Display omitted
•50 plastic additives are screened using ToxCast to identify MP toxicity mechanisms.•Deep learning models were developed to predict missing data.•Assays that could reflect animal ...toxicity were found through correlation analysis.•Neurotoxicity, inflammation, lipid metabolism, and cancer are potential mechanisms.•Potential Adverse Outcome Pathways relevant to MP were proposed.
Various additives are used in plastic products to improve the properties and the durability of the plastics. Their possible elution from the plastics when plastics are fragmented into micro- and nano-size in the environment is suspected to one of the major contributors to environmental and human toxicity of microplastics. In this context, to better understand the hazardous effect of microplastics, the toxicity of chemical additives was investigated. Fifty most common chemicals presented in plastics were selected as target additives. Their toxicity was systematically identified using apical and molecular toxicity databases, such as ChemIDplus and ToxCast™. Among the vast ToxCast assays, those having intended gene targets were selected for identification of the mechanism of toxicity of plastic additives. Deep learning artificial neural network models were further developed based on the ToxCast assays for the chemicals not tested in the ToxCast program. Using both the ToxCast database and deep learning models, active chemicals on each ToxCast assays were identified. Through correlation analysis between molecular targets from ToxCast and mammalian toxicity results from ChemIDplus, we identified the fifteen most relevant mechanisms of toxicity for the understanding mechanism of toxicity of plastic additives. They are neurotoxicity, inflammation, lipid metabolism, and cancer pathways. Based on these, along with, previously conducted systemic review on the mechanism of toxicity of microplastics, here we have proposed potential adverse outcome pathways (AOPs) relevant to microplastics pollution. This study also suggests in vivo and in vitro toxicity database and deep learning model combined approach is appropriate to provide insight into the toxicity mechanism of the broad range of environmental chemicals, such as plastic additives.
Display omitted
•Toxicity mechanism of HDPE MPs was identified using C. elegans RNAi and zebrafish.•NER and TGF-β signaling pathways were involved in the toxicity of HDPE.•Human health implications ...of HDPE toxicity were suggested using CTD analysis.•Related AOPs were identified from AOP Wiki.
To gain insight into the human health implications of microplastics, in this study, we investigated the possible mechanisms affecting the toxicity of high-density polyethylene (HDPE) in the nematode Caenorhabditis elegans using RNAi screening and a bioinformatics-based unbiased approach. The candidate pathways identified from C. elegans study were also confirmed using vertebrate model, zebrafish, Danio rerio and human relevance was then inferred using Comparative Toxicogenomics Database (CTD) analysis. Prior to evaluating the toxicity, label-free Raman mapping was conducted to investigate whether or not the organisms could uptake HDPE. C. elegans transcription factor RNAi screening results showed that the nucleotide excision repair (NER) and transforming growth factor-beta (TGF-β) signaling pathways were significantly associated with HDPE exposure, which was also confirmed in zebrafish model. Gene-disease interaction analysis using the CTD revealed the possible human health implications of microplastics. Finally, based on this finding, related AOPs were identified from AOP Wiki (http://aopwiki.org), which are “Peroxisome proliferator-activated receptors γ inactivation leading to lung fibrosis” and “AFB1: Mutagenic Mode-of-Action leading to Hepatocellular Carcinoma”. Further studies are needed for the validation of these AOPs with various microplastics.
Recently, there have been reports that many microplastics are found in the air, which has raised concerns about their toxicity. To date, however, only limited research has investigated the effects of ...micro(nano)plastics on human health, and even less the potential for inhalation toxicity. To fill this research gap, we investigated the potential inhalation toxicity of micro(nano)plastics using a modified OECD Guideline for Testing of Chemicals No. 412 ‘28-Day (subacute) inhalation toxicity study’ using a whole-body inhalation system. Sprague-Dawley rats were exposed to three different exposure concentrations of polystyrene micro(nano)plastics (PSMPs), as well as control, for 14 days of inhalation exposure. After 14 days, alterations were observed on sevral endpoints in physiological, serum biochemical, hematological, and respiratory function markers measured on the samples exposed to PSMPs. However, no concentration-response relationships were observed, suggesting that these effects may not be definitively linked to exposure of PSMPs. On the other hand, the expression of inflammatory proteins (TGF-β and TNF-α) increased in the lung tissue in an exposure concentration-dependent manner. The overall results indicate that 14-day inhalation exposure of PSMPs to rats has a more pronounced effect at the molecular level than at the organismal one. These results suggest that if the exposure sustained, alterations at the molecular level may lead to subsequent alterations at the higher levels, and consequently, the health risks of inhalation exposed micro(nano)plastics should not be neglected.
Display omitted
•Inhalation toxicity of microplastics were investigated on PSMP exposed rat using modified OECD TG412.•14-day inhalation exposure of PSMPs led minor alterations on physiological and biochemical endpoints.•Effects on inflammation-related molecular markers were also observed in PSMP exposed rat.
is an aerobic, gram-positive, endospore-forming bacterium that promotes plant growth. Numerous strains of this species have been reported to suppress the growth of microbial pathogens, including ...bacteria, fungi, and nematodes. Based on recent phylogenetic analysis, several
species have been reclassified as
. However, this information has yet to be integrated into a well-organized resource. Genomic analysis has revealed that
possesses strain-specific clusters of genes related to the biosynthesis of secondary metabolites, which play significant roles in both pathogen suppression and plant growth promotion. More specifically,
exhibits a high genetic capacity for synthesizing cyclic lipopeptides (i.e., surfactin, bacillomycin-D, fengycin, and bacillibactin) and polyketides (i.e., macrolactin, bacillaene, and difficidin). Secondary metabolites produced by
can also trigger induced systemic resistance in plants, a process by which plants defend themselves against recurrent attacks by virulent microorganisms. This is the first study to integrate previously published information about the
species, newly reclassified as
, and their beneficial metabolites (i.e., siderophore, bacteriocins, and volatile organic compounds).
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.
To understand the molecular mechanism of previously observed cerium oxide (CeO(2)) nanoparticles-induced oxidative stress, an in vitro toxicity assay was conducted using human bronchial epithelial ...cell, Beas-2B, focusing on the involvement of the oxidative stress responding signal transduction pathway and transcription factors in the toxicity of CeO(2) nanoparticles. Extracellular signal-regulating kinase (ERK), p38 and c-Jun N-terminal kinase (JNK) signaling pathways, along with nuclear factor-kappaB (NF-kappaB) and nuclear factor-E2-related factor-2 (Nrf-2), were investigated as the upstream events of oxidative stress from exposure to CeO(2) nanoparticles. The overall results suggest that CeO(2) nanoparticles may exert their toxicity through oxidative stress, as they cause significant increases in the cellular reactive oxygen species (ROS) concentrations, subsequently leading to the strong induction of heme oxygenase-1 (HO-1) via the p38-Nrf-2 signaling pathway. Further studies on the mechanism by which CeO(2) nanoparticles induce the p38-Nrf-2 signaling pathway are warranted for a better understanding of the CeO(2) nanoparticles-induced oxidative stress; studies with other signaling pathways, with concentration-response and time course experiments would also be justified.
Molecular docking is used to analyze structural complexes of a target with its ligand for understanding the chemical and structural basis of target specificity. This method has the potential to be ...applied for discovering molecular initiating events (MIEs) in the Adverse Outcome Pathway framework. In this study, we aimed to develop in silico⁻in vivo combined approach as a tool for identifying potential MIEs. We used environmental chemicals from Tox21 database to identify potential endocrine-disrupting chemicals (EDCs) through molecular docking simulation, using estrogen receptor (ER), androgen receptor (AR) and their homology models in the nematode
(NHR-14 and NHR-69, respectively). In vivo validation was conducted on the selected EDCs with
reproductive toxicity assay using wildtype N2,
, and
loss-of-function mutant strains. The chemicals showed high binding affinity to tested receptors and showed the high in vivo reproductive toxicity, and this was further confirmed using the mutant strains. The present study demonstrates that the binding affinity from the molecular docking potentially correlates with in vivo toxicity. These results prove that our in silico⁻in vivo combined approach has the potential to be applied for identifying MIEs. This study also suggests the potential of
as useful in the in vivo model for validating the in silico approach.
Silver nanoparticles (AgNPs), which have well-known antimicrobial properties, are extensively used in various medical and general applications. Despite the widespread use of AgNPs, relatively few ...studies have been undertaken to determine the cytotoxic effects of AgNPs exposure. This study investigates possible molecular mechanisms underlying the cytotoxic effects of AgNPs. Here, we show that AgNPs-induced cytotoxicity was higher compared than that observed when AgNO
3 was used as a silver ion source. AgNPs induced reactive oxygen species (ROS) generation and suppression of reduced glutathione (GSH) in human Chang liver cells. ROS generated by AgNPs resulted in damage to various cellular components, DNA breaks, lipid membrane peroxidation, and protein carbonylation. Upon AgNPs exposure, cell viability decreased due to apoptosis, as demonstrated by the formation of apoptotic bodies, sub-G
1 hypodiploid cells, and DNA fragmentation. AgNPs induced a mitochondria-dependent apoptotic pathway via modulation of Bax and Bcl-2 expressions, resulting in the disruption of mitochondrial membrane potential (Δ
ψ
m). Loss of Δ
ψ
m was followed by cytochrome c release from the mitochondria, resulting in the activation of caspases 9 and 3. The apoptotic effect of AgNPs was exerted via the activation of c-Jun NH
2-terminal kinase (JNK) and was abrogated by the JNK-specific inhibitor, SP600125 and siRNA targeting JNK. In summary, the results suggest that AgNPs cause cytotoxicity by oxidative stress-induced apoptosis and damage to cellular components.
Display omitted
•Toxicity mechanism of DPM was investigated using tiered approach based on the AOP206.•Individual chemicals in DPM were screened for ToxCast assays and deep learning models.•34 ...chemicals were active in PPARγ (MIE)-related assays.•PPARγ binding affinity of selected chemicals was calculated using molecular docking.•Expression of AO marker tended to be increased by DPM exposure.
Diesel particulate matter (DPM), a major subset of urban fine particulate matter (PM2.5), raises huge concerns for human health and has therefore been classified as a group 1 carcinogen by the International Agency for Research on Cancer (IARC). However, as DPM is a complex mixture of various chemicals, understanding of DPM’s toxicity mechanism remains limited. As the major exposure route of DPM is through inhalation, we herein investigated its toxicity mechanism based on the Adverse Outcome Pathway (AOP) of pulmonary fibrosis, which we previously submitted to AOPWiki as AOP ID 206 (AOP206). We first screened whether individual chemicals in DPM have the potential to exert their toxicity through AOP206 by using the ToxCast database and deep learning models approach, then confirmed this by examining whether DPM as a mixture alters the expression of the molecular initiating event (MIE) and key events (KEs) of AOP206. For identifying the activeness of the component chemicals of DPM, we used 24 ToxCast assays potentially related to AOP206 and deep learning models based on these assays, which were identified and developed in our previous study. Of the 100 individual chemicals in DPM, 34 were active in PPARγ (MIE)-related assay, of which 17 were active in one or more KEs. To further identify whether individual chemicals in DPM are related to the MIE of AOP206, we performed molecular docking simulation on PPARγ for the chemicals showing activeness. Benzoepyrene, benzoapyrene and other related chemicals were the most likely to bind to PPARγ. In in vitro experiments, PPARγ activity increased with exposure of the DPM mixture, and the protein expression of PPARγ (MIE), and fibronectin (AO) also tended to be increased. Overall, we have demonstrated that AOP206 can be applied to identify the toxicity pathway of DPM. Further, we suggest that applying the AOP approach using ToxCast and deep learning models is useful for identifying potential toxicity pathways of chemical mixtures, such as DPM, by determining the activity of individual chemicals.
PDF
