Rajini PS et al. (2008) J. Toxicol. Environ. Health Part A "A comparative study on the relationship between various toxicological endpoints in Caenorhabditis elegans exposed to organophosphorus insecticides"

Rajini PS, Williams PL, Melstrom P

[J. Toxicol. Environ. Health Part A, 2008]

The toxicity of 10 organophophorus (OP) insecticides-acephate, dimethoate, dichlorvos, dicrotophos, monocrotophos, methamidophos, phosphamidon, omethoate, phosdrin, and trichlorfon-was evaluated in Caenorhabditis elegans using lethality, movement, and acetylcholinesterase (AChE) activity as the endpoints after a 4-hr- exposure period. The OP insecticides tested showed LC50 values ranging from 0.039 mM (for dichlorovs) to 472.8 mM (for methamidophos). The order of toxicity for lethality and movement was not significantly different when tested using the rank order correlation coefficient. AChE activity was markedly affected by all the OP insecticide exposures that caused significant inhibition in movement, indicating that the mechanism of toxicity of OP insecticides in C. elegans is the same as in higher animals. All OP insecticides induced greater than 50% inhibition of AChE at the lowest tested OP insecticide concentration resulting in inhibition in movement. While a significant correlation was evident between LC50 values in C. elegans and the LD50 values in rats for the 10 OP insecticides studied, a correlation was not evident between EC50 values in C. elegans and LD50 values in rats. Overall, the two endpoints, LC50 and movement, were more reliable and easier to perform than measurement of AChE activity in C. elegans for determining the toxicity of OP insecticides. Further, ranking of these endpoints with respect to the OP insecticides studied indicates that these parameters in C. elegans are predictive of OP insecticides mammalian neurotoxicity.

Taira N et al. (2016) J Agric Food Chem "Effect of Okinawa Propolis on PAK1 activity, Caenorhabditis elegans Longevity, Melanogenesis, and Growth of Cancer Cells."

Be Tu PT, Taira N, Tawata S, Nguyen BC

[J Agric Food Chem, 2016]

Propolis from different areas has been reported to inhibit oncogenic/ageing kinase PAK1, which is responsible for a variety of conditions, including cancer, longevity and melanogenesis. Here, crude extract of Okinawa propolis (OP) was tested against PAK1 activity, Caenorhabditis elegans (C. elegans) longevity, melanogenesis, and growth of cancer cells. We found that OP blocks PAK1 and exhibits anti-cancer activity in A549 cell (human lung cancer cell) line with IC50 values of 6 g/mL and 12 g/mL, respectively. Most interestingly, OP (1 g/mL) significantly reduces reproduction and prolongs the lifespan of C. elegans by activating HSP-16.2 gene, as shown in the PAK1-deficient strain. Furthermore, OP inhibits melanogenesis in a melanoma cell line (B16F10), by downregulating intracellular tyrosinase activity with an IC50 of 30 g/mL. Our results suggest that OP demonstrated life span extending effect C. elegans, anticancer and antimelanogenic effects via PAK1 inactivation, therefore, this can be a potent natural medicinal supplement against PAK1-dependent diseases.

Takeuchi S et al. (2024) Biosci Microbiota Food Health "Lactococcus kimchii extends lifespan and alleviates motility decline in Caenorhabditis elegans through ins-20, an insulin-like peptide gene."

Takeuchi S, Ali MS, Kage-Nakadai E, Tanimoto Y

[Biosci Microbiota Food Health, 2024]

<i>Lactococcus kimchii</i> is isolated from commercial kimchi, which is a traditional Korean fermented food. This study was conducted to evaluate the probiotic effects of <i>L. kimchii</i>. <i>Caenorhabditis elegans</i> was fed <i>L. kimchii</i>, and its longevity, motility, and gene expression were examined. When fed a 1:1 mixture of <i>Escherichia coli</i> OP50 and <i>L. kimchii</i> (OP+LK), <i>C. elegans</i> had a significantly longer lifespan and increased locomotion than when it was fed OP alone. There was no significant difference in brood size between the OP+LK and OP groups, suggesting that these effects occurred in a dietary restriction-independent manner. RNA sequencing and Gene Ontology analysis showed that the expression of <i>ins-20</i>, an insulin-like peptide and agonist of the insulin receptor, was significantly upregulated in the OP+LK group. The <i>ins-20</i> mutation annulled the effects of OP+LK on lifespan extension and motility. In addition, OP+LK failed to extend the lifespan of <i>C. elegans</i> deficient in <i>daf-2</i>, a receptor for the insulin-like signaling pathway. These results suggest that <i>L. kimchii</i> extends the lifespan and alleviates motility decline in <i>C. elegans</i> through the insulin signaling pathway, highlighting the potential of using <i>L. kimchii</i> as a beneficial bacterium for probiotics and postbiotics.

Vinuela A et al. (2011) PLoS One "Gene expression modifications by temperature-toxicants interactions in Caenorhabditis elegans."

Snoek LB, Kammenga JE, Vinuela A, Riksen JA

[PLoS One, 2011]

Although organophosphorus pesticides (OP) share a common mode of action, there is increased awareness that they elicit a diverse range of gene expression responses. As yet however, there is no clear understanding of these responses and how they interact with ambient environmental conditions. In the present study, we investigated genome-wide gene expression profiles in the nematode Caenorhabditis elegans exposed to two OP, chlorpyrifos and diazinon, in single and combined treatments at different temperatures. Our results show that chlorpyrifos and diazinon induced expression of different genes and that temperature affected the response of detoxification genes to the pesticides. The analysis of transcriptional responses to a combination of chlorpyrifos and diazinon shows interactions between toxicants that affect gene expression. Furthermore, our combined analysis of the transcriptional responses to OP at different temperatures suggests that the combination of OP and high temperatures affect detoxification genes and modified the toxic levels of the pesticides.

ten Dijke P et al. (1994) J Biol Chem "Identification of type I receptors for osteogenic protein-1 and bone morphogenetic protein-4."

Reddi AH, Sampath TK, Ichijo H, Yamashita H, Riddle DL, ten Dijke P, Estevez M, Miyazono K, Heldin CH

[J Biol Chem, 1994]

Bone morphogenetic proteins (BMPs) are multifunctional proteins, structurally related to transforming growth factor-beta (TGF-beta) and activin. TGF-beta and activin exert their effects by forming heteromeric complexes of type I and type II serine/threonine kinase receptors. We have previously identified a series of type I serine/threonine kinase receptors, termed activin receptor-like kinase (ALK)-1 to -6. ALK-5 is a TGF-beta type I receptor, whereas ALK-2 and ALK-4 are activin type I receptors. Here we investigated the binding of proteins in the BMP family to ALKs. In transfected COS cells, the binding of osteogenic protein (OP)-1 and BMP-4 to certain ALKs was observed in the absence of type II receptors, and their binding was increased after co-transfection of a BMP type II receptor from Caenorhabditis elegans, DAF-4. OP-1 bound to ALK-2 and ALK-6 efficiently, and to ALK-3 less efficiently, whereas BMP-4 bound to ALK-3 and ALK-6 efficiently. Similarly, OP-1 bound to ALK-2, ALK-3, and/or ALK-6 in various nontransfected cell lines, although the binding profiles were different between different cell types. BMP-4 bound to ALK-3 in MC3T3-E1 osteoblasts and human foreskin fibroblasts. These results suggest that ALK-3 and ALK-6 are type I receptors for OP-1 and BMP-4; in addition, ALK-2 is a type I receptor shared by activin and OP-1, but not by BMP-4.

Lewis JA et al. (2009) BMC Genomics "Distinct patterns of gene and protein expression elicited by organophosphorus pesticides in Caenorhabditis elegans."

Lewis JA, Dennis WE, Gehman E, Szilagyi M, Jackson DA

[BMC Genomics, 2009]

BACKGROUND: The wide use of organophosphorus (OP) pesticides makes them an important public health concern. Persistent effects of exposure and the mechanism of neuronal degeneration are continuing issues in OP toxicology. To elucidate early steps in the mechanisms of OP toxicity, we studied alterations in global gene and protein expression in Caenorhabditis elegans exposed to OPs using microarrays and mass spectrometry. We tested two structurally distinct OPs (dichlorvos and fenamiphos) and employed a mechanistically different third neurotoxicant, mefloquine, as an out-group for analysis. Treatment levels used concentrations of chemical sufficient to prevent the development of 10%, 50% or 90% of mid-vulval L4 larvae into early gravid adults (EGA) at 24 h after exposure in a defined, bacteria-free medium. RESULTS: After 8 h of exposure, the expression of 87 genes responded specifically to OP treatment. The abundance of 34 proteins also changed in OP-exposed worms. Many of the genes and proteins affected by the OPs are expressed in neuronal and muscle tissues and are involved in lipid metabolism, cell adhesion, apoptosis/cell death, and detoxification. Twenty-two genes were differentially affected by the two OPs; a large proportion of these genes encode cytochrome P450s, UDP-glucuronosyl/UDP-glucosyltransferases, or P-glycoproteins. The abundance of transcripts and the proteins they encode were well correlated. CONCLUSION: Exposure to OPs elicits a pattern of changes in gene expression in exposed worms distinct from that of the unrelated neurotoxicant, mefloquine. The functional roles and the tissue location of the genes and proteins whose expression is modulated in response to exposure is consistent with the known effects of OPs, including damage to muscle due to persistent hypercontraction, neuronal cell death, and phase I and phase II detoxification. Further, the two different OPs evoked distinguishable changes in gene expression; about half the differences are in genes involved in detoxification, likely reflecting differences in the chemical structure of the two OPs. Changes in the expression of a number of sequences of unknown function were also discovered, and these molecules could provide insight into novel mechanisms of OP toxicity or adaptation in future studies.

Wang Y et al. (2020) Sci Total Environ "Assessing the combined toxicity of carbamate mixtures as well as organophosphorus mixtures to Caenorhabditis elegans using the locomotion behaviors as endpoints."

Wang ZJ, Xu YQ, Wang Y, Liu SS, Huang P

[Sci Total Environ, 2020]

Carbamate pesticides (CMs) and organophosphorus pesticides (OPs) have been widely used in agriculture and toxicologically affect non-target organisms. Although there are many reports about their toxicities, the combined behavioral toxicities of CM/OP mixtures on Caenorhabditis elegans have rarely been studied. In this study, body bend inhibition (BBI), head thrash inhibition (HTI), and swimming speed inhibition (SSI) by CMs and OPs were chosen as the toxicity endpoints. The locomotion behavioral toxicities of individual pesticides (carbofuran (CAR), methomyl (MET), chlorpyrifos (CPF), and triazophos (TAP)) and their binary mixtures on C. elegans were determined systematically and the toxicological interaction profiles of various CM/OP mixture rays constructed using the combination index. It was shown that four pesticides and their binary mixture rays have significant inhibitory effects on the locomotion behavior of C. elegans; that is, they produce locomotion behavioral toxicities and the toxicity of two OPs is higher than those of two CMs. The toxicological interactions in the binary CM and OP mixtures are different from each other. For example, one mixture ray (CAR-MET-R1) in the CM system on the SSI endpoint exhibits synergism at all concentration levels, another ray (CAR-MET-R3) displays low-dose synergism and high-dose additive action on BBI and HTI endpoints, and weak synergism at high-dose on SSI, and other rays perform additive action. Two rays (CPF-TAP-R1 and CPF-TAP-R2) in the OP mixture system display low-dose additive action and high-dose antagonism on the three endpoints. Another ray (CPF-TAP-R3) shows the additive action at all concentration levels. It can be concluded that it is not sufficient to evaluate the combined toxicity of binary CM/OP mixtures using only one concentration ratio ray and that it is necessary to examine multiple concentration ratios.

Lewis JA et al. (2013) BMC Genomics "Alterations in gene expression in Caenorhabditis elegans associated with organophosphate pesticide intoxication and recovery."

Lewis JA, Gehman EA, Baer CE, Jackson DA

[BMC Genomics, 2013]

BACKGROUND: The principal toxicity of acute organophosphate (OP) pesticide poisoning is the disruption of neurotransmission through inhibition of acetylcholinesterase (AChE). However, other mechanisms leading to persistent effects and neurodegeneration remain controversial and difficult to detect. Because Caenorhabditis elegans is relatively resistant to OP lethality--particularly through the inhibition of AChE--studies in this nematode provide an opportunity to observe alterations in global gene expression following OP exposure that cannot be readily observed in less resistant organisms. RESULTS: We exposed cultures of worms in axenic, defined medium to dichlorvos under three exposure protocols. In the first, worms were exposed continuously throughout the experiment. In the second and third, the worms were exposed for either 2 or 8 h, the dichlorvos was washed out of the culture, and the worms were allowed to recover. We then analyzed gene expression using whole genome microarrays from RNA obtained from worms sampled at multiple time points throughout the exposure. The worms showed a time-dependent increase in the expression of genes involved in stress responses. Early in the exposure, the predominant effect was on metabolic processes, while at later times, an immune-like response and cellular repair mechanisms dominated the expression pattern. Following removal of dichlorvos, the gene expression in the worms appeared to relatively rapidly return to steady-state levels. CONCLUSION: The changes in gene expression observed in the worms following exposure to dichlorvos point towards two potential mechanisms of toxicity: inhibition of AChE and mitochondrial disruption.

Sammi SR et al. (2022) Toxicol Sci "Complementary biological and computational approaches identify distinct mechanisms of chlorpyrifos versus chlorpyrifos oxon induced dopaminergic neurotoxicity."

Conrow KD, Leung MCK, Sammi SR, Cannon JR, Syeda T

[Toxicol Sci, 2022]

Organophosphate (OP) pesticides are widely used in agriculture. While acute cholinergic toxicity has been extensively studied, chronic effects on other neurons are less understood. Here, we demonstrated that the OP pesticide chlorpyrifos (CPF) and its oxon metabolite are dopaminergic neurotoxicants in Caenorhabditis elegans. CPF treatment led to inhibition of mitochondrial complex II, II + III, and V in rat liver mitochondria, while CPF oxon did not (complex II + III, and IV inhibition observed only at high doses). While the effect on C. elegans cholinergic behavior was mostly reversible with toxicant washout, dopamine-associated deficits persisted, suggesting dopaminergic neurotoxicity was irreversible. CPF reduced the mitochondrial content in a dose-dependent manner and the fat modulatory genes cyp-35A2 and cyp-35A3 were found to have a key role in CPF neurotoxicity. These findings were consistent with in vitro effects of CPF and CPF oxon on nuclear receptor signaling and fatty acid/steroid metabolism observed in ToxCast assays. Two-way hierarchical analysis revealed in vitro effects on estrogen receptor (ER,) pregnane X receptor (PXR), and peroxisome proliferator-activated receptor gamma (PPAR gamma) pathways as well as neurotoxicity of chlorpyrifos, malathion, and diazinon, while these effects were not detected in malaoxon and diazoxon. Taken together, our study suggests that mitochondrial toxicity and metabolic effects of CPF, but not CPF-oxon, have a key role of CPF neurotoxicity in the low-dose, chronic exposure. Further mechanistic studies are needed to examine mitochondria as a common target for all OP pesticide parent compounds, since this has important implications on cumulative pesticide risk assessment.

Komura T et al. (2013) Biogerontology "Mechanism underlying prolongevity induced by bifidobacteria in Caenorhabditis elegans."

Komura T, Ikeda T, Nishikawa Y, Yasui C, Saeki S

[Biogerontology, 2013]

Lactobacilli and bifidobacteria are probiotic bacteria that modify host defense systems and have the ability to extend the lifespan of the nematode Caenorhabditis elegans. Here, we attempted to elucidate the mechanism by which bifidobacteria prolong the lifespan of C. elegans. When the nematode was fed Bifidobacterium infantis (BI) mixed at various ratios with the standard food bacterium Escherichia coli strain OP50 (OP), the mean lifespan of worms was extended in a dose-dependent manner. Worms fed BI displayed higher locomotion and produced more offspring than control worms. The growth curves of nematodes were similar regardless of the amount of BI mixed with OP, suggesting that BI did not induce prolongevity effects through caloric restriction. Notably, feeding worms the cell wall fraction of BI alone was sufficient to promote prolongevity. The accumulation of protein carbonyls and lipofuscin, a biochemical marker of aging, was also lower in worms fed BI; however, the worms displayed similar susceptibility to heat, hydrogen peroxide, and paraquat, an inducer of free radicals, as the control worms. As a result of BI feeding, loss-of-function mutants of daf-16, jnk-1, aak-2, tol-1, and tir-1 exhibited a longer lifespan than OP-fed control worms, but BI failed to extend the lifespan of pmk-1, skn-1, and vhp-1 mutants. As skn-1 induces phase 2 detoxification enzymes, our findings suggest that cell wall components of bifidobacteria increase the average lifespan of C. elegans via activation of skn-1, regulated by the p38 MAPK pathway, but not by general activation of the host defense system via DAF-16.