM range. Importantly, the effects were dependent on the worms' developmental stage as well as organismic age: the highest susceptibility was observed in L1, whereas the lowest was observed in L4 worms. In adult worms, susceptibility to alkylating agents increased with advanced age, especially to HN2. To examine reproductive effects, L4 worms were exposed to CEES and HN2, and both the offspring and the percentage of unhatched eggs were assessed. Moreover, germline apoptosis was assessed by using ced-1p::GFP (MD701) worms. In contrast to concentrations that elicited low toxicities to L4 worms, CEES and HN2 were highly toxic to germline cells, manifesting as increased germline apoptosis as well as reduced offspring number and percentage of eggs hatched. Again, HN2 exhibited stronger effects than CEES. Compound specificity was also evident in toxicities to dopaminergic neurons-HN2 exposure affected expression of dopamine transporter DAT-1 (strain BY200) at lower concentrations than CEES, suggesting a higher neurotoxic effect. Mechanistically, nicotinamide adenine dinucleotide (NAD+) has been linked to mustard agent toxicities. Therefore, the NAD+-dependent system was investigated in the response to CEES and HN2 treatment. Overall NAD+ levels in worm extracts were revealed to be largely resistant to mustard exposure except for high concentrations, which lowered the NAD+ levels in L4 worms 24 h post-treatment. Interestingly, however, mutant worms lacking components of NAD+-dependent pathways involved in genome maintenance, namely pme-2, parg-2, and sirt-2.1 showed a higher and compound-specific susceptibility, indicating an active role of NAD+ in genotoxic stress response. In conclusion, the present results demonstrate that C. elegans represents an attractive model to study the toxicology of alkylating agents, which supports its use in mechanistic as well as intervention studies with major strength in the possibility to analyze toxicities at different life cycle stages.},
  language  = {en}
}
@article{RuszkiewiczdeMacedoMirandaVizueteetal.2018,
  author    = {Ruszkiewicz, Joanna and de Macedo, Gabriel Teixeira and Miranda-Vizuete, Antonio and Teixeira da Rocha, Joao B. and Bowman, Aaron B. and Bornhorst, Julia and Schwerdtle, Tanja and Aschner, Michael},
  title     = {The cytoplasmic thioredoxin system in Caenorhabditis elegans affords protection from methylmercury in an age-specific manner},
  series = {Neurotoxicology : the interdisciplinary journal of effects to toxic substances on the nervous system},
  volume    = {68},
  journal   = {Neurotoxicology : the interdisciplinary journal of effects to toxic substances on the nervous system},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {0161-813X},
  doi       = {10.1016/j.neuro.2018.08.007},
  pages     = {189 -- 202},
  year      = {2018},
  abstract  = {Methylmercury (MeHg) is an environmental pollutant linked to many neurological defects, especially in developing individuals. The thioredoxin (TRX) system is a key redox regulator affected by MeHg toxicity, however the mechanisms and consequences of MeHg-induced dysfunction are not completely understood. This study evaluated the role of the TRX system in C. elegans susceptibility to MeHg during development. Worms lacking or overexpressing proteins from the TRX family were exposed to MeHg for 1 h at different developmental stage: L1, L4 and adult. Worms without cytoplasmic thioredoxin system exhibited age-specific susceptibility to MeHg when compared to wild-type (wt). This susceptibility corresponded partially to decreased total glutathione (GSH) levels and enhanced degeneration of dopaminergic neurons. In contrast, the overexpression of the cytoplasmic system TRX-1/TRXR-1 did not provide substantial protection against MeHg. Moreover, transgenic worms exhibited decreased protein expression for cytoplasmic thioredoxin reductase (TRXR-1). Both mitochondrial thioredoxin system TRX-2/TRXR-2, as well as other thioredoxin-like proteins: TRX-3, TRX-4, TRX-5 did not show significant role in C. elegans resistance to MeHg. Based on the current findings, the cytoplasmic thioredoxin system TRX-1/TRXR-1 emerges as an important age-sensitive protectant against MeHg toxicity in C. elegans.},
  language  = {en}
}