Molecular Mechanism Of Linc-37 And Linc-5 In Regulating The Graphene Oxide Toxicity In Caenorhabditis Elegans

Graphene oxide?GO?,a new carbon nanomaterial,has a wide application prospect in the field of biomedicine due to its unique physicochemical properties,such as good hydrophilicity,excellent biocompatibility,and ultra-high surface area.Although a great deal of researches have been done with the concern on the application of this new nanomaterial,its biosafety and potential toxicity on environmental organisms and human health have attracted more and more attention.Caenorhabditis elegans has emerged as an important animal model in various fields,including neurotoxicology,genetic toxicology,and environmental toxicology.Previous studies have described the molecular mechanism on induction of graphene oxide toxicity in C.elegans at the mRNA,microRNA,and lncRNA levels.Long noncoding RNAs?lncRNAs?are commonly defined as non protein-coding transcripts with longer than 200 nucleotides in length that can be spliced,capped and polyadenylated but have little or no protein-coding potential.They have been proven to be required for various biological processes.However,the molecular mechanisms and biological functions in regulating the toxicity of engineered nanomaterials for the most the annoted lncRNAs remain unknown.In this study,C.elegans was used as an in vivo assessment system to determine the molecular mechanism of certain lncRNAs in regulating the GO toxicity.Firstly,based on qRT-PCR analysis,we screened out 4 dysregulated lncRNAs,including linc-37,linc-5,linc-103,and XLOC₀10849,in GO?100 ?g/L?exposed nematodes.Using RNAi knockdown technique,we found that RNAi knockdown of linc-37 or linc-5 caused the resistance of nematodes to GO toxicity in inducing ROS production and in decreasing locomotion behavior.That is,alteration in expressions of linc-37 orlinc-5 mediated a protective response to GO exposure.Moreover,we found that linc-37 acted in both the intestine and the neurons to regulate the GO toxicity.In the neurons,linc-37 acted upstream of jnk-1 in the JNK signaling pathway,and further regulated the function of p38 MAPK?NSY-1-SEK-1-PMK-1?and insulin DAF-2-DAF-16 signaling cascades in the intestine to regulate the GO toxicity.linc-5 acted mainly in the neurons to play a role in regulating the GO toxicity.Neuronal linc-5 acted upstream of mpk-1 in ERK signaling pathway,and further regulated the function of the intestinal p38 MAPK?NSY-1-SEK-1-PMK-1?signaling cascade to regulate the GO toxicity.Together,our results elucidated the molecular mechanisms of neuronal linc-37 and linc-5 in regulating the GO toxicity in nematodes.Our data implies that linc-37 and linc-5 can at least regulate the GO toxicity by influencing the functions of some known signaling pathways.Our study provides the support for the involvement of noncoding RNA in regulating the toxicity of engineered nanomaterials,and is also helpful for further design of effective prevention strategies.