Abstract
Graphene oxide (GO) has been shown to cause multiple toxicities in various organisms. However, the underlying molecular mechanisms for GO-induced shortened longevity are still unclear. We employed Caenorhabditis elegans to investigate the possible involvement of insulin signaling pathway in the control of GO toxicity and its underlying molecular mechanisms. Mutation of daf-2, age-1, akt-1, or akt-2 gene induced a resistant property of nematodes to GO toxicity, while mutation of daf-16 gene led to a susceptible property of nematodes to GO toxicity, suggesting that GO may dysregulate the functions of DAF-2/IGF-1 receptor, AGE-1, AKT-1 and AKT-2-mediated kinase cascade, and DAF-16/FOXO transcription factor. Genetic interaction analysis suggested the involvement of signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16 in the control of GO toxicity on longevity. Moreover, intestinal RNA interference (RNAi) analysis demonstrated that GO reduced longevity by affecting the functions of signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16 in the intestine. DAF-16 could also regulate GO toxicity on longevity by functioning upstream of SOD-3, which encodes an antioxidation system that prevents the accumulation of oxidative stress. Therefore, intestinal insulin signaling may encode two different molecular mechanisms responsible for the GO toxicity in inducing the shortened longevity. Our results highlight the key role of insulin signaling pathway in the control of GO toxicity in organisms.
Highlights
Caenorhabditis elegans is a classic animal model that offer an assay system for investigating the in vivo toxicological mechanisms of toxicants including the ENMs13
Daf-18(ok480) mutants were susceptible to Graphene oxide (GO) toxicity on locomotion behavior or lifespan (Fig. 2c,d, Table S2). These results suggest that AGE-1, AKT-1, and AKT-2 constitute a kinase cascade for insulin signaling pathway, which is involved in the control of GO toxicity in nematodes
We found that intestine-specific RNA interference (RNAi) of the daf-2, age-1, akt-1, or akt-2 gene resulted in prolonged lifespan, whereas intestine-specific RNAi of the daf-16 or daf-18 gene led to reduced lifespan (Fig. 5, Table S5)
Summary
Caenorhabditis elegans is a classic animal model that offer an assay system for investigating the in vivo toxicological mechanisms of toxicants including the ENMs13. Insulin/insulin-like growth factor (IGF) signaling pathway has been implicated as a key molecular mechanism for longevity control in nematodes[22,23]. This signaling pathway has been shown to play key roles in regulating other important biological processes including fat storage, innate immunity, and stress response[24,25,26]. Our results suggest that the insulin signaling pathway may encode two different molecular mechanisms for the shortened lifespan induced by GO in nematodes. The examination of these molecular mechanisms of the regulation of GO toxicity by the insulin signaling pathway provides an important basis for further elucidation of molecular networks involved in the control of GO toxicity in organisms
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