Liu H et al. (2024) Sci Total Environ "Amino-modified nanoplastics at predicted environmental concentrations cause transgenerational toxicity through activating germline EGF signal in Caenorhabditis elegans."

Wu Y, Tan X, Wang Z, Lei S, Li X, Liu H

[Sci Total Environ, 2024]

In the real environment, some chemical functional groups are unavoidably combined on the nanoplastic surface. Reportedly, amino-modified polystyrene nanoparticles (PS-A NPs) exposure in parents can induce severe transgenerational toxicity, but the underlying molecular mechanisms remain largely unclear. Using Caenorhabditis elegans as the animal model, this study was performed to investigate the role of germline epidermal growth factor (EGF) signal on modulating PS-A NPs' transgenerational toxicity. As a result, 1-10 μg/L PS-A NPs exposure transgenerationally enhanced germline EGF ligand/LIN-3 and NSH-1 levels. Germline RNAi of lin-3 and nsh-1 was resistant against PS-A NPs' transgenerational toxicity, implying the involvement of EGF ligand activation in inducing PS-A NPs' transgenerational toxicity. Furthermore, LIN-3 overexpression transgenerationally enhanced EGF receptor/LET-23 expression in the progeny, and let-23 RNAi in F1-generation notably suppressed PS-A NPs' transgenerational toxicity in the exposed worms overexpressing germline LIN-3 at P0 generation. Finally, LET-23 functioned in neurons and intestine for regulating PS-A NPs' transgenerational toxicity. LET-23 acted at the upstream DAF-16/FOXO within the intestine in response to PS-A NPs' transgenerational toxicity. In neurons, LET-23 functioned at the upstream of DAF-7/DBL-1, ligands of TGF-β signals, to mediate PS-A NPs' transgenerational toxicity. Briefly, this work revealed the exposure risk of PS-A NPs' transgenerational toxicity, which was regulated through activating germline EGF signal in organisms.

Brockhaus M et al. (1998) Neuroreport "Caspase-mediated cleavage is not required for the activity of presenilins in amyloidogenesis and NOTCH signaling."

Loetscher H, Wittenburg N, Baumeister R, Rohrig S, Haass C, Brockhaus M, Grunberg J, Jacobsen H

[Neuroreport, 1998]

The Alzheimer's disease (AD) associated presenilin (PS) proteins are proteolytically processed. One of the processing pathways involves cleavage by caspases. Pharmacological inhibition of caspases is currently being discussed as a treatment for a variety of neurodegenerative diseases, including AD. We therefore inhibited caspase mediated processing of PS-1 and PS-2 in cells transfected with wt and mutant PS by mutagenizing the substrate recognition site or by using specific peptide aldehydes known to block caspases. We found that the inhibition of caspase mediated processing of PS proteins does not decrease its amyloidogenic activity. PS cDNA constructs with mutations in the caspase cleavage site are biologically active in Caenorhabditis elegans such as the wt human PS proteins, demonstrating that caspase-mediated cleavage is not required for the physiological PS function in NOTCH signaling.

Baumeister R et al. (1997) International C. elegans Meeting "CONSERVATION OF FUNCTION AND PROCESSING OF HUMAN PRESENILIN-1 AND C. elegans SEL-12: IS THERE A FUNCTIONAL LINK BETWEEN ALZHEIMER'S DISEASE AND NOTCH SIGNALLING"

Jakubek C, Baumeister R

[International C. elegans Meeting, 1997]

Mutants in the C.elegans gene sel-12 suppress the Multivulva phenotype of dominant lin-12/Notch mutants, suggesting that sel-12 functions somewhere in the Notch pathway of intercellular signalling. sel-12 encodes a protein with about 50 % amino acid identity to the human presenilin proteins PS-1 and PS-2. Mutations of the PS genes are responsible for the majority of cases of Familial Alzheimer's Disease (FAD). These genes encode two homologous eight-trans-membrane proteins located within the endoplasmic reticulum and the early Golgi. We show here that sel-12 is expressed in many neural and non-neural cell types. In order to test the functional conservation of sel-12 and PS-1, we expressed human PS-1 cDNA constructs in C.elegans sel-12 mutant animals and tested their rescuing potential. Human PS-1 expressed from the sel-12 promoter fully complements the sel-12 egg-laying phenotype. In contrast, missense mutations isolated from FAD patients did not rescue the sel-12 defect and are loss-of-function alleles. We also demonstrate that part of the large hydrophilic loop and trans-membrane domain 7 are required for the PS-1 function in C.elegans. PS-1 protein is proteolytically cleaved in C.elegans like in human cells. A PS-1 splice variant (Dexon9) which does not undergo proteolytic cleavage also rescues sel-12 indicating that proteolytic processing is not, as proposed, a prerequisite of PS-1 function. The conservation of function and processing of human PS-1 and C.elegans sel-12 suggests that presenilin proteins are required - directly or indirectly - for the proper operation of the Notch signalling pathway. The FAD associated mutants tested show different rescuing activities indicating that they might affect different functional or regulatory aspects of PS-1.

Kim HM et al. (2020) J Hazard Mater "Comprehensive phenotyping and multi-omic profiling in the toxicity assessment of nanopolystyrene with different surface properties."

Min JE, Kwon SW, Long NP, Yoon SJ, Anh NH, Kim HM, Kim SJ

[J Hazard Mater, 2020]

There is a growing concern regarding the toxic effects of terrestrial nanoplastic contaminants. However, an all-encompassing phenotyping- and omics-based strategy for the toxicity assessment of nanoplastics with different surface properties on soil living organisms remains to be established. Herein, we devised a comprehensive phenotyping and multi-omic profiling method to examine the molecular disturbance of nanopolystyrene (PS)-exposed Caenorhabditis elegans. The exposure time was 24 h with either 1 g/mL or 10 g/mL of PS. We found that PS considerably affected the reproduction and locomotion, as well as increased the oxidative stress of worms regardless of their surface properties. Nevertheless, each type of PS affected the metabolome and lipidome of the nematodes differently. Uncharged PS (PS-N) triggered significant metabolic disturbances, whereas the metabolic influences from PS-NH₂ and PS-COOH were subtle. The dysregulated transcriptome profiles of PS-N were strongly associated with the metabolic pathways. Besides, the altered expression of several genes associated with autophagy and longevity was observed. Collectively, we demonstrated that comprehensive phenotyping and omics-based profiling establish a practical framework that allows us to gain deeper insights into the maladaptive consequences of PS in nematodes. It can be utilized for the evaluation of other environmental contaminants in the terrestrial ecosystem.

Zhou T et al. (2023) Int J Mol Sci "Seawater Accelerated the Aging of Polystyrene and Enhanced Its Toxic Effects on Caenorhabditis elegans."

Wu J, Liu Y, Xu A, Zhou T

[Int J Mol Sci, 2023]

Microplastics (MPs) are emerging pollutants and pose a significant threat to marine ecosystems. Although previous studies have documented the mechanisms and toxic effects of aging MPs in various environments, the impact of the marine environment on MPs remains unclear. In the present study, the aging process of polystyrene (PS) in seawater was simulated and the changes in its physicochemical properties were investigated. Our results showed that the surface of the PS eroded in the seawater, which was accompanied by the release of aged MPs with a smaller size. In situ optical photothermal infrared microspectroscopy revealed that the mechanism of PS aging was related to the opening of the carbonyl group and breaking of the bond between carbon and benzene removal. To verify the toxic effects of aged PS, <i>Caenorhabditis elegans</i> was exposed to PS. Aged PS resulted in a greater reduction in locomotion, vitality, and reproduction than virgin PS. Mechanistically, aged PS led to oxidative stress, high glutathione s-transferase activity, and high total glutathione in worms. Together, our findings provided novel information regarding the accelerated aging of PS in seawater and the increased toxicity of aged PS, which could improve our understanding of MPs' ecotoxicity in the marine environment.

Zhao Y et al. (2022) Toxics "Nanoplastic Exposure at Predicted Environmental Concentrations Induces Activation of Germline Ephrin Signal Associated with Toxicity Formation in the Caenorhabditis elegans Offspring."

Zhao Y, Wang D, Hua X, Bian Q

[Toxics, 2022]

In nematode Caenorhabditis elegans, exposure to polystyrene nanoparticles (PS-NPs) at predicted environmental concentrations can cause induction of transgenerational toxicity. However, the underlying mechanisms for toxicity formation of PS-NP in the offspring remain largely unknown. In this study, based on high-throughput sequencing, Ephrin ligand EFN-3 was identified as a target of KSR-1/2 (two kinase suppressors of Ras) in the germline during the control of transgenerational PS-NP toxicity. At parental generation (P0-G), exposure to 0.1-10 &#956;g/L PS-NP caused the increase in expression of germline efn-3, and this increase in germline efn-3 expression could be further detected in the offspring, such as F1-G and F2-G. Germline RNAi of efn-3 caused a resistance to transgenerational PS-NP toxicity, suggesting that the activation of germline EFN-3 at P0-G mediated transgenerational PS-NP toxicity. In the offspring, Ephrin receptor VAB-1 was further activated by the increased EFN-3 caused by PS-NP exposure at P0-G, and RNAi of vab-1 also resulted in resistance to transgenerational PS-NP toxicity. VAB-1 acted in both the neurons and the germline to control toxicity of PS-NP in the offspring. In the neurons, VAB-1 regulated PS-NP toxicity by suppressing expressions of DBL-1, JNK-1, MPK-1, and GLB-10. In the germline, VAB-1 regulated PS-NP toxicity by increasing NDK-1 and LIN-23 expressions and decreasing EGL-1 expression. Therefore, germline Ephrin ligand EFN-3 and its receptor VAB-1 acted together to mediate the formation of transgenerational PS-NP toxicity. Our data highlight the important role of activation in germline Ephrin signals in mediating transgenerational toxicity of nanoplastics at predicted environmental concentrations in organisms.

Yu Y et al. (2020) Sci Total Environ "Polystyrene microplastics (PS-MPs) toxicity induced oxidative stress and intestinal injury in nematode Caenorhabditis elegans."

Chen X, Ding P, Li H, Yu Y, Han Y, Hua X, Dang Y, Yu Z, Chen H

[Sci Total Environ, 2020]

To understand the toxicity and mechanism of polystyrene microplastics (PS-MPs) exposure, Caenorhabditis elegans (C. elegans) was exposed to various concentrations (0, 0.1, 1, 10, and 100g/L) of PS-MPs, and the levels physiological, biochemical, and molecular parameters were measured as endpoints. Subacute exposure to 1-100g/L of PS-MPs resulted in adverse physiological effects in C. elegans, and PS-MPs were ingested and accumulated in the intestine of C. elegans. Exposure to 100g/L of PS-MPs significantly increased reactive oxygen species (ROS) production, lipofuscin accumulation, and the expression oxidative stress-related genes, which suggests that PS-MPs exposure induced oxidative stress by ROS. In addition, exposure to 100g/L of PS-MPs caused a hyperpermeable state of the intestinal barrier and altered the expression of genes related to intestinal development, which indicates intestinal damage in C. elegans. According to Pearson correlation analyses, oxidative stress and intestinal damage were significantly correlated with adverse effects of PS-MPs in C. elegans. Therefore, it was speculated that the toxicity induced by PS-MPs resulted from the combination of oxidative stress and intestinal injury.

Zhao Y et al. (2021) Ecotoxicol Environ Saf "Induction of protective response to polystyrene nanoparticles associated with dysregulation of intestinal long non-coding RNAs in Caenorhabditis elegans."

Wang J, Zhao Y, Rui Q, Wang D, Xu R, Chen X

[Ecotoxicol Environ Saf, 2021]

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 (1-100g/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.

Baumeister R et al. (1997) Genes Funct "Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing."

Jakubek C, Baumeister R, Zweckbronner I, Haass C, Leimer U, Grunberg J

[Genes Funct, 1997]

The majority of cases with familial Alzheimer's disease (FAD) are linked to mutations of the presenilin (PS) genes. These genes show considerable sequence similarity to the sel-12 gene of Caenorhabditis elegans, which has been postulated to function in the facilitated signalling by lin-12 and glp-1. In order to analyse the functional conservation of the presenilins, we introduced the human PS-1 cDNA, as well as clinical and deletion mutant proteins, into sel-12 mutant animals and tested their potential to rescue the egg-laying defect. Human PS-1 expressed from the sel-12 promoter fully rescued the sel-12 phenotype, whereas two missense mutations, C410Y and A246E, identified in pedigrees with FAD, exhibited a strongly decreased rescuing activity. The large hydrophilic loop and transmembrane domain 7 are required for the biological activity of PS-1. PS-1 protein was proteolytically cleaved in C. elegans as it is in human cells. A PS-1 splice variant (FAD mutation deltaexon9) that does not undergo proteolytic cleavage also substituted for sel-12. The conservation of function of human PS-1 and C. elegans sel-12 suggests that presenilin proteins are required, directly or indirectly, for the proper operation of the Notch signalling pathway. FAD-associated mutant proteins tested showed different rescuing activities, indicating that they might affect different functional or regulatory aspects of PS-1. Proteolytic processing is not a prerequisite for PS-1 function in C. elegans.

Liu H et al. (2021) J Hazard Mater "Acetylation regulation associated with the induction of protective response to polystyrene nanoparticles in Caenorhabditis elegans."

Liu H, Tian L, Wang D, Qu M

[J Hazard Mater, 2021]

Caenorhabditis elegans is a useful animal model to assess nanoplastic toxicity. Using polystyrene nanoparticles (PS-NPs) as the example of nanoplastics, we found that exposure to PS-NPs (1-100g/L) from L1-larvae for 6.5 days increased expression of cbp-1 encoding an acetyltransferase. The susceptibility to PS-NPs toxicity was observed in cbp-1(RNAi) worms, suggesting that CBP-1-mediated histone acetylation regulation reflects a protective response to PS-NPs. The functions of CBP-1 in intestine, neurons, and germline were required for formation of this protective response. In intestinal cells, CBP-1 controlled PS-NPs toxicity by modulating functions of insulin and p38 MAPK signaling pathways. In neuronal cells, CBP-1 controlled PS-NPs toxicity by affecting functions of DAF-7/TGF- and JNK MAPK signaling pathways. In germline cells, CBP-1 controlled PS-NPs toxicity by suppressing NHL-2 activity, and NHL-2 further regulated PS-NPs toxicity by modulating insulin communication between germline and intestine. Therefore, our data suggested that the CBP-1-mediated histone acetylation regulation in certain tissues is associated with the induction of protective response to PS-NPs in C. elegans.