Abstract
The increased application of graphene oxide (GO), a new carbon-based engineered nanomaterial, has generated a potential toxicity in humans and the environment. Previous studies have identified some dysregulated microRNAs (miRNAs), such as up-regulated mir-235, in organisms exposed to GO. However, the detailed mechanisms of the dysregulation of miRNA underlying GO toxicity are still largely elusive. In this study, we employed Caenorhabditis elegans as an in vivo model to investigate the biological function and molecular basis of mir-235 in the regulation of GO toxicity. After low concentration GO exposure, mir-235 (n4504) mutant nematodes were sensitive to GO toxicity, implying that mir-235 mediates a protection mechanism against GO toxicity. Tissue-specific assays suggested that mir-235 expressed in intestine is required for suppressing the GO toxicity in C. elegans. daf-12, a gene encoding a member of the steroid hormone receptor superfamily, acts as a target gene of mir-235 in the nematode intestine in response to GO treatment, and RNAi knockdown of daf-12 suppressed the sensitivity of mir-235(n4503) to GO toxicity. Further genetic analysis showed that DAF-12 acted in the upstream of DAF-16 in insulin/IGF-1 signaling pathway and PMK-1 in p38 MAPK signaling pathway in parallel to regulate GO toxicity. Altogether, our results revealed that mir-235 may activate a protective mechanism against GO toxicity by suppressing the DAF-12-DAF-16 and DAF-12-PMK-1 signaling cascade in nematodes, which provides an important molecular basis for the in vivo toxicity of GO at the miRNA level.
Highlights
The increased application of graphene oxide (GO), a new carbon-based engineered nanomaterial, has generated a potential toxicity in humans and the environment
Recent studies have indicated that some microRNAs may function in the control of GO toxicity, which further improves our understanding of the molecular mechanism of GO toxicity18–20. miRNAs are a class of endogenous nucleotide non-protein-encoding RNAs with 21–23 bases, and regulate eukaryotic gene expression at the post-transcriptional level21,22. miRNAs inhibit gene expression primarily by binding to certain sites of the 3′ untranslated regions (3′ UTRs) of target mRNAs, which results in degradation of mRNA and inhibition of protein translation[23,24,25]
Our results indicated that the intestinal mir-235/DAF-12 acted the upstream of both DAF-16 in the insulin/insulin growth factor-1 (IGF-1) and PMK-1 in p38 MAP Kinase (MAPK) signaling pathway in parallel to regulate GO toxicity in nematodes
Summary
The increased application of graphene oxide (GO), a new carbon-based engineered nanomaterial, has generated a potential toxicity in humans and the environment. Previous studies have identified some dysregulated microRNAs (miRNAs), such as up-regulated mir-235, in organisms exposed to GO. We employed Caenorhabditis elegans as an in vivo model to investigate the biological function and molecular basis of mir-235 in the regulation of GO toxicity. Our results revealed that mir-235 may activate a protective mechanism against GO toxicity by suppressing the DAF-12-DAF-16 and DAF-12PMK-1 signaling cascade in nematodes, which provides an important molecular basis for the in vivo toxicity of GO at the miRNA level. Owing to its sensitivity to environmental toxicants, C. elegans has been widely used as an in vivo model for studying the toxicity assessment and toxicological mechanisms of environmental toxicants[11]. Let-7 acted as a downstream target for epidermal BLI-1 in the regulation of GO-PEG toxicity[20]
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