Wild-type Worms Research Articles

MicroRNA Expression Influences Methylmercury-Induced Lipid Accumulation and Mitochondrial Toxicity in Caenorhabditis elegans.

Metabolic effects of methylmercury (MeHg) are gaining wider attention. We have previously shown that MeHg causes lipid dysregulation in Caenorhabditis elegans (C. elegans), leading to altered gene expression, increased triglyceride levels and lipid storage, and altered feeding behaviors. Transcriptional regulators, such as transcription factors and microRNAs (miRNAs), have been shown to regulate lipid storage, serum triglycerides, and adipogenic gene expression in human and rodent models of metabolic diseases. As we recently investigated adipogenic transcription factors induced by MeHg, we were, therefore, interested in whether MeHg may also regulate miRNA sequences to cause metabolic dysfunction. Lipid dysregulation, as measured by triglyceride levels, lipid storage sites, and feeding behaviors, was assessed in wild-type (N2) worms and in transgenic worms that either were sensitive to miRNA expression or were unable to process miRNAs. Worms that were sensitive to the miRNA expression were protected from MeHg-induced lipid dysregulation. In contrast, the mutant worms that were unable to process miRNAs had exacerbated MeHg-induced lipid dysregulation. Concurrent with differential lipid homeostasis, miRNA-expression mutants had altered MeHg-induced mitochondrial toxicity as compared to N2, with the miRNA-sensitive mutants showing mitochondrial protection and the miRNA-processing mutants showing increased mitotoxicity. Taken together, our data demonstrate that the expression of miRNAs is an important determinant in MeHg toxicity and MeHg-induced metabolic dysfunction in C. elegans.

Dityrosine Crosslinking of Collagen and Amyloid-β Peptides Is Formed by Vitamin B12 Deficiency-Generated Oxidative Stress in Caenorhabditis elegans.

(1) Background: Vitamin B12 deficiency in Caenorhabditis elegans results in severe oxidative stress and induces morphological abnormality in mutants due to disordered cuticle collagen biosynthesis. We clarified the underlying mechanism leading to such mutant worms due to vitamin B12 deficiency. (2) Results: The deficient worms exhibited decreased collagen levels of up to approximately 59% compared with the control. Although vitamin B12 deficiency did not affect the mRNA expression of prolyl 4-hydroxylase, which catalyzes the formation of 4-hydroxyproline involved in intercellular collagen biosynthesis, the level of ascorbic acid, a prolyl 4-hydroxylase coenzyme, was markedly decreased. Dityrosine crosslinking is involved in the extracellular maturation of worm collagen. The dityrosine level of collagen significantly increased in the deficient worms compared with the control. However, vitamin B12 deficiency hardly affected the mRNA expression levels of bli-3 and mlt-7, which are encoding crosslinking-related enzymes, suggesting that deficiency-induced oxidative stress leads to dityrosine crosslinking. Moreover, using GMC101 mutant worms that express the full-length human amyloid β, we found that vitamin B12 deficiency did not affect the gene and protein expressions of amyloid β but increased the formation of dityrosine crosslinking in the amyloid β protein. (3) Conclusions: Vitamin B12-deficient wild-type worms showed motility dysfunction due to decreased collagen levels and the formation of highly tyrosine-crosslinked collagen, potentially reducing their flexibility. In GMC101 mutant worms, vitamin B12 deficiency-induced oxidative stress triggers dityrosine-crosslinked amyloid β formation, which might promote its stabilization and toxic oligomerization.

Methylmercury-Induced Metabolic Alterations in Caenorhabditis elegans Are Diet-Dependent.

Methylmercury (MeHg) is a well-known neurotoxicant; however, its role in metabolic diseases has been gaining wider attention. Chronic exposure to MeHg in human populations shows an association with diabetes mellitus and metabolic syndrome (MS). As the incidences of both obesity and MS are on the rise globally, it is important to understand the potential role of MeHg in the development of the disease. There is a dearth of information on dietary interactions between MeHg and lipids, which play an important role in developing MS. We have previously shown that MeHg increases food seeking behaviors, lipid levels, fat storage, and pro-adipogenic gene expression in C. elegans fed the standard OP50 Escherichia coli diet. However, we hypothesized that these metabolic changes could be prevented if the worms were fed a bacterial diet lower in lipid content. We tested whether C. elegans developed metabolic alterations in response to MeHg if they were fed two alternative E. coli strains (HT115 and HB101) that are known absorb significantly less lipids from their media. Additionally, to explore the effect of a high-lipid and high-cholesterol diet on MeHg-induced metabolic dysfunction, we supplemented the OP50 strain with twice the standard concentration of cholesterol in the nematode growth media. Wild-type worms fed either the HB101 or HT115 diet were more resistant to MeHg than the worms fed the OP50 diet, showing a significant right-hand shift in the dose–response survival curve. Worms fed the OP50 diet supplemented with cholesterol were more sensitive to MeHg, showing a significant left-hand shift in the dose–response survival curve. Changes in sensitivity to MeHg by differential diet were not due to altered MeHg intake in the worms as measured by inductively coupled mass spectrometry. Worms fed the low-fat diets showed protection from MeHg-induced metabolic changes, including decreased food consumption, lower triglyceride content, and lower fat storage than the worms fed either of the higher-fat diets. Oxidative stress is a common characteristic of both MeHg exposure and high-fat diets. Worms fed either OP50 or OP50 supplemented with cholesterol and treated with MeHg had significantly higher levels of reactive oxygen species, carbonylated proteins, and loss of glutathione than the worms fed the HT115 or HB101 low-lipid diets. Taken together, our data suggest a synergistic effect of MeHg and dietary lipid levels on MeHg toxicity and fat metabolism in C. elegans, which may affect the ability of MeHg to cause metabolic dysfunction.

Nonpathogenic Cutibacterium acnes Confers Host Resistance against Staphylococcus aureus.

ABSTRACTCutibacterium acnes is a human skin-resident bacterium. Although C. acnes maintains skin health by inhibiting invasion from pathogens like Staphylococcus aureus, it also contributes to several diseases, including acne. Studies suggest that differences in genetic background may explain the diverse phenotypes of C. acnes strains. In this study, we investigated the effects of C. acnes strains on the Caenorhabditis elegans life span and observed that some strains shortened the life span, whereas other strains, such as strain HL110PA4, did not alter it. Next, we assessed the effects of C. acnes HL110PA4 on host resistance against S. aureus. The survival time of C. acnes HL110PA4-fed wild-type animals was significantly longer than that of Escherichia coli OP50 control bacterium-fed worms upon infection with S. aureus. Although the survival times of worms harboring mutations at the daf-16/FoxO and skn-1/Nrf2 loci were similar to those of wild-type worms after S. aureus infection, administration of C. acnes failed to improve survival times of tir-1/SARM1, nsy-1/mitogen-activated protein kinase kinase kinase (MAPKKK), sek-1/mitogen-activated protein kinase kinase (MAPKK), and pmk-1/p38 mitogen-activated protein kinase (MAPK) mutants. These results suggest that the TIR-1 and p38 MAPK pathways are involved in conferring host resistance against S. aureus in a C. acnes-mediated manner.IMPORTANCE Cutibacterium acnes is one of the most common bacterial species residing on the human skin. Although the pathogenic properties of C. acnes, such as its association with acne vulgaris, have been widely described, its beneficial aspects have not been well characterized. Our study classifies C. acnes strains based on its pathogenic potential toward the model host C. elegans and reveals that the life span of C. elegans worms fed on C. acnes was consistent with the clinical association of C. acnes ribotypes with acne or nonacne. Furthermore, nonpathogenic C. acnes confers host resistance against the opportunistic pathogen Staphylococcus aureus. Our study provides insights into the impact of C. acnes on the host immune system and its potential roles in the ecosystem of skin microbiota.

Structural recognition of the mRNA 3' UTR by PUF-8 restricts the lifespan of C. elegans.

The molecular mechanisms of aging are unsolved fundamental biological questions. Caenorhabditis elegans is an ideal model organism for investigating aging. PUF-8, a PUF (Pumilio and FBF) protein in C. elegans, is crucial for germline development through binding with the 3′ untranslated regions (3′ UTR) in the target mRNAs. Recently, PUF-8 was reported to alter mitochondrial dynamics and mitophagy by regulating MFF-1, a mitochondrial fission factor, and subsequently regulated longevity. Here, we determined the crystal structure of the PUF domain of PUF-8 with an RNA substrate. Mutagenesis experiments were performed to alter PUF-8 recognition of its target mRNAs. Those mutations reduced the fertility and extended the lifespan of C. elegans. Deep sequencing of total mRNAs from wild-type and puf-8 mutant worms as well as in vivo RNA Crosslinking and Immunoprecipitation (CLIP) experiments identified six PUF-8 regulated genes, which contain at least one PUF-binding element (PBE) at the 3′ UTR. One of the six genes, pqm-1, is crucial for lipid storage and aging process. Knockdown of pqm-1 could revert the lifespan extension of puf-8 mutant animals. We conclude that PUF-8 regulate the lifespan of C. elegans may not only via MFF but also via modulating pqm-1-related pathways.

Bisphenol S promotes fat storage in multiple generations of Caenorhabditis elegans in a daf-16/nhr-49 dependent manner

Bisphenol S (BPS) has been gradually used in all kinds of productions. Our previous study has demonstrated that BPS increases the obesogenic effects of a high-glucose diet through regulating lipid metabolism in Caenorhabditis elegans (C. elegans). Whether the effects pass on to the next generations remains uncovered. In the present study, C. elegans was selected as the model organism to investigate the effects of BPS on lipid metabolism in multiple generations. Oil Red O staining and triglyceride assays showed that multi-generational exposure to BPS in C. elegans significantly increased the fat accumulation in wild type worms, while not in the daf-16 gene-deficient worms. In addition, BPS affected the expressions of fat-7 and acs-2 in four generations of C. elegans. Furthermore, BPS promotes fat storage in C. elegans of multiple generations by the daf-16/nhr-49-mediated signaling pathway.

High-speed large-scale 4D activities mapping of moving C. elegans by deep-learning-enabled light-field microscopy on a chip

We report a novel fusion of microfluidics and light-field microscopy, to achieve high-speed 4D (space + time) imaging of moving C. elegans on a chip. Our approach combines automatic chip-based worm loading/compartmentalization/flushing/reloading with instantaneous deep-learning light-field imaging of behaving worm. Taken together, we realized intoto image-based screening of wild-type and uncoordinated-type worms at a volumetric imaging rate of 33 Hz, with sustained observation of 1 worm per minute and totally 42 worms per hour. Through four-dimensionally visualizing the dynamics of all the worms at an ultra-high throughput of 84000 image volumes in an hour, we can quantitatively analyze their behaviors as well as the neural activities, and correlate the phenotypes with the neuron functions. The different types of worms can be readily identified as a result of the high-throughput activity mapping. Our approach shows great potential for various lab-on-a-chip biological studies, such as high-throughput embryo sorting and cell growth assays.

Extraction, Screening, and Characterization of Bioactive Compounds from Moringa oleifera: Extends Life-span of Caenorhabditis elegans

Moringa oleifera is the most commonly cultivated species of the Moringaceae family. It has high nutritional value and a remarkable range of therapeutic uses. Every plant part is beneficial in many ways including medicinal uses. The present study aimed to investigate the presence of various phytochemicals and bioactive compounds from flowers and leaves and to check its effect on lifespan extension of Caenorhabditis elegans. InitiaM. oleiferal phytochemical screening of flowers and leaves methanolic extracts estimated the presence of flavonoids, alkaloids, tannins, and vitamin C. Further quantitative analysis revealed a considerable concentration of phenols, vitamin C, and flavonoids. The plant extracts also showed in vitro antioxidant activity through DPPH, FRAP, and reducing power assay. TLC analysis was performed for the optimization of a specific solvent system suitable for the separation of various compounds. The characterization performed by UV absorption, GC-MS and FTIR revealed the presence of palmitic acid, linolenic acid, and linoleic acid. Moreover, the in vivo life-span assay was carried out on C. elegans. M. oleifera extracts were applied to C. elegans to investigate its anti-aging potential. The extracts were applied to N2 wild-type worms in different concentrations such as 10μg/ml, 20μg/ml, and 40μg/ml. Treatment with plant extracts showed an increase in lifespan from 2 to 8 days. The effect of Moringa on C. elegans proved its antiaging potential and the compounds characterized have potential antioxidant activities that can be further purified and used in pharmaceuticals.

Distinct metabolic alterations in different Caenorhabditis elegans mitochondrial mutants

Mitochondria play an essential role in various biochemical processes that maintain cellular homeostasis. Minor defects in the mitochondrial genome can lead to aversive behavioral responses in an organism. Nevertheless, little is known about the impact of mitochondrial mutations on the metabolome of Caenorhabditis elegans (C. elegans). In this study, an untargeted metabolomics approach was employed to elucidate the metabolic aberrant caused by mitochondrial DNA mutations in C. elegans. Specifically, three mutant strains of C. elegans, including clk-1, mev-1, and phb-2, were adopted to study corresponding metabolic signatures. Adult worms were collected, and metabolites were extracted and analyzed by gas chromatography–mass spectrometry. Uni- and multivariate analyses were performed to elucidate perturbed metabolism between wildtype worms and mutant strains, and metabolic differences among the mutants. The tricarboxylic acid cycle intermediates, amino acids, and sugars were significantly affected in the mitochondrial mutants. Overall, each mitochondrial DNA mutation exhibited a different pattern of metabolic alterations. The shift of metabolome appeared to be associated with the lifespan of C. elegans. In particular, clk-1 and mev-1 strains, which had the opposite phenotypes of lifespan, had apparently different metabolomes. Our findings set light on the metabolic consequences of mitochondrial genetic variants, which may help better understand mitochondrial disease mechanisms.

The Role of Human LRRK2 in Acute Methylmercury Toxicity in Caenorhabditis elegans.

Methylmercury (MeHg) exposure and its harmful effects on the developing brain continue to be a global environmental health concern. Decline in mitochondrial function is central to the toxic effects of MeHg and pathogenesis of mitochondria-related diseases including Parkinson's disease (PD). LRRK2 (Leucine-rich repeat kinase 2) mutation is one of the most common genetic risk factors for PD. In this study, we utilize an acute toxicity model of MeHg exposure in the model organism Caenorhabditis elegans (C. elegans) to compare lifespan, developmental progression, mitochondrial membrane potential and reactive oxygen species (ROS) between the wild-type N2 strain, wild-type LRRK2 transgenic strain (WLZ1), and mutant LRRK2(G2019S) transgenic strain (WLZ3). Additionally, the expression levels of skn-1 and gst-4 were investigated. Our results show that acute MeHg exposure (5 and 10µM) caused a significant developmental delay in the N2 and WLZ3 worms. Notably, the worms expressing wild-type LRRK2 were resistant to 5µM MeHg- induced developmental retardation. ROS levels in response to MeHg exposure were increased in the N2 worms, but not in the WLZ1 or WLZ3 worms. The mitochondrial membrane potential was decreased in the N2 worms but increased in the WLZ1 and WLZ3 worms following MeHg exposure. Furthermore, MeHg exposure increased the expression of skn-1 in N2, but not in WLZ1 worms. Although skn-1 expression was increased in the WLZ3 worms following MeHg exposure, gst-4 expression was not induced. Both skn-1 and gst-4 had higher basal expression levels in LRRK2s transgenic than wild-type N2 worms. Knocking down of skn-1 with feeding RNAi had a significant developmental effect in WLZ1 worms; however, the effect was not found in WLZ3 worms. These results suggest that mitochondrial dysfunction and a defect in the SKN-1 signaling in the LRRK2 G2019S worms contribute to the severe developmental delay, establishing a modulatory role of LRRK2 mutation in MeHg-induced acute toxicity.

Fast whole‐body motor neuron calcium imaging of freely moving Caenorhabditis elegans without coverslip pressed

Caenorhabditis elegans (C. elegans) is an ideal model organism for studying neuronal functions at the system level. This article develops a customized system for whole-body motor neuron calcium imaging of freely moving C. elegans without the coverslip pressed. Firstly, we proposed a fast centerline localization algorithm that could deal with most topology-variant cases costing only 6ms for one frame, not only benefits for real-time localization but also for post-analysis. Secondly, we implemented a full-time two-axis synchronized motion strategy by adaptively adjusting the motion parameters of two motors in every short-term motion step (~50 ms). Following the above motion tracking configuration, the tracking performance of our system has been demonstrated to completely support the high spatiotemporal resolution calcium imaging on whole-body motor neurons of wild-type (N2) worms as well as two mutants (unc-2, unc-9), even the instantaneous speed of worm moving without coverslip pressed was extremely up to 400 μm/s.

Caenorhabditis elegans as a model for studies on quinolinic acid-induced NMDAR-dependent glutamatergic disorders

Quinolinic acid (QUIN) is an agonist of the neurotransmitter glutamate (Glu) capable of binding to N-methyl-D-aspartate receptors (NMDAR) increasing glutamatergic signaling. QUIN is known for being an endogenous neurotoxin, able to induce neurodegeneration. In Caenorhabditis elegans, the mechanism by which QUIN induces behavioral and metabolic toxicity has not been fully elucidated. The effects of QUIN on behavioral and metabolic parameters in nmr-1 and nmr-2 NMDA receptors in transgenic and wild-type (WT) worms were performed to decipher the pathway by which QUIN exerts its toxicity. QUIN increased locomotion parameters such as wavelength and movement amplitude medium, as well as speed and displacement, without modifying the number of body bends in an NMDAR-dependent-manner. QUIN increased the response time to the chemical stimulant 1-octanol, which is modulated by glutamatergic neurotransmission in the ASH neuron. Brood size increased after exposure to QUIN, dependent upon nmr-2/NMDA-receptor, with no change in lifespan. Oxygen consumption, mitochondrial membrane potential, and the flow of coupled and unbound electrons to ATP production were reduced by QUIN in wild-type animals, but did not alter citrate synthase activity, altering the functionality but the mitochondrial viability. Notably, QUIN modified fine locomotor and chemosensory behavioral parameters, as well as metabolic parameters, analogous to previously reported effects in mammals. Our results indicate that QUIN can be used as a neurotoxin to elicit glutamatergic dysfunction in C. elegans in a way analogous to other animal models.

Cleistocalyx nervosum var. paniala seed extracts exhibit sigma-1 antagonist sensitive neuroprotective effects in PC12 cells and protects C. elegans from stress via the SKN-1/NRF-2 pathway

BACKGROUND: Cleistocalyx nervosum var. paniala (C. nervosum) is a plant that produces berries that are popular as a health food in Thailand. In previous studies we have identified C. nervosum fruit extracts to have anti-aging and anti-stress properties in C.elegans OBJECTIVE: Evaluate the neuroprotective properties of C. nervosum seed extracts and investigate the mechanisms behind their neuroprotective properties. METHODS: PC12 cells were differentiated using NGF and treated with amyloid-β (Aβ)(25–35) creating a model of neurodegeneration, in which C. nervosum seed extracts were tested for neuroprotective properties. Cell viability was measured after 24 hours of using the MTT assay. We also measured the lifespan and “health span” of various C.elegans mutants and the wild type. RESULTS: C. nervosum seed extract protects PC12 cells from Aβ(25–35) toxicity, as well as potentiating NGF induced neurite outgrowth in the same cell line potentially under the control of the sigma-1 receptor. C. nervosum seed extracts have anti-aging properties in C. elegans, causing a significant increase in lifespan of Aβ expressing C. elegans and wild type worms. This appears to be regulated by SKN-1/NRF-2, possibly via the sigma-1 receptor. The DAF-16 pathway is also involved in the lifespan extension of C. elegans. CONCLUSIONS: C. nervousum has been often used as a functional food. We have shown its neuroprotective properties which are sensitive to sigma-1 receptor antagonism in PC12 cells, and involve the SKN-1/NRF-2 and DAF-16 pathway in C.elegans. Further research into the active compounds may lead to future drugs for preventing or treating neurodegenerative disease.

The Effect of Mianserin on Lifespan of Caenorhabditis elegan is Abolished by Glucose.

The antidepressant Mianserin has been shown to extend the lifespan of Caenorhabditis elegan (C. elegan), a well-established model organism used in ageing research. The extension of lifespan in C. elegan was shown to be dependent on increased expression of the scaffolding protein (ANK3/unc-44). In contrast, antidepressant use in humans is associated with an increased risk of death. The C. elegan elegan in the laboratory are fed Escherichia coli (E. coli), a diet high in protein and low in carbohydrate, whereas a typical human diet is high in carbohydrates. We hypothesized that dietary carbohydrates might mitigate the lifespan-extension effect of mianserin. To investigate the effect of glucose added to the diet of C. elegan on the lifespan-extension effect of mianserin. Wild-type Bristol N2 and ANK3/unc-44 inactivating mutants were cultured on agar plates containing nematode growth medium and fed E. coli. Treatment groups included (C) control, (M50) 50 μM mianserin, (G) 73 mM glucose, and (M50G) 50 μM mianserin and 73 mM glucose. Lifespan was determined by monitoring the worms until they died. Statistical analysis was performed using the Kaplan-Meier version of the log-rank test. Mianserin treatment resulted in a 12% increase in lifespan (P<0.05) of wild-type Bristol N2 worms but reduced lifespan by 6% in ANK3/unc-44 mutants, consistent with previous research. The addition of glucose to the diet reduced the lifespan of both strains of worms and abolished the lifespan-extension by mianserin. The addition of glucose to the diet of C. elegan abolishes the lifespan-extension effects of mianserin.

DMD-10 is dispensable for the initial development of amphid sensory neurons and their survival in mature C. elegans.

Mechanosensory or chemosensory activation of glutamatergicASH amphid sensory neurons promotes avoidancebehaviors in C. elegans. Wormswith mutations in the transcription factor DMD-10 have impaired ASH-mediated sensorimotor reflexes. We hypothesized that the behavioral dysfunction in dmd-10 mutants could arise from impaired ASH development or survival leading to disrupted glutamatergic signaling.To test this, we performed in vivo fluorescence microscopy of young adult C. elegans amphid neurons after labeling with the lipophilic dye DiI. We quantified the number of ASH neurons as well as five other amphid sensory neuron pairs. We found that the number of amphid neurons in dmd-10 mutants was the same as in wild-type worms. Our results suggest that dmd-10 is not required for amphid neuron development or survival in mature C. elegans.

SYP-5 regulates meiotic thermotolerance in Caenorhabditis elegans.

Meiosis produces the haploid gametes required by all sexually reproducing organisms, occurring in specific temperature ranges in different organisms. However, how meiotic thermotolerance is regulated remains largely unknown. Using the model organism Caenorhabditis elegans, here, we identified the synaptonemal complex (SC) protein SYP-5 as a critical regulator of meiotic thermotolerance. syp-5-null mutants maintained a high percentage of viable progeny at 20°C but produced significantly fewer viable progeny at 25°C, a permissive temperature in wild-type worms. Cytological analysis of meiotic events in the mutants revealed that while SC assembly and disassembly, as well as DNA double-strand break repair kinetics, were not affected by the elevated temperature, crossover designation, and bivalent formation were significantly affected. More severe homolog segregation errors were also observed at elevated temperature. A temperature switching assay revealed that late meiotic prophase events were not temperature-sensitive and that meiotic defects during pachytene stage were responsible for the reduced viability of syp-5 mutants at the elevated temperature. Moreover, SC polycomplex formation and hexanediol sensitivity analysis suggested that SYP-5 was required for the normal properties of the SC, and charge-interacting elements in SC components were involved in regulating meiotic thermotolerance. Together, these findings provide a novel molecular mechanism for meiotic thermotolerance regulation.

Oocyte aging is controlled by mitogen-activated protein kinase signaling.

Oogenesis is one of the first processes to fail during aging. In women, most oocytes cannot successfully complete meiotic divisions already during the fourth decade of life. Studies of the nematode Caenorhabditis elegans have uncovered conserved genetic pathways that control lifespan, but our knowledge regarding reproductive aging in worms and humans is limited. Specifically, little is known about germline internal signals that dictate the oogonial biological clock. Here, we report a thorough characterization of the changes in the worm germline during aging. We found that shortly after ovulation halts, germline proliferation declines, while apoptosis continues, leading to a gradual reduction in germ cell numbers. In late aging stages, we observed that meiotic progression is disturbed and crossover designation and DNA double‐strand break repair decrease. In addition, we detected a decline in the quality of mature oocytes during aging, as reflected by decreasing size and elongation of interhomolog distance, a phenotype also observed in human oocytes. Many of these altered processes were previously attributed to MAPK signaling variations in young worms. In support of this, we observed changes in activation dynamics of MPK‐1 during aging. We therefore tested the hypothesis that MAPK controls oocyte quality in aged worms using both genetic and pharmacological tools. We found that in mutants with high levels of activated MPK‐1, oocyte quality deteriorates more rapidly than in wild‐type worms, whereas reduction of MPK‐1 levels enhances quality. Thus, our data suggest that MAPK signaling controls germline aging and could be used to attenuate the rate of oogenesis quality decline.

Early-life chronic di(2-ethylhexyl)phthalate exposure worsens age-related long-term associative memory decline associated with insulin/IGF-1 signaling and CRH-1/CREB in Caenorhabditis elegans

The ubiquitous contamination of di(2-ethylhexyl)phthalate (DEHP) in the environment, biota, and food poses potential ecological and human health risks. DEHP exposure can adversely affect learning and memory, yet the underlying mechanisms remain unclear. In this study, Caenorhabditis elegans was used to investigate the effect of early-life DEHP exposure on age-related long-term associative memory (LTAM) decline, as well as the associations with the cAMP-responsive element-binding protein (CREB) transcription factor and insulin/IGF-1 signaling (IIS). We showed that early-life exposure to DEHP reduced LTAM in wild-type worms at day-0 adulthood. Chronic exposure to DEHP from the L1 stage to day-5 adulthood worsened the age-dependent decline of LTAM. Moreover, the effect of DEHP on age-related LTAM requires CRH-1, a homolog of CREB. Mutations in daf-2, the sole receptor of C. elegans IIS, ameliorated the inhibition of LTAM by DEHP, and the effect depended on daf-16. In addition, daf-2 mutation restored the CRH-1 level in DEHP-exposed worms, and the effect required daf-16. Our study suggests that early-life chronic exposure to DEHP worsens age-related LTAM decline and the effect is associated with CRH-1 and IIS in C. elegans. The evolutionary conservation of IIS and CREB implies possible adverse effects by DEHP across species.

Bisphenol Z and its analogs alter meiosis in C. elegans

Bisphenol A (BPA), a synthetic plasticizer, has been repeatedly linked to reproductive disorders. Because of growing human health concerns, manufacturers started seeking alternatives, which resulted in the replacement of BPA with other bisphenols, such as bisphenol S (BPS) and bisphenol Z (BPZ). Whereas numerous studies suggest that BPS may be as toxic as BPA, the impact of BPZ is less understood. To investigate the effect of BPZ on the reproductive health, we used a nematode C. elegans. Previous studies in this model organism have showed that BPA and BPS prevent timely meiotic double-strand break repair and result in increased apoptosis of the germline nuclei. The worms exposed to BPZ and its three novel analogs appear to be affected in a similar fashion. All four chemicals caused a marked reduction in the brood size compared to the wild type worms. In addition, the number of apoptotic nuclei was significantly increased by the exposure to all evaluated bisphenols. Our preliminary findings suggest that BPZ as well as its analogs alter meiosis in C. elegans resulting in diminished reproductive capacity.

C. elegans detects toxicity of traumatic brain injury generated tau

Traumatic brain injury (TBI) is associated with widespread tau pathology in about 30% of patients surviving late after injury. We previously found that TBI in mice induces the formation of an abnormal form of tau (tauTBI) which progressively spreads from the site of injury to remote brain regions. Intracerebral inoculation of TBI brain homogenates into naïve mice induced progressive tau pathology, synaptic loss and late cognitive decline, suggesting a pivotal role of tauTBI in post-TBI neurodegeneration. However, the possibility that tauTBI was a marker of TBI-associated neurodegeneration rather than a toxic driver of functional decline could not be excluded.Here we employed the nematode C. elegans as a biosensor to test the pathogenic role of TBI generated tau. The motility of this nematode depends on efficient neuromuscular transmission and is exceptionally sensitive to the toxicity of amyloidogenic proteins, providing a tractable model for our tests. We found that worms exposed to brain homogenates from chronic but not acute TBI mice, or from mice in which tauTBI had been transmitted by intracerebral inoculation, had impaired motility and neuromuscular synaptic transmission. Results were similar when worms were given brain homogenates from transgenic mice overexpressing tau P301L, a tauopathy mouse model, suggesting that TBI-induced and mutant tau have similar toxic properties. P301L brain homogenate toxicity was similar in wild-type and ptl-1 knock-out worms, indicating that the nematode tau homolog protein PTL-1 was not required to mediate the toxic effect. Harsh protease digestion to eliminate the protein component of the homogenates, pre-incubation with anti-tau antibodies or tau depletion by immunoprecipitation, abolished the toxicity. Homogenates of chronic TBI brains from tau knock-out mice were not toxic to C. elegans, whereas oligomeric recombinant tau was sufficient to impair their motility.This study indicates that tauTBI impairs motor activity and synaptic transmission in C. elegans and supports a pathogenic role of tauTBI in the long-term consequences of TBI. It also sets the groundwork for the development of a C. elegans-based platform for screening anti-tau compounds.