Alteration in Wnt signaling mediates induction of transgenerational toxicity of polystyrene nanoplastics in C. elegans.

Polystyrene nanoparticles (PS-NPs) have a potential toxicity on offspring after the exposure. However, the molecular basis for PS-NP in inducing transgenerational toxicity remains largely unknown. In this study, the role and the underlying mechanism of germline Wnt signaling in regulating transgenerational toxicity of PS-NPs were determined using an in vivo animal model of Caenorhabditis elegans. Exposure to PS-NP (1-100 µg/L) increased expression of Wnt ligand LIN-44 and decreased expression of Wnt receptor MIG-1. After the exposure, the transgenerational PS-NP toxicity on locomotion behavior and brood size were inhibited in lin-44(RNAi) nematodes, while enhanced in mig-1(RNAi) nematodes. The resistance to transgenerational PS-NP toxicity induced by RNAi of lin-44 in P0 generation (P0-G) was inhibited by RNAi of mig-1 in F1-G. In addition, after PS-NP exposure, germline RNAi of lin-44 at P0-G could increase the mig-1 expression in F1-G. Exposure to PS-NP (1-100 µg/L) further decreased expressions of Dishevelled proteins of DSH-1/2, increased APC complex component APR-1, and decreased expression of BAR-1/ß-catenin. Meanwhile, transgenerational PS-NP toxicity was enhanced by RNAi of dsh-1, dsh-2, or bar-1 and inhibited by RNAi of apr-1, suggesting that the DSH-1/2-APR-1-BAR-1 signaling cascade acted downstream of Wnt receptor MIG-1 to control transgenerational PS-NP toxicity. Moreover, BAR-1 acted upstream of DVE-1 to activate mitochondrial unfolded protein response (mt UPR) against the transgenerational PS-NP toxicity. Our data highlights the potential link between alteration in germline Wnt signaling and induction of transgenerational nanoplastic toxicity in organisms.

Polystyrene nanoparticles cause dynamic alteration in mitochondrial unfolded protein response from parents to the offspring in C. elegans.

The mitochondrial unfolded protein response (mt UPR) is important for organisms against the toxicity from toxicants and stresses. Polystyrene nanoparticle (PS-NP), one of the emerging pollutants, has aroused increasing concern for its toxicity in the offspring. Nevertheless, the molecular basis for this transgenerational toxicity remains largely unclear. In this study, the role of mt UPR in the induction of transgenerational toxicity was determined in Caenorhabditis elegans (C. elegans) after parental exposure to PS-NP. After exposure to PS-NP (1-100 µg/L), the suppression in mt UPR showed the concentration-dependent in nematodes from P0 generation (P0-G) to F2-G. Moreover, the decreased expression of genes required for controlling mt UPR (atfs-1, dve-1, and ubl-5 genes) were observed from P0-G to F2-G after exposure to PS-NP (1 µg/L). The adverse effects on locomotion and reproductive capacity were more severe over generations in nematodes with RNAi of these three genes, indicating that these genes were involved in controlling transgenerational toxicity. After parental PS-NP exposure (1 µg/L), the mt UPR was significantly inhibited by RNAi of atfs-1, dve-1, and ubl-5, indicating the association between the transgenerational PS-NP toxicity and mt UPR suppression. Additionally, during the transgenerational process, RNAi of atfs-1, dve-1, and ubl-5 enhanced the PS-NP toxicity by suppressing mt UPR, while RNAi of daf-2 encoding an insulin receptor inhibited the PS-NP toxicity by increasing mt UPR. Therefore, our data highlighted the role of inhibition in mt UPR in mediating the transgenerational nanoplastic toxicity in nematodes.

Multi-walled carbon nanotubes induce transgenerational toxicity associated with activation of germline long non-coding RNA linc-7 in C.elegans.

With the increase in application, multi-walled carbon nanotubes (MWCNTs) are potentially bioavailable to environmental organisms. However, the potential transgenerational effect of MWCNTs and underlying mechanisms remains still unclear. Here, we examined transgenerational MWCNT toxicity and the underlying mechanism mediated by germline long non-coding RNAs (lncRNAs) in Caenorhabditis elegans. Exposure to 0.1-10 µg/L MWCNT caused transgenerational toxicity reflected by endpoints of brood size and locomotion behavior. Meanwhile, among germline lncRNAs, expression of 5 lncRNAs were dysregulated by MWCNT exposure. Among these 5 dysregulated lncRNAs, only germline RNAi of linc-7 affected MWCNT toxicity. Increase in germline linc-7 expression was observed transgenerationally, and transgenerational MWCNT toxicity was prevented in linc-7(RNAi) nematodes. Moreover, germline linc-7 controlled transgenerational MWCNT toxicity by activating downstream DAF-12, a transcriptional factor. Therefore, our data indicated the association between induction of transgenerational MWCNT toxicity and increase in germline linc-7 expression in organisms.

Induction of protective response to polystyrene nanoparticles associated with dysregulation of intestinal long non-coding RNAs in Caenorhabditis elegans.

Intestinal barrier plays a crucial function during the response to polystyrene nanoparticles (PS-NPs) in nematode Caenorhabditis elegans. Long non-coding RNAs (lncRNAs) are involved in the control of various biological processes, including stress response. We here used C. elegans to determine intestinal lncRNAs dysregulated by PS-NPs (1-100 µg/L). In intestine of PS-NPs exposed worms, we found four lncRNAs (linc-61, linc-50, linc-9, and linc-2) in response to PS-NPs and with the function in controlling PS-NPs toxicity. The alteration in expressions of these four intestinal lncRNAs reflected a protective response to PS-NPs exposure. During the response to PS-NPs, limited number of transcriptional factors functioned as the downstream targets of these four lncRNAs. linc-2 acted upstream of DAF-16, linc-9 acted upstream of NHR-77, linc-50 functioned upstream of DAF-16, and linc-61 regulated the functions of DAF-16, DVE-1, and FKH-2 to control PS-NPs toxicity. The obtained data demonstrated the important role of lncRNAs in intestinal barrier to mediate a protective response to PS-NPs exposure at low concentrations.