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Micro/nanoplastics (MNPs) have emerged as a significant environmental concern due to their widespread distribution and potential adverse effects on human health and the environment. In this study, to integrate exposure and toxicity pathways of MNPs, a comprehensive review of the occurrence, toxicokinetics (absorption, distribution, and excretion [ADE]), and toxicity of MNPs were investigated using the aggregate exposure pathway (AEP) and adverse outcome pathway (AOP) frameworks. Eighty-five papers were selected: 34 papers were on detecting MNPs in environmental samples, 38 papers were on the ADE of MNPs in humans and fish, and 36 papers were related to MNPs toxicity using experimental models. This review not only summarizes individual studies but also presents a preliminary AEP-AOP framework. This framework offers a comprehensive overview of pathways, enabling a clearer visualization of intricate processes spanning from environmental media, absorption, distribution, and molecular effects to adverse outcomes. Overall, this review emphasizes the importance of integrating exposure and toxicity pathways of MNPs by utilizing AEP-AOP to comprehensively understand their impacts on human and ecological organisms. The findings contribute to highlighting the need for further research to fill the existing knowledge gaps in this field and the development of more effective strategies for the safe management of MNPs. [Display omitted] • Exposure and toxicity pathways of micro/nanoplastics (MNPs) were visually integrated. • MNPs are omnipresent in all environmental media, foods, and in human organs. • Toxicokinetic studies were revealed systemic distribution of MNPs throughout the organs. • Polyethylene was common in the environment, while polystyrene predominated in toxicity studies. • Oxidative stress and inflammation were most frequently observed toxicity of MNPs. [ABSTRACT FROM AUTHOR]

Unusual cases of fatal lung injury, later determined to be a result of exposure to chemicals used as humidifier disinfectants, were reported among Korean children from 2006 to 2011. This resulted in considerable study of the pulmonary toxicity of humidifier disinfectant chemicals to establish the causal relationship between exposure and lung disease. However, the systemic toxicity of the former and health effects other than lung disease are not fully understood. Here, we investigated the effect of 5-chloro-2-methyl-4-isothiazoline-3-one and 2-methyl-4-isothiazolin-3-one (CMIT/MIT), among the humidifier disinfectants used in the accidents, on the development of metabolic toxicity in the model organism, Caenorhabditis elegans using an exposure scenario comparison. We screened the potential of CMIT/MIT to induce metabolic toxicity using C. elegans oga-1(ok1207) and ogt-1(ok1474) mutants. We also performed a pathway analysis based on C. elegans transcription factor RNAi library screening to identify the underlying toxicity mechanisms. Finally, to understand the critical window of exposure for metabolic toxicity, responses to exposure during different periods in the life cycles of the worms were compared. We determined that CMIT/MIT could induce metabolic toxicity through O-linked N -acetylglucosamine transferase and early life seems to be the critical window for exposure for metabolic toxicity for this substance. The O-linked N -acetylglucosamine transferase pathway is conserved from worms to humans; our results thus insinuate that early-life exposure to CMIT/MIT could cause metabolic health problems during adult life in humans. We therefore suggest that a systemic toxicity approach should be considered to comprehensively understand the adverse health effects of humidifier disinfectant misuse. • Metabolic toxicity of a biocide, CMIT/MIT, was investigated in C. elegans oga-1(ok1207) and ogt-1(ok1474) mutants. • CMIT/MIT causes metabolic toxicity via the O-linked N-acetylglucosamine transferase (OGT) pathway. • Oxidative stress, fatty acid metabolism and locomotive behavior were associated with CMIT/MIT-induced metabolic toxicity. • FOXO signaling pathway was involved in CMIT/MIT-induced metabolic toxicity. • Early life seems to be the critical window for exposure for metabolic toxicity of CMIT/MIT. [ABSTRACT FROM AUTHOR]

The stress response mechanisms of Bisphenol A (BPA), an endocrine disrupting compound, remain to be elucidated. In this study, we explored the effects of BPA on the non-biting midge Chironomus riparius through basic ecotoxicity assays, DNA damage (comet assay), eco-epigenetics (global DNA and histone methylations) and non-targeted global metabolomics (NMR based) approaches. The reproduction failure, increase in DNA damage, global DNA hyper-methylation, and increased global histone modification (H3K36) status were evident due to BPA exposure at 10% lethal concentration (LC 10 : 1 mg/L, based on 48 h acute toxicity). Moreover, non-targeted global metabolomics followed by pathway analysis identified alterations of energy metabolism, amino acids, and methionine metabolisms etc. Most importantly, we found a potential cross-talk between altered epigenetics and metabolites, such as, increase in methionine and o-phosphocholine metabolites corresponds with the phenomena of global hyper-methylation in DNA and H3K36 mark. Overall, our results suggests that the crosstalk of global metabolomics and epigenetic modification was fundamental of the underlying mechanisms in BPA-induced stress response in C. riparius. [ABSTRACT FROM AUTHOR]

Living organisms adapt to their environment, and this adaptive response to environmental changes is influenced by both genomic and epigenomic components. As adaptation underpins tolerance to stressors, it is crucial to consider biological adaptation in evaluating the adverse outcomes of environmental chemicals, such as biocides. Daphnid studies have revealed differences in sensitivity to environmental chemicals between conspecific populations or clones, as well as between species. This study aimed to identify whether sensitivity to chemicals is subject to intraspecific variation, and whether this sensitivity depends on the genetic and epigenetic backgrounds of the daphnid population. We used an integrative approach to assess the comparative toxicity of a mixture of 5-chloro-2-methyl-4-isothiazoline-3-one and 2-methyl-4-isothiazolin-3-one (CMIT/MIT), a commonly used isothiazolinone biocide, by measuring mortality, reproduction, physiological traits, global DNA methylation, and proteomic expression at the species and strain levels. The results showed that the variation in sensitivity to CMIT/MIT between conspecific strains (Daphnia pulex ; DPR vs. DPA strains) could exceed that observed between congeneric species (D. magna vs. D. pulex DPR strain). Under the control conditions, DPR (the strain most sensitive to CMIT/MIT) was characterized by a larger body size, a higher heart rate, and a higher level of global DNA methylation compared to its counterpart (DPA), and proteome profiles differed between the two strains. Particularly, the study identified strain-specific epigenetic and proteomic responses to LC20 of CMIT/MIT, demonstrating putative critical proteins and biological pathways associated with the observed differences in phenotype and sensitivity to CMIT/MIT. Downregulation of certain proteins (e.g., SAM synthase, GSTs, hemoglobin, and cuticle proteins) and DNA hypomethylation can be proposed as key events (KEs) of adverse outcome pathway (AOP) for isothiazolinone toxicity. Our findings indicate that both genetic variations and epigenetic modifications can lead to intraspecific variation in sensitivity to chemicals, and this variation should be considered in the ecological risk assessment framework for chemical substances. We suggest conducting further analysis on methylated gene regions and observing transgenerational effects to verify the role of crosstalk between genetic and epigenetic factors in phenotypic and protein expressions. Proteomic data is available in supplementary materials. [Display omitted] • Intraspecific sensitivity to CMIT/MIT can exceed interspecific sensitivity. • Observed intraspecific variations in physiology, DNA methylation, and proteomics. • The epigenetic response to CMIT/MIT differed between two D. pulex strains. • Proteomics reveals strain-specific pathways and proteins linked to the toxicity of CMIT/MIT. • Identified potential critical proteins that underlie intraspecific variation. [ABSTRACT FROM AUTHOR]

Abstract: Calcium plays a critical role in a variety of cellular processes in cells. However, relatively little is known about the biological effects of Ca2+ signaling on morphogenesis and pathogenesis in the rice blast fungus Magnaporthe oryzae compared to other signaling pathways. We have previously demonstrated that MoPLC1-mediated calcium regulation is important for infection-related development and pathogenicity in M. oryzae. In the present study, four genes encoding phospholipase C (PLC) isozymes (MoPLC2 to MoPLC5), which differ from MoPLC1 in their domain organization, were additionally identified. The C2 domain involved in Ca2+-dependent membrane binding is found only in MoPLC2 and MoPLC3. Detailed functional analysis using deletion mutants for MoPLC2 and MoPLC3 indicated that MoPLC2 and MoPLC3 play essential roles in development. The two deletion mutants for MoPLC2 and MoPLC3 showed reduced conidiation and a defect in appressorium-mediated penetration. Reintroduction of the genes restored defects of ΔMoplc2 and ΔMoplc3. Notably, ΔMoplc2 and ΔMoplc3 mutants developed multiple appressoria on separate germ tubes of a conidium, indicating that MoPLC2- and MoPLC3-regulated signaling suppresses a feedback loop of a pathway for appressorial development. The similarity in phenotypic defects between the two mutants indicates that both MoPLC2 and MoPLC3 are important for regulation of appropriate levels of signaling molecules in a similar manner. Comparative analysis indicated that the two MoPLCs-mediated signaling pathways have interrelated, but distinct, roles in the development of M. oryzae. [Copyright &y& Elsevier]

Abstract: Ca2+-dependent signaling plays important roles in cellular development and metabolism in fungi. Pharmacological and molecular evidence clearly indicates that Ca2+-dependent signaling is required for infection-related development and pathogenicity in the rice blast fungus Magnaporthe oryzae. However, little information is available on downstream regulators in the Ca2+-dependent signaling pathway. To understand the role of a calcineurin-dependent transcription factor in the rice blast fungus, an ortholog of Saccharomyces cerevisiae CRZ1 in M. oryzae, MoCRZ1, was identified and functionally characterized. The Δmocrz1 mutant exhibited impaired growth in the presence of Ca2+ ions or cell wall perturbing agents. The Δmocrz1 mutant also showed reduced conidiation and reduced pathogenicity, which is mainly due to a defect in host penetration. MoCRZ1 fused to EGFP was trans-localized into the nucleus in a Ca2+/calcineurin-dependent manner. The MoCRZ1 gene is also required for the calcineurin-dependent transcriptional induction of FKS1, a gene encoding a β-1,3 glucan synthase, CHS2 and CHS4, genes encoding two chitin synthases, and PMC and PMR gene families encoding P-type ATPases in response to Ca2+. These results suggest that MoCRZ1 is a downstream regulator in Ca2+-dependent signaling for pathogenicity in M. oryzae, and its biochemical mechanisms are well conserved among fungal species. [Copyright &y& Elsevier]

Abstract: To investigate the effects of chlorpyrifos (CP), an organophosphorus insecticide, on the soil nematode Caenorhabditis elegans, the toxicity of the insecticide on the molecular, biochemical, and physiological levels were investigated upon sublethal exposure, and an acute toxicity test was conducted using lethality as an endpoint. To assess the molecular-level effect, stress-related gene expression was investigated, and the neurotoxicity indicator, acetylcholinesterase (AChE) activity was assessed as the biochemical-level response. Growth, reproduction and development were also studied as physiological-level responses. The overall results indicate that CP exposure leads to the alteration of the expression of some stress genes, such as of heat shock protein, metallothionein, vitellogenin and C. elegans p53-like protein genes; the inhibition of AChE activity; and the retardation of development. These data suggest that the toxicity of CP on C. elegans occurred in multiple biological organizations; nevertheless this is not sufficient to conclude that there is a casual relationship between them. Thus, direct experimental demonstrations of the wider relationships between the molecular/biochemical effects of CP exposure and their consequences at higher levels of biological organization are needed to fully understand the effects of this compound on C. elegans. [Copyright &y& Elsevier]

Abstract: This study was conducted to determine the toxic effects of bisphenol A (BPA) and ethynyl estradiol (EE), well-known endocrine disruptors, on Chironomus riparius under controlled laboratory conditions. Mortality, enzyme activities, and growth/development parameters were studied as acute, biochemical, and physiological toxicities, respectively. The results of the present study showed activation of catalase and glutathione-S-transferase after BPA and EE exposure, as well as increased emergence failure after EE exposure. This study on the effects of BPA and EE on C. riparius can be an important addition to the knowledge that has been obtained regarding the toxicology of BPA and EE in aquatic organism, on which limited data are available. The data obtained from this study, however, are not sufficient to establish any correlation or casual relationship between these two compounds and the response of C. riparius. Thus, further research is required to come up with direct experimental demonstrations of the wider relationship between the biochemical effects of BPA and EE on C. riparius and their consequences at higher levels of biological organization. [Copyright &y& Elsevier]

Saf. Corrigendum to "Effect of soil microbial feeding on gut microbiome and cadmium toxicity in Caenorhabditis elegans" [Ecotoxicol. [Extracted from the article]

Microbial community of an organism plays an important role on its fitness, including stress responses. In this study, we investigated the effect of the culturable subset of soil microbial community (SMB) on the stress response of the soil nematode Caenorhabditis elegans , upon exposure to one of the major soil contaminants, cadmium (Cd). Life history traits and the stress responses to Cd exposure were compared between SMB- and Escherichia coli strain OP50-fed worms. SMB-fed worms showed higher reproduction rates and longer lifespans. Also, the SMB-fed worms showed more tolerant response to Cd exposure. Gene expression profiling suggested that the chemical stress and immune response of worms were boosted upon SMB feeding. Finally, we investigated C. elegans gut microbial communities in the presence and absence of Cd in OP50- and SMB-fed C. elegans. In the OP50-fed worms, changes in microbial community by Cd exposure was severe, whereas in the SMB-fed worms, it was comparatively weak. Our results suggest that the SMB affects the response of C. elegans to Cd exposure and highlight the importance of the gut microbiome in host stress response. • The effect of SMB on chemical stress response was investigated in C. elegans. • SMB-fed C.elegans showed higher reproduction than OP50-fed worms. • SMB-fed C.elegans showed more tolerant response to Cd exposure than OP50-fed worms. • Changes in microbial community by Cd was severe in OP50-fed C.elegans. • Overall results highlight the importance of the gut microbiome in host stress response. [ABSTRACT FROM AUTHOR]

Recent studies have highlighted the potential of the ToxCast™ database for mechanism-based prioritization of chemicals. To explore the applicability of ToxCast data in the context of regulatory inventory chemicals, we screened 510 priority existing chemicals (PECs) regulated under the Act on the Registration and Evaluation, etc. of Chemical Substances (K-REACH) using ToxCast bioassays. In our analysis, a hit-call data matrix containing 298984 chemical-gene interactions was computed for 949 bioassays with the intended target genes, which enabled the identification of the putative toxicity mechanisms. Based on the reactivity to the chemicals, we analyzed 412 bioassays whose intended target gene families were cytochrome P450, oxidoreductase, transporter, nuclear receptor, steroid hormone, and DNA-binding. We also identified 141 chemicals based on their reactivity in the bioassays. These chemicals are mainly in consumer products including colorants, preservatives, air fresheners, and detergents. Our analysis revealed that in vitro bioactivities were involved in the relevant mechanisms inducing in vivo toxicity; however, this was not sufficient to predict more hazardous chemicals. Overall, the current results point to a potential and limitation in using ToxCast data for chemical prioritization in regulatory context in the absence of suitable in vivo data. • A mechanism-based prioritization approach for identifying potential toxicants was proposed. • Significant ToxCast bioassays and priority existing chemicals were prioritized based the reactiveness. • Genes targeted by selected in vitro bioassays were involved in relevant mechanism inducing apical in vivo toxicity. • A potential and limitation of the application of ToxCast data to regulatory inventory chemicals were presented. [ABSTRACT FROM AUTHOR]

Nanoplastics (NPs) are potentially toxic and pose a health risk as they can induce an inflammatory response and oxidative stress at cellular and organismal levels. Humans can be exposed to NPs through various routes, including ingestion, inhalation, and skin contact. Notably, uptake into the body via inhalation could result in brain accumulation, which may occur directly across the blood-brain barrier or via other routes. NPs that accumulate in the brain may be endocytosed into neurons, inducing neurotoxicity. Recently, we demonstrated that exposure to polystyrene (PS)-NPs reduces the viability of neurons. We have also reported that inhibiting the retrograde transport of PS-NPs by histone deacetylase 6 (HDAC6) prevents their intracellular accumulation and promotes their export in mouse embryonic fibroblasts. However, whether HDAC6 inhibition can improve neuronal viability by increasing exocytosis of PS-NPs from neurons remains unknown. In this study, mice were intranasally administered fluorescent PS-NPs (PS-YG), which accumulated in the brain and showed potential neurotoxic effects. In cultured neurons, the HDAC6 inhibitor ACY-1215 reduced the fluorescence signal detected from PS-YG, suggesting that the removal of PS-YG from neurons was promoted. Therefore, these results suggest that blocking the retrograde transport of PS-NPs using an HDAC6 inhibitor can alleviate the neurotoxic effects of PS-NPs that enter the brain. • Intranasal administration of PS-NPs causes their accumulation in the mouse brain. • PS-NP accumulation in the mouse brain induces acute neurotoxic effects. • HDAC6 inhibition results in the rapid export of PS-NPs from neurons by exocytosis. • The rapid export of PS-NPs from neurons alleviates neurotoxic effects of PS-NPs. • The rapid export of PS-NPs from neurons reduces oxidative stress induced by PS-NPs. [ABSTRACT FROM AUTHOR]

An adverse outcome pathway (AOP) framework can facilitate the use of alternative assays in chemical regulations by providing scientific evidence. Previously, an AOP, peroxisome proliferative-activating receptor gamma (PPARγ) antagonism that leads to pulmonary fibrosis, was developed. Based on a literature search, PPARγ inactivation has been proposed as a molecular initiating event (MIE). In addition, a list of candidate chemicals that could be used in the experimental validation was proposed using toxicity database and deep learning models. In this study, the screening of environmental chemicals for MIE was conducted using in silico and in vitro tests to maximize the applicability of this AOP for screening inhalation toxicants. Initially, potential inhalation exposure chemicals that are active in three or more key events were selected, and in silico molecular docking was performed. Among the chemicals with low binding energy to PPARγ, nine chemicals were selected for validation of the AOP using in vitro PPARγ activity assay. As a result, rotenone, triorthocresyl phosphate, and castor oil were proposed as PPARγ antagonists and stressor chemicals of the AOP. Overall, the proposed tiered approach of the database- in silico - in vitro can help identify the regulatory applicability and assist in the development and experimental validation of AOP. [Display omitted] • A tiered approach for identify potential stressors of AOP was proposed. • Potential inhalation exposure and hazardous chemicals were collected from database. • In silico molecular docking identifies chemicals with low binding energy to PPARγ. • 3 chemicals were proposed as PPARγ antagonists by using in vitro PPARγ activity assay. [ABSTRACT FROM AUTHOR]

Abstract: Oxygen radicals attack guanine bases in DNA but they also attack cytoplasmic GTP forming 8-oxoGTP. The presence of 8-oxoGTP in cytoplasm is evidenced by the fact that cells contain MutT/MTH1 which hydrolyze 8-oxoGTP into 8-oxoGMP. In this study, the interaction between 8-oxoGTP and Ras, a small GTP-binding protein, was tested in vitro, and the action of 8-oxoGTP was compared to that of GTP. When purified Ras was treated with 8-oxoGTPγS, Ras was activated, as indicated by the enhanced binding of Ras with Raf-1. GTPγS also activated Ras but 8-oxoGTPγS had a much more potent effect. In lysates of human embryo kidney 293 cells, 8-oxoGTPγS activated not only Ras but also the downstream effectors of the Ras-ERK pathway, i.e., Raf-1 and ERK1/2. In contrast to Ras, other small GTP-binding proteins, Rac1 and Cdc42, were inactivated by 8-oxoGTPγS, whereas both of these proteins were activated by GTPγS, indicating that the biological natures of 8-oxoGTP and GTP differ. These results suggest the possibility that 8-oxoGTP is not a simple by-product but a functional molecule transmitting an oxidative signal to small GTP-binding proteins like Ras. [Copyright &y& Elsevier]

Abstract: In the present study, nanotoxicity mechanism associated with silver nanoparticles (AgNPs) exposure was investigated on the nematode, Caenorhabditis elegans focusing on the hypoxia response pathway. In order to test whether AgNPs-induced hypoxia inducible factor-1 (HIF-1) activation was due to hypoxia or to oxidative stress, depletion of dissolved oxygen (DO) in the test media and a rescue effect using an antioxidant were investigated, respectively. The results suggested that oxidative stress was involved in activation of the HIF-1 pathway. We then investigated the toxicological implications of HIF-1 activation by examining the HIF-1 mediated transcriptional response. Of the genes tested, increased expression of the flavin containing monooxygenase-2 (FMO-2) gene was found to be the most significant as induced by AgNPs exposure. We found that AgNPs exposure induced FMO-2 activation in a HIF-1 and p38 MAPK PMK-1 dependent manner, and oxidative stress was involved in it. We conducted all experiments to include comparison of AgNPs and AgNO3 in order to evaluate whether any observed toxicity was due to dissolution or particle specific. The AgNPs and AgNO3 did not produce any qualitative differences in terms of exerting toxicity in the pathways observed in this study, however, considering equal amount of silver mass, in every endpoint tested the AgNPs were found to be more toxic than AgNO3. These results suggest that Ag nanotoxicity is dependent not only on dissolution of Ag ion but also on particle specific effects and HIF-1–FMO-2 pathway seems to be involved in it. [Copyright &y& Elsevier]

Changes in the physical state of the cells can serve as important indicators of stress responses because they are closely linked with the changes in the pathophysiological functions of the cells. Physical traits can be conveniently assessed by analyzing the morphological features and the stresses at the cell-matrix and cell-cell adhesions in both single-cell and monolayer model systems in 2D. In this study, we investigated the mechano-stress responses of human bronchial epithelial cells, BEAS-2B, to two functionally distinct groups of biocides identified during the humidifier disinfectant accident, namely, guanidine (PHMG) and isothiazolinone (CMIT/MIT). We analyzed the physical traits, including cell area, nuclear area, and nuclear shape. While the results showed inconsistent average responses to the biocides, the degree of dispersion in the data set, measured by standard deviation, was remarkably higher in CMIT/MIT treated cells for all traits. As mechano-stress endpoints, traction and intercellular stresses were also measured, and the cytoskeletal actin structures were analyzed using immunofluorescence. This study demonstrates the versatility of the real-time imaging-based biomechanical analysis, which will contribute to identifying the temporally sensitive cellular behaviors as well as the emergence of heterogeneity in response to exogenously imposed stress factors. This study will also shed light on a comparative understanding of less studied substance, CMIT/MIT, in relation to a more studied substance, PHMG, which will further contribute to more strategic planning for proper risk management of the ingredients involved in toxicological accidents. [Display omitted] • Physical traits were analyzed to assess the cytotoxicity of distinct groups of biocides. • Cell area, nuclear area, and nuclear shape were analyzed as mechanical stress endpoints. • Guanidine and isothiazolinone groups caused distinct mechanical stress to the cells. [ABSTRACT FROM AUTHOR]