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Objective: To evaluate the effect of homogeneous spinal-shortening axial decompression procedure (HSAD) on bladder function in patients with spina bifida tethered syndrome. Methods and materials: Patients with tethered spinal cord syndrome were collected prospectively, and all patients were treated with lumbar HSAD. Patients' urodynamic evaluation mainly included detrusor function, sphincter function, sphincter coordination (Ig TLR, ratio of tension and loose of urethral sphincter), and bladder compliance. Meanwhile, all patients were followed up with ICI-Q-SF, SF-12, and Rantala scores. Results: Twenty-four patients were included, with the average age of 27 ± 16 years. At the final follow-up, patients' detrusor function, sphincter function, sphincter coordination, and bladder compliance, were all improved dramatically (all P < 0.01). The preoperative SF-12 score, ICQ, and Rantala score were [52.16 ± 5.64, 14.11 ± 5.25, 7.84 ± 4.87], whereas the postoperative mean was [33.53 ± 3.53, 9.05 ± 4.89, 15 ± 3.77] (P < 0.01, respectively). According to objective evaluation, 16.7% of them recovered to normal. According to the subjective evaluation, 25% of the patients returned to normal. Only one patient (4.2%) deteriorated. Limitations include none-randomized controlled design and limited patient samples. Conclusions: The HSAD can significantly restore the bladder function in patients with long-term urinary incontinence. [ABSTRACT FROM AUTHOR]

• Conceptual framework of developmental abnormality were developed. • The hazard of graphene and plastic additives in aquatic ecosystems were revealed. • The interaction of 111 mutual genes was considered as key elements. • Oxidative stress and gonad development were noted as the key molecular event. • Apoptosis, inflammatory response, etc. were mainly enriched phenotypes. Increasing number of complex mixtures of organic pollutants in coastal area (especially for nanomaterials and micro/nanoplastics associated chemicals) threaten aquatic ecosystems and their joint hazards are complex and demanding tasks. Mussels are the most sensitive marine faunal groups in the world, and their early developmental stages (embryo and larvae) are particularly susceptible to environmental contaminants, which can distinguish the probable mechanisms of mixture-induced growth toxicity. In this study, the potential critical target and biological processes affected by graphene and triphenyl phosphate (TPP) were developed by mining public toxicogenomic data. And their combined toxic effects were verified by toxicological assay at early developmental stages in filter-feeding mussels (embryo and larvae). It showed that interactions among graphene/TPP with 111 genes (ABCB1, TP53, SOD, CAT, HSP , etc.) affected phenotypes along conceptual framework linking these chemicals to developmental abnormality endpoints. The PPAR signaling pathway, monocarboxylic acid metabolic process, regulation of lipid metabolic process, response to oxidative stress, and gonad development were noted as the key molecular pathways that contributed to the developmental abnormality. Enriched phenotype analysis revealed biological processes (cell proliferation, cell apoptosis, inflammatory response, response to oxidative stress, and lipid metabolism) affected by the investigated mixture. Combined, our results supported that adverse effects induced by contaminants/ mixture could not only be mediated by single receptor signaling or be predicted by the simple additive effect of contaminants. The results offer a framework for better comprehending the developmental toxicity of environmental contaminants in mussels and other invertebrate species, which have considerable potential for hazard assessment of coastal mixture. [ABSTRACT FROM AUTHOR]

As a typical brominated flame retardant (BFR), tetrabromobisphenol A (TBBPA) has been frequently detected in both biotic and abiotic matrices in marine environment. Our previous study found that genes related to metabolism phase I/II/III as well as steroid metabolism in Mytilus galloprovincialis were significantly altered by TBBPA treatment. However, the time- and dose-dependent response profiles of these genes to TBBPA exposure were rarely reported. In this study, the time- and dose-dependent effects of TBBPA on detoxification and reproductive endocrine disruption in M. galloprovincialis were explored by evaluating the responses of related gene expressions, enzymatic activities and gametogenesis to different concentrations of TBBPA (0.6, 3, 15, 75 and 375 μg/L) for different durations (14, 21 and 28 days). The results showed that the TBBPA accumulation increased linearly with the increases of exposure time and dose. Cytochrome P450 family 3 (CYP3A1-like) cooperated with CYP4Y1 for phase I biotransformation of TBBPA in mussels. The dose-response curves of phase II/III genes (glutathione-S-transferase (GST), P-glycoprotein (ABCB), and multidrug resistance protein (ABCC)) showed similar response profiles to TBBPA exposure. The common induction of phase I/II/III (CYPs , GST , ABCB and ABCC) suggested TBBPA detoxification regulation in mussels probably occurred in a step-wise manner. Concurrently, direct sulfation mediated by sulfotransferases (SULTs) on TBBPA was also the vital metabolic mechanism for TBBPA detoxification, which was supported by the coincidence between up-regulation of SULT1B1 and TBBPA accumulation. The significant promotion of steroid sulfatase (STS) might result from TBBPA-sulfate catalyzed by SULT1B1 due to its chemical similarity to estrone-sulfate. Furthermore, the promotion of gametogenesis was consistent with the induction of STS , suggesting that STS might interrupt steroids hydrolysis process and was responsible for reproductive endocrine disruption in M. galloprovincialis. This study provides a better understanding of the detoxification and endocrine-disrupting mechanisms of TBBPA. [Display omitted] • Step-wise metabolism of phase I/II/III was involved in TBBPA detoxification. • Sulfation mediated by SULT was an important means for TBBPA detoxification. • TBBPA exposure promoted gametogenesis in mussels. • Induction of STS might be responsible for reproductive endocrine disruption. [ABSTRACT FROM AUTHOR]

• Rhizosphere microbial communities differed between healthy and infected monkshood plants. • Dominant isolates from diseased samples facilitated Sclerotium rolfsii infection. • Dominant isolates from healthy samples prevented pathogen infection. • Distinct nonpathogenic microorganisms affected plant health during infection. Southern blight of monkshood (Aconitum carmichaelii Debx.) caused by Sclerotium rolfsii is one of the most destructive diseases causing tuber rot in the monoculture system. No studies have explored the differences of rhizosphere microbial communities between healthy and S. rolfsii -infected monkshood plants. Further, it remains unknown whether the rhizosphere microorganisms are associated with plant resistance to S. rolfsii infection. Therefore, in this study, the relationship between rhizosphere microorganisms and plant health of monkshood was assessed after S. rolfsii infection. High-throughput sequencing and culture-dependent methods were used to analyze the rhizosphere microbiome of healthy and diseased monkshood plants. Petri dish assays were performed to determine the effects of 10 dominant isolates from healthy or diseased samples on the growth of S. rolfsii hyphae and melon seedlings (as a model plant to test the plant growth promotion effect of these isolates). Two synthetic communities were constructed to verify the effects of dominant isolates on the growth and resistance of monkshood plants in pots after infection. The results showed that there were pronounced structural and functional differences in the bacterial and fungal communities between the rhizosphere soils of healthy and diseased plants. The diluted culture filtrates of some dominant isolates from diseased samples (such as Humicola fuscoatra and Fusarium commune) either promoted hyphal growth of S. rolfsii or inhibited seedling growth of melon; the synthetic community showed an inhibitory effect on monkshood growth and leaf L-phenylalanin ammonia-lyase activity, resulting in early and severe symptoms. Conversely, the diluted culture filtrates of some dominant isolates from healthy samples (such as Trichoderma hamatum and Streptomyces fungicidicus) inhibited S. rolfsii growth while promoting melon growth; the synthetic community elicited an improvement of monkshood growth and defense enzyme activity, resulting in mild symptoms. The results provide new insight into the role of rhizosphere microorganisms in plant health and open new avenues for controlling southern blight of monkshood. [ABSTRACT FROM AUTHOR]

Endocrine-disrupting chemicals can interfere with hormone action via various pathways, thereby increasing the risk of adverse health outcomes. Organophosphorus ester (OPEs) retardants, a group of new emerging endocrine disruption chemicals, have been referred to as metabolism disruptors and reported to induce chronic health problems. However, the toxicity pathways were mainly focused on nuclear receptor signaling pathways. Significantly, the membrane receptor pathway (such as G protein-coupled estrogen receptor 1 (GPER) signaling pathway) had been gradually realized as the important role in respond more effective to lipid metabolism disorder than traditional nuclear receptors, whereas the detailed mechanism was unclear yet. Therefore, this study innovatively integrated the bibliometric analysis, in silico and in vitro approach to develop toxicity pathways for the mechanism interpretation. Bibliometric analysis found that the typical OPEs - triphenyl phosphate was a major concern of lipid metabolism abnormality. Results verified that TPP could damage the structures of cell membranes and exert an agonistic effect of GPER as the molecular initiating event. Then, the activated GPER could trigger the PI3K-Akt/NCOR1 and mTOR/S6K2/PPARα transduction pathways as key event 1 (KE1) and affect the process of lipid metabolism and synthesis (CPT1A , CPT2, SREBF2 and SCD) as KE2. As a result, these alterations led to lipid accumulation as adverse effect at cellular-levels. Furthermore, the potential outcomes (such as immunity damage, weight change and steatohepatitis) at high biological levels were expanded. These findings improved knowledge to deeply understand toxicity pathways of phosphorus flame retardants and then provided a theoretical basis for risk assessments. [Display omitted] • TPP was considered as major concern of candidate EDCs and metabolism disruptors. • TPP exerted agonistic effect of GPER as MIE. • MIE affected KEs (PI3K/mTOR/PPARα , CPT2/SCD) to induced lipid accumulation. • Toxicity pathway of lipid metabolic disorders was developed. [ABSTRACT FROM AUTHOR]

The occurrence of microplastics (MPs) in various marine and freshwater matrices has attracted great attention. However, the effect of MPs in natural environment on the locomotor performance of aquatic biota is still controversial. Therefore, this meta-analysis was conducted, involving 116 effect sizes from 2347 samples, to quantitatively evaluate the alteration in locomotor behavior of aquatic organisms induced by MPs at environmentally relevant concentrations (≤ 1 mg/L, median = 0.125 mg/L). It was shown that MP exposure significantly inhibited the average speed and moved distance of aquatic organisms by 5% and 8% (p < 0.05), respectively, compared with the control, resulting in an obvious reduction of locomotor ability by 6% (p < 0.05). Egger's test indicated that the results were stable without publication bias (p > 0.05). The complex influence of MPs on the locomotor ability were characterized through random-effects meta-regression analyses, presenting size-, time-, concentration-dependent manners and multi-factors interactions. In addition, several physiological changes, including energy reserve reduction, metabolism disorder, gut microbiota dysbiosis, inflammation response, neurotoxic response, and oxidative stress, of aquatic organisms triggered by MP exposure at environmentally relevant concentrations were also provided, which might account for the MPs-induced locomotor activity decline. [Display omitted] • Microplastics (MPs) inhibited the locomotor activity by 6% at realistic concentrations. • MPs decreased the average speed by 5% and the moved distance by 8%. • Egger's test indicated the results were stable without obvious publication bias. • Effects presented size-, time-, concentration-dependent patterns and multi-factors interactions. • Potential mechanisms underlying MPs-induced locomotor activity decline were provided. [ABSTRACT FROM AUTHOR]

Glycolysis-related lactylation has gained wide attention for regulating various cellular functions and diseases. Nevertheless, its intricate involvement in intervertebral disc degeneration (IVDD) is not yet fully understood. In this study, we unrevealed the intricate association between elevated lactylation levels and the development of IVDD. Subsequently, we harvested the lactylation-related genes (LRGs) and systematically analysed the expression levels of these genes to establish a gene signature related to IVDD through multiple bulk RNA sequencing data. Six hub LRGs were determined and closely associated with the increased severity of IVDD. Among the six genes, CBX3 was the most upregulated in both in vivo and in vitro experiments. Furthermore, molecular docking identified atosiban acetate as a specific inhibitor for CBX3, and inhibiting the expression of CBX3 using atosiban acetate significantly repressed the glycolysis activity and global lactylation level, thus alleviating the progression of IVDD. In conclusion, the lactylation correlates positively with IVDD and the LRG signature could be used as a biomarker for the effective clinical treatment of IVDD. CBX3 emerged as one of the key LRGs in IVDD, and atosiban acetate, as a specific inhibitor for CBX3, may be a promising therapeutic candidate for IVDD by affecting lactylation., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Cadmium (Cd) is a typical heavy metal contaminant along China coasts. Clams Ruditapes philippinarum are widely distributed in multiple climatic zones. However, few research has been conducted on the different responses to Cd in clams from different climatic zones. In this study, the temperate zone Bohai Sea (BS) and tropical zone South China Sea (SCS) clams exhibited distinct background metabolome profiles, characterized by different strategies of osmotic regulation, energy metabolism, and anaerobiosis tendencies, suggesting different tolerance and enrichment capacities to Cd. After Cd treatments, the BS clams demonstrated quicker and higher accumulations of Cd than the SCS clams. Despite differences in their background metabolomes, both BS and SCS clams displayed similar metabolomic responses to Cd, such as anaerobiosis inhibition and increased energy demands. Overall, these findings suggested that the inconsistency of biological responses induced by geographic conditions should be considered in ecotoxicological studies. CAPSULE ABSTRACT: This study elucidated the biological differences in clams Ruditapes philippinarum from the Bohai Sea and South China Sea, and the metabolomic responses in these two clam populations after Cd (200 μg/L) treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Developing efficiency and long-lived room-temperature phosphorescence (RTP) materials through straightforward methods is highly desired. In this work, a stepwise stabilization strategy was proposed by the coordination and in-situ precipitation reactions among organic precursors, inorganic cation and anions, producing room-temperature phosphorescence materials with high emission efficiency (phosphorescence quantum yield of 45 %). Structural and photophysical characterizations revealed the coordination reaction reduced the energy gaps between singlet and triplet states and stabilized the excited states of the guest molecules. The in-situ precipitation reaction produced a solid matrix, which provided isolated environments for protecting the excitons from quenching. The applications of RTP materials in information encryption were demonstrated. The presented results provided a new clue for producing RTP materials, and extended their applications in wide fields., (© 2024 Wiley-VCH GmbH.)

Background and Objectives: Cauda equina syndrome with retention (CESR) is a severe lumbar condition characterized by painless urine retention due to cauda equina nerve injury. The standard treatment, posterior lumbar interbody fusion (PLIF), often yields suboptimal results. This study aims to compare the clinical safety and efficacy of a novel technique, capsule lumbar interbody fusion (CLIF), with PLIF in CESR patients, hypothesizing that CLIF can enhance neurological recovery by reducing nerve tension., Methods: A single-center, retrospective study was conducted on 83 patients with CESR due to lumbar disc herniation, who underwent either PLIF (n = 44) or CLIF (n = 39). Patients were assessed preoperatively and at 3, 12, and 24 months postoperatively using the Oswestry Disability Index (ODI), Visual Analogue Scale (VAS), International Consultation on Incontinence Questionnaire Short Form (ICI-Q-SF), and Rintala score. Urodynamic studies and nerve tension measurements were also performed. Statistical analysis included t tests, Mann-Whitney U tests, and Spearman's correlation., Results: Both groups showed significant postoperative improvements, but the CLIF group had superior outcomes. At 12 months, the CLIF group had lower VAS scores (1.15 ± 0.84 vs. 1.68 ± 0.60, p = 0.001) and ODI scores (23.31 ± 7.51 vs. 28.30 ± 8.26, p = 0.005). At 24 months, the CLIF group continued to show better results with ODI scores (15.97 ± 6.43 vs. 22.11 ± 6.41, p < 0.001) and higher ODI recovery rates (60.41 ± 17.6% vs. 44.71 ± 18.99%, p < 0.001). The CLIF group also had better ICI-Q-SF scores (2.13 ± 1.23 vs. 3.02 ± 1.45, p = 0.004) and Rintala scores (17.97 ± 1.43 vs. 16.59 ± 1.54, p < 0.001). Lower postoperative nerve tension in the CLIF group correlated with these improved outcomes., Conclusions: CLIF demonstrated superior efficacy over PLIF in treating CESR, with significant improvements in pain relief, functional recovery, and bladder and bowel function. This study highlights the potential of CLIF as a more effective surgical option for CESR, emphasizing its importance in improving patient outcomes and reducing the burden of CESR on patients and society., (© 2024. The Author(s).)

Background and Objectives: Spinal cord injury (SCI) results in significant neurological deficits, and microglia play the critical role in regulating the immune microenvironment and neurological recovery. Protein lactylation has been found to modulate the function of immune cells. Therefore, this study aimed to elucidate the effects of glycolysis-derived lactate on microglial function and its potential neuroprotective mechanisms via lactylation after SCI., Methods: Single-cell RNA sequencing (scRNA-seq) data were obtained from figshare to analyze cellular and molecular alterations within the spinal cord post-SCI, further focusing on the expression of microglia-related genes for cell sub-clustering, trajectory analysis, and glycolysis function analysis. We also evaluated the expression of lactylation-related genes in microglia between day 7 after SCI and sham group. Additionally, we established the mice SCI model and performed the bulk RNA sequencing in a time-dependent manner. The expression of glycolysis- and lactylation-related genes was evaluated, as well as the immune infiltration analysis based on the lactylation-related genes. Then, we investigated the bio-effects of lactate on the inflammation and polarization phenotype of microglia. Finally, adult male C57BL/6 mice were subjected to exercise first to increase lactate level, before SCI surgery, aiming to evaluate the protective effects of lactate-mediated lactylation of microglia-related proteins on SCI., Results: scRNA-seq identified a subcluster of microglia, recombinant chemokine C-X3-C-motif receptor 1 + (CX3CR1 + ) microglia, which is featured by M1-like phenotype and increased after SCI. KEGG analysis revealed the dysfunctional glycolysis in microglia after SCI surgery, and AUCell analysis suggested that the decreased glycolysis an increased oxidative phosphorylation in CX3CR1 + microglia. Differential gene analysis suggested that several lactylation-related genes (Fabp5, Lgals1, Vim, and Nefl) were downregulated in CX3CR1 + microglia at day 7 after SCI, further validated by the results from bulk RNA sequencing. Immunofluorescence staining indicated the expression of lactate dehydrogenase A (LDHA) in CX3CR1 + microglia also decreased at day 7 after SCI. Cellular experiments demonstrated that the administration of lactate could increase the lactylation level and inhibit the pro-inflammatory phenotype in microglia. Functionally, exercise-mediated lactate production resulted in improved locomotor recovery and decreased inflammatory markers in SCI mice compared to SCI alone., Conclusions: In the subacute phase of SCI, metabolic remodeling in microglia may be key therapeutic targets to promote nerve regeneration, and lactate contributed to neuroprotection after SCI by influencing microglial lactylation and inflammatory phenotype, which offered a novel approach for therapeutic intervention., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

MicroRNA(miRNA) is a class of non-coding small RNA that plays an important role in plant growth, development, and response to environmental stresses. Unlike most miRNAs, which usually target homologous genes across a variety of species, miR827 targets different types of genes in different species. Research on miR827 mainly focuses on its role in regulating phosphate (Pi) homeostasis of plants, however, little is known about its function in plant response to virus infection. In the present study, miR827 was significantly upregulated in the recovery tissue of virus-infected Nicotiana tabacum. Overexpression of miR827 could improve plants resistance to the infection of chilli veinal mottle virus (ChiVMV) in Nicotiana benthamiana, whereas interference of miR827 increased the susceptibility of the virus-infected plants. Further experiments indicated that the antiviral defence regulated by miR827 was associated with the reactive oxygen species and salicylic acid signalling pathways. Then, fructose-1,6-bisphosphatase (FBPase) was identified to be a target of miR827, and virus infection could affect the expression of FBPase. Finally, transient expression of FBPase increased the susceptibility to ChiVMV-GFP infection in N. benthamiana. By contrast, silencing of FBPase increased plant resistance. Taken together, our results demonstrate that miR827 plays a positive role in tobacco response to virus infection, thus providing new insights into understanding the role of miR827 in plant-virus interaction., (© 2024 Scandinavian Plant Physiology Society.)

The ecological risks of trace metals (Cu, Zn, As, Cd, Pb, and Hg) and PAHs in seawater from three typical bays of the Bohai Sea (the Liaodong Bay, Bohai Bay, and Laizhou Bay) were comprehensively assessed by recompiling 637 sites. Results highlighted that scrutiny should be given to the ecological risks of Cu (3.80 μg/L) in the Bohai Bay and Hg (0.23 μg/L) in the Laizhou Bay. Conversely, the Liaodong Bay exhibited negligible ecological risks related to trace metals. The risks of ΣPAHs in the Liaodong Bay, Bohai Bay, and Laizhou Bay were moderate, with mean concentrations of 368.16 ng/L, 731.93 ng/L, and 187.58 ng/L, respectively. The source allocation of trace metals and PAHs required consideration of spatial variability and anthropogenic factors, which greatly affected the distribution and composition of these pollutants. The combined ecological risks in the Bohai Bay (6.80 %) and Laizhou Bay (5.43 %) deserved more attention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Scalable fabrication of all-perovskite tandem solar cells is challenging because the narrow-bandgap subcells made of mixed lead-tin (Pb-Sn) perovskite films suffer from nonuniform crystallization and inferior buried perovskite interfaces. We used a dopant from Good's list of biochemical buffers, aminoacetamide hydrochloride, to homogenize perovskite crystallization and used it to extend the processing window for blade-coating Pb-Sn perovskite films and to selectively passivate defects at the buried perovskite interface. The resulting all-perovskite tandem solar module exhibited a certified power conversion efficiency of 24.5% with an aperture area of 20.25 square centimeters.

MiRNAs play an important role in regulating plant growth and immune response. Mosaic diseases are recognized as the most important plant diseases in the world, and mosaic symptoms are recovery tissues formed by plants against virus infection. However, the mechanism of the formation of mosaic symptoms remains elusive. In this study, two typical mosaic systems consisting of Nicotiana tabacum-cucumber mosaic virus (CMV) and N. tabacum-tobacco mosaic virus (TMV) were used to investigate the relevance of miRNAs to the appearance of mosaic symptoms. The results of miRNA-seq showed that there were significant differences in miRNA abundance between dark green tissues and chlorotic tissues in mosaic leaves caused by the infection of CMV or TMV. Compared with healthy tissues, miRNA expression was significantly increased in chlorotic tissues, but slightly increased in dark green tissues. Three miRNAs, namely miR1919, miR390a, and miR6157, were identified to be strongly up-regulated in chlorotic tissues of both mosaic systems. Results of overexpressing or silencing of the three miRNAs proved that they were related to chlorophyll synthesis, auxin response, and small GTPase-mediated immunity pathway, which were corresponding to the phenotype, physiological parameters and susceptibility of the chlorotic tissues in mosaic leaves. Besides, the newly identified novel-miRNA48, novel-miRNA96 and novel-miRNA103 may also be involved in this formation of mosaic symptoms. Taken together, our results demonstrated that miR1919, miR390a and miR6157 are involved in the formation of mosaic symptoms and plant antiviral responses, providing new insight into the role of miRNAs in the formation of recovery tissue and plant immunity., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cultivation of Larimichthys crocea in low salinity water has been regarded as an effective way to treat diseases induced by pathogens in seawater. The kidney of euryhaline teleost plays important roles in not only osmoregulation but also regulation of intermediary metabolism. However, the renal responses of metabolism and osmoregulation in L. crocea to low salinity waters are still rarely reported. In this work, renal metabolomic analysis based on MS technique was conducted on the L. crocea following cultivation in salinities of 24, 8, 6, 4, and 2 ppt for 40 days. A total of 485 metabolites covering organic acids and derivatives (34.17 %), lipids and lipid-like molecules (17.55 %), organoheterocyclic compounds (12.22 %), nucleosides, nucleotides, and analogues (11.91 %), and organic oxygen compounds (10.97 %), were identified in L. crocea kidney. Compared with control group (salinity 24), nearly all amino acids, nucleotides, and their derivatives were decreased in the kidney of L. crocea, whereas most of lipid-related metabolites including phospholipid, glycerophospholipids, and fatty acids were increased. The decrease in urea and inorganic ions as well as TMAO, betaine and taurine in L. crocea kidney suggested the less demand for maintaining osmotic homeostasis. Several intermediary metabolites covering amino acids, TCA cycle intermediates, and fatty acids were also significantly changed to match with the shift of energy allocation from osmoregulation to other biological processes. The reduced energy demand for osmoregulation might contribute to the promotion of L. crocea growth under low salinity environment. What is more, carbamoylphosphate and urea that showed linear salinity response curves and higher ED 50 values were potential biomarkers to adaptation to low salinity water. Overall, the characterization of metabolomes of L. crocea kidney under low salinity provided a better understanding of the adaptive mechanisms to low salinity water and potentially contributed to a reference for optimal culture salinity and feed formula of L. crocea culture in low salinity water., Competing Interests: Declaration of competing interest This article has not been published previously and is not under consideration for publication elsewhere. All authors have approved the paper for release and are in agreement with its content. All authors declare that they have no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Cadmium (Cd) contamination in marine environment poses great risks to the organisms due to its potential adverse effects. In the present study, the toxicological effects and mechanisms of Cd at environmentally relevant concentrations (5 and 50 μg/L) on clam Ruditapes philippinarum after 21 days were investigated by combined ionomic, metabolomic, and transcriptomic analyses. Results showed that the uptake of Cd significantly decreased the concentrations of Cu, Zn, Sr, Se, and Mo in the whole soft tissue from 50 μg/L Cd-treated clams. Significantly negative correlations were observed between Cd and essential elements (Zn, Sr, Se, and Mo). Altered essential elements homeostasis was associated with the gene regulation of transport and detoxification, including ATP-binding cassette protein subfamily B member 1 (ABCB1) and metallothioneins (MT). The crucial contribution of Se to Cd detoxification was also found in clams. Additionally, gene set enrichment analysis showed that Cd could interfere with proteolysis by peptidases and decrease the translation efficiency at 50 μg/L. Cd inhibited lipid metabolism in clams and increased energy demand by up-regulating glycolysis and TCA cycle. Osmotic pressure was regulated by free amino acids, including alanine, glutamate, taurine, and homarine. Meanwhile, significant alterations of some differentially expressed genes, such as dopamine-β-hydroxylase (DBH), neuroligin (NLGN), NOTCH 1, and chondroitin sulfate proteoglycan 1 (CSPG1) were observed in clams, which implied potential interference with synaptic transmission. Overall, through integrating multiple omics, this study provided new insights into the toxicological mechanisms of Cd, particularly in those mediated by dysregulation of essential element homeostasis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The novel brominated flame retardant DBDPE has become a widespread environmental contaminant and could affect reproductive endocrine system in vertebrates. However, information about reproductive endocrine-disrupting effects of DBDPE on invertebrates is totally unknown. In this study, mussels Mytilus galloprovincialis were exposed to 1, 10, 50, 200 and 500 μg/L DBDPE for 30 days. Histopathological and transcriptomic analyses were performed to assess the reproductive endocrine-disrupting effects of DBDPE in mussels and the potential mechanisms. DBDPE promoted the gametogenesis in mussels of both sexes according to histological observation, gender-specific gene expression (VERL and VCL) and histological morphometric parameter analysis. Transcriptomic analysis demonstrated that DBDPE suppressed the genes related to cholesterol homeostasis and transport in both sexes via different LRPs- and ABCs-mediated pathways. DBDPE also disturbed nongenomic signaling pathway including signaling cascades (GPR157-IP3-Ca 2+ ) in males and secondary messengers (cGMP) in females, and subsequently altered the expression levels of reproductive genes (VMO1, ZAN, Banf1 and Hook1). Additionally, dysregulation of energy metabolism in male mussels induced by DBDPE might interfere with the reproductive endocrine system. Overall, this is the first report that DBDPE evoked reproductive endocrine-disruptions in marine mussels. These findings will provide important references for ecological risk assessment of DBDPE pollution in marine environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This study recompiled a national dataset to characterize the pollution level and health risk of cadmium (Cd), copper (Cu), lead (Pb) and zinc (Zn) in oysters along the coastal areas of China. Results showed that the median concentrations of Cd, Cu, Pb and Zn in nationwide oysters were 5.5, 335, 1.3 and 1280 mg/kg dry weight, respectively. Generally, oysters from the north coasts presented lower metal pollution and higher quality than those from the south. The regional characteristics of trace metals in oysters might be contributed by the interspecific differences. Nationally, the noncarcinogenic risk posed by these four metals in oysters was relatively low, with the risk only occurring in a few hotspots such as the Pearl River Estuary and the Jiulong River Estuary. However, more attention should be paid to the carcinogenic risk of Cd, and priority should be given to formulating control measures to mitigate Cd pollution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The prevalence of microplastics (MPs) in global aquatic environments has received considerable attention. Currently, concerns have been raised regarding reports that the adverse effect of MPs on aquatic animals in the exposure phase may not be (completely) reversed in the depuration phase. In order to provide insights into the legacy effect of MPs from the depuration phase, this study evaluated the kinetic characteristics and recovery potential of aquatic animals after the exposure to MPs. More specifically, a total of 68 depuration kinetic curves were highly fitted to estimate the retention time of MPs. It was shown that the retention time ranged from 1.26 to 3.01 days, corresponding to the egestion of 90 % to 99 % of ingested MPs. The retention time decreased with the increased retention rate. Furthermore, variables potentially affecting the retention time were ranked by the decision tree-based eXtreme Gradient Boosting (XGBoost) algorithm, suggesting that the particle size and tested species were of great importance for explaining the difference in retention time of MPs. Moreover, a biomarker profile was recompiled to determine the toxic changes. Results indicated that the MPs-induced toxicity significantly reduced in the depuration phase, evidenced by the recovery of energy reserves and metabolism, hepatotoxicity, immunotoxicity, hematological parameters, neurotoxicity and oxidative stress. However, the continuous detoxification and remarkable genotoxicity implied that the toxicity was not completely alleviated. In addition, the current knowledge gaps are also highlighted, with recommendations proposed for future research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Facing billions of tons of pollutants entering the ocean each year, aquatic toxicity is becoming a crucial endpoint for evaluating chemical adverse effects on ecosystems. Notably, huge amount of toxic chemicals at environmental relevant doses can cause potential adverse effects. However, chronic aquatic toxicity effects of chemicals are much scarcer, especially at population level. Rotifers are highly sensitive to toxicants even at chronic low-doses and their communities are usually considered as effective indicators for assessing the status of aquatic ecosystems. Therefore, the no observed effect concentration (NOEC) for population abundance of rotifers were selected as endpoints to develop machine learning models for the prediction of chemical aquatic chronic toxicity. In this study, forty-eight binary models were built by eight types of chemical descriptors combined with six machine learning algorithms. The best binary model was 1D & 2D molecular descriptors - random trees model (RT) with high balanced accuracy (BA) (0.83 for training and 0.83 for validation set), and Matthews correlation coefficient (MCC) (0.72 for training set and 0.67 for validation set). Moreover, the optimal model identified the primary factors (SpMAD&#95;Dzp, AMW, MATS2v) and filtered out three high alerting substructures [c1cc(Cl)cc1, CNCO, CCOP(=S)(OCC)O] influencing the chronic aquatic toxicity. These results showed that the compounds with low molecular volume, high polarity and molecular weight could contribute to adverse effects on rotifers, facilitating the deeper understanding of chronic toxicity mechanisms. In addition, forecast models had better performances than the common models embedded into ECOSAR software. This study provided insights into structural features responsible for the toxicity of different groups of chemicals and thereby allowed for the rational design of green and safer alternatives., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Response of rhizosphere microbial community structure and co-occurrence patterns to liquid organic fertilizer in sunflower cropland was investigated. Moderate and severe saline-alkaline soils were treated with liquid organic fertilizer containing mainly small molecular organic compounds (450 g L -1 ) at a rate of 4500 L ha -1  year -1 over 2 years. Compared with the untreated soils, organic fertilizer treatment increased soil nutrient concentrations by 13.8-137.1% while reducing soil pH and salinity by 5.6% and 54.7%, respectively. Organic fertilizer treatment also improved sunflower yield, plant number, and plant height by 28.6-67.3%. Following organic fertilizer treatment, fungal α-diversity was increased, and the effects of salinity-alkalinity stress on rhizosphere microbial communities were alleviated. The relative abundances of some halotolerant microbes and phytopathogenic fungi were reduced in organic fertilizer-treated soils, in contrast to increases in the relative abundances of plant growth-promoting microbes and organic matter decomposers, such as Nocardioides, Rhizophagus, and Stachybotrys. Network analysis revealed that severe salinity-alkalinity stress stimulated cooperation among bacteria, while organic fertilizer treatment tended to stimulate the ecosystem functions of fungi with higher proportions of fungi-bacteria and fungi-fungi links. More keystone taxa (e.g., Amycolatopsis, Variovorax, and Gemmatimonas) were positively correlated with soil nutrient concentrations and crop yield-related traits in organic fertilizer-treated soils. Overall, liquid organic fertilizer amendment could attenuate the adverse effects of salinity-alkalinity stress on sunflower yield by improving soil quality and optimizing rhizosphere microbial community structure and co-occurrence patterns., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The organic flame retardants (OFRs) have attracted global concerns due to their potential toxicity and ubiquitous presence in the aquatic environment. Hormesis refers to a biphasic dose response, characterized by low-dose stimulation and high-dose inhibition. The present study provided substantial evidence for the widespread occurrence of OFRs-induced hormesis in aquatic animals, including 202 hormetic dose response relationships. The maximum stimulatory response (MAX) was commonly lower than 160% of the control response, with a combined value of 134%. Furthermore, the magnitude of MAX varied significantly among multiple factors and their interactions, such as chemical types and taxonomic groups. Moreover, the distance from the dose of MAX to the no-observed-adverse-effect-level (NOAEL) (NOAEL: MAX) was typically below 10-fold (median = 6-fold), while the width of the hormetic zone (from the lowest dose inducing hormesis to the NOAEL) was approximately 20-fold. Collectively, the quantitative features of OFRs-induced hormesis in aquatic animals were in accordance with the broader hormetic literature. In addition, the implications of hormetic dose response model for the risk assessment of OFRs were discussed. This study offered a novel insight for understanding the biological effects of low-to-high doses of OFRs on aquatic animals and assessing the potential risks of OFRs in the aquatic environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

With the phase-out of legacy halogenated flame retardants (HFRs), such as decabromodiphenyl ether (BDE-209), emerging ones, such as decabromodiphenyl ethane (DBDPE), are being widely produced. We conducted field campaigns to assess the trophic transfer of legacy and emerging HFRs in estuarine and coastal food webs of Laizhou Bay, which are located near the largest HFR manufacturing base in China. Seawater, sediment, plankton, invertebrates, and fish were collected from both sites. BDE-209 was the predominant compound in the estuary, whereas DBDPE was the main contributor to HFRs in the bay, followed by BDE-209. Invertebrates, especially bivalves and sea cucumbers, showed higher levels of BDE-209 and DBDPE than fish. The HFR levels in the organisms of the two coastal zones were comparable to each other, although their concentrations in the estuarine water were one order of magnitude higher than those in the bay. The HFR profiles in benthic organisms were similar to those in the sediments, indicating that the bioaccumulation of HFRs in coastal food webs depended on the habitat. The ΣHFR concentrations followed the order filter-feeding > carnivorous for invertebrates, and demersal non-migratory fish showed higher HFR levels than oceanodromous fish. The trophic magnification factors estimated for BDE-209, dechlorane plus, and DBDPE were lower than 1, suggesting biodilution potential in both food webs, whereas several PBDE congeners exhibited biomagnification capacity. Feeding habits, habitats, hydrophobicity, bioavailability, and metabolism may be the main factors impacting the bioaccumulation of HFRs in organisms in estuarine-coastal ecosystems of northern China., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cadmium (Cd) is one of the typical metal pollutants in the Bohai Sea. To evaluate the acute toxicological effects of Cd on marine crustaceans, juvenile Fenneropenaeus chinensis and Portunus trituberculatus were exposed to Cd at environmentally relevant concentrations (5 and 50 μg/L) for 96 h. Cd accumulation, antioxidants and metabolite profiles were characterized to elucidate the responses of juvenile crustaceans to Cd stress. Significant Cd accumulation was observed in both juvenile crustaceans in 50 μg/L Cd-treated group. Results showed that Cd exposure induced hormesis based on the alterations of GSH, SOD and CAT activities (i.e. increased levels in the low concentration of Cd treatment and recovered levels in the high concentration of Cd treatment) in juvenile P. trituberculatus. Similarly, the responses of GSH contents presented hormesis pattern in Cd-treated juvenile F. chinensis. Na + -K + -ATPase contents were significantly elevated in 50 μg/L Cd-treated group. In addition, untargeted NMR-based metabolomics indicated Cd caused the disturbance in osmotic regulation and energy consumption in both juvenile F. chinensis and P. trituberculatus via different pathways. The immunotoxicity and movement disorder were uniquely demonstrated in juvenile P. trituberculatus after Cd exposure., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Both immune regulation and endocrine systems are great challenges to marine organisms, and effective protocols for determining these adverse outcome pathways are limited, especially in vivo. The increasing usage of graphene nanomaterials can lead to the frequent exposure to marine organisms. Triphenyl phosphate (TPP), an organophosphate flame retardant, is frequently detected in natural environments. In this study, the combined toxic effects of co-exposure to graphene and TPP was investigated in Mytilus galloprovincialis using computational toxicology and multi-omics technology. Noticeably, graphene could disturb the membrane stability and increase the tissue accumulation of TPP. The adsorption behavior of TPP on graphene could inhibit the surface activity of graphene. In the digestive gland, transcriptomics analysis revealed the down-regulated genes in graphene + TPP treatment, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), sorbitol dehydrogenase (SORD), glutathione s-transferase mu 3 (GSTM3) and 4-aminobutyrate aminotransferase (ABAT), were mainly associated with oxidative stress and energy metabolism. Moreover, metabolic responses indicated that graphene + TPP could cause disturbances in energy metabolism and osmotic regulation marked by differentially altered ATP, glucose and taurine in mussels. These data underline the need for further knowledge on the potential interactions of nanomaterials with existing contaminants in marine organisms., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

As emerging pollutants, microplastics (MPs) have been found globally in various freshwater and marine matrices. This study recompiled 270 endpoints of 3765 individuals from 43 publications, reporting the onset of enhanced biological performance and reduced oxidative stress biomarkers induced by MPs in aquatic organisms at environmentally relevant concentrations (≤1 mg/L, median = 0.1 mg/L). The stimulatory responses of consumption, growth, reproduction and survival ranged from 131% to 144% of the control, with a combined response of 136%. The overall inhibitory response of 9 oxidative stress biomarkers was 71% of the control, and commonly below 75%. The random-effects meta-regression indicated that the extents of MPs-induced responses were independent of habitat, MP composition, morphology, particle size and exposure duration. The results implied that the exposure to MPs at low and high concentrations might induce opposite/non-monotonic responses in aquatic biota. Correspondingly, the hormetic dose response relationships were found at various endpoints, such as reproduction, genotoxicity, immunotoxicity, neurotoxicity and behavioral alteration. Hormesis offers a novel perspective for understanding the dose response mode of aquatic organisms exposed to low and high concentrations of MPs, highlighting the necessity to incorporate the hormetic dose response model into the ecological/environmental risk assessment of MPs., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Tetrabromobisphenol A (TBBPA) pollution in marine environmental media poses great risks to marine organisms due to its potential endocrine-disrupting effects. However, limited attention of TBBPA's endocrine-disrupting effects has been paid on marine invertebrates. In this work, the reproductive endocrine-disrupting effects of TBBPA were evaluated by observing the gametes development, quantifying the gender-specific gene expression, and determining vertebrate sex hormones in mussels Mytilus galloprovincialis treated with TBBPA for 30 days. Additionally, transcriptomic profiling and enzymes activities were conducted to investigate the potential mechanisms of reproductive endocrine-disrupting effects. We found that promotion of gametogenesis and alterations of vertebrate sex hormones occurred in TBBPA-treated mussels of both sexes. Meanwhile, estrogen sulfotransferase (SULT1E1) and steroid sulfatase (STS) were up-regulated at transcript level as a result of TBBPA treatments, suggesting that TBBPA disrupted the steroidogenesis in mussels through promoting steroids sulfonation and hydrolysis of sulfate steroids. The induction of SULTs for TBBPA biotransformation might be responsible for the dysregulation of steroidogenesis and steroids metabolism. Overall, these findings provide a new insight into assessing impact of TBBPA as well as TBBPA biomonitoring in marine environment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Apoptosis is one of the typical features of liver diseases, therefore molecular targets of hepatic apoptosis and regulatory mechanisms need to be further investigated. The caspases play important functions in the execution of apoptosis and many studies have focused on classical caspase-dependent cell death pathways. However, other types of cell death pathways (such as mitochondrial poly (ADP-ribose) polymerase-1 (PARP1) pathway) are suggested to be also as important as the caspase-mediated pathways in reflection of early toxic effects in hepatocytes, which requires additional research. In this work, an approach integrated in silico and in vitro was used to investigate the underlying toxicological mechanisms of hepatocyte apoptosis through the PARP1 dependent cell death pathway induced by triphenyl phosphate (TPP). Docking view showed that TPP could interact with helix αJ to affect the activation of PARP1 as a molecular initial event. In vitro assays suggested some biochemical events downstream of PARP1 activation, such as mitochondrial injury, apoptosis inducing factor (AIF) release, reactive oxygen species (ROS) production, and DNA damage. Moreover, the apoptosis was alleviated when cells were pretreated with PJ34 hydrochloride (PARP1 inhibitor), suggesting the mitochondrial PARP1 dependent pathway played a pivotal role in L02 cells apoptosis. This study indicated that PARP1 was an important molecular target in this process. And it also helped to understand the mechanism of hepatocytes apoptosis, early hepatic toxicity, and even liver diseases., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) are known to have complicated functions in aquatic species, but little is known about the role of miRNAs in mollusk species under environmental stress. In this study, we performed small RNA sequencing to characterize the differentially expressed miRNAs in different tissues (whole tissues, digestive glands, gills, and gonads) of blue mussels (Mytilus galloprovincialis) exposed to cadmium (Cd). In summary, 107 known miRNAs and 32 novel miRNAs were significantly (p < 0.01) differentially expressed after Cd exposure. The peak size of miRNAs was 22 nucleotides. Target genes of these differentially expressions of miRNAs related to immune defense, apoptosis, lipid and xenobiotic metabolism showed significant changes under Cd stress. These findings provide the first characterization of miRNAs in mussel M. galloprovincialis and expressions of many target genes in response to Cd stress., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Cadmium (Cd) is being frequently detected in marine organisms. However, dose-dependent effects of Cd challenged unraveling the toxicological mechanisms of Cd to marine organisms and developing biomarkers. Here, the dose-dependent effects of Cd on clams Ruditapes philippinarum following exposure to 5 doses of Cd (3, 9, 27, 81, 243 μg/L) were investigated using benchmark dose (BMD) method. By model fitting, calculation of BMD values was performed on transcriptomic profiles, metals concentrations, and antioxidant indices. Cd exposure induced not only significant Cd accumulation in clams, but also marked alterations of essential metals such as Ca, Cu, Zn, Mn, and Fe. Gene regulation posed little influence on essential metal homeostasis, indicated by poor enrichment of differentially expressed genes (DEGs) associated with metal binding and metal transport in lower concentrations of Cd-treated groups. BMD analysis on biological processes and pathways showed that peptide cross-linking was the most sensitive biological process to Cd exposure, followed by focal adhesion, ubiquitin mediated proteolysis, and apoptosis. Occurrence of apoptosis was also confirmed by TUENL-positive staining in gills and hepatopancreas of clams treated with Cd. Furthermore, many DEGs, such as transglutaminases (TGs), metallothionein (MT), STEAP2-like and laccase, which presented linear or monotonic curves and relatively low BMD values, were potentially preferable biomarkers in clams to Cd. Overall, BMD analysis on transcriptomic profiles, metals concentrations and biochemical endpoints unraveled the sensitiveness of key events in response to Cd treatments, which provided new insights in exploring the toxicological mechanisms of Cd in clams as well as biomarker selection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Trichloropropyl phosphate (TCPP) is a halogenated organophosphate ester that is widely used as flame retardants and plasticizers. In this study, gender-specific accumulation and responses in mussel Mytilus galloprovincialis to TCPP exposure were focused and highlighted. After TCPP (100 nmol L -1 ) exposure for 42 days, male mussels showed similar average bioaccumulation (37.14 ± 6.09 nmol g -1 fat weight (fw)) of TCPP with that in female mussels (32.28 ± 4.49 nmol g -1 fw). Proteomic analysis identified 219 differentially expressed proteins (DEPs) between male and female mussels in control group. There were 52 and 54 DEPs induced by TCPP in male and female mussels, respectively. Interestingly, gender-specific DEPs included 37 and 41 DEPs induced by TCPP in male and female mussels, respectively. The proteomic differences between male and female mussels were related to protein synthesis and degradation, energy metabolism, and functions of cytoskeleton and motor proteins. TCPP influenced protein synthesis, energy metabolism, cytoskeleton functions, immunity, and reproduction in both male and female mussels. Protein-protein interaction (PPI) networks indicated that protein synthesis and energy metabolism were the main biological processes influenced by TCPP. However, DEPs involved in these processes and their interaction patterns were quite different between male and female mussels. Basically, twelve ribosome DEPs which directly or indirectly interacted were found in protein synthesis in TCPP-exposed male mussels, while only 3 ribosome DEPs (not interacted) in TCPP-exposed female mussels. In energy metabolism, only 4 DEPs (with the relatively simple interaction pattern) mainly resided in fatty acid metabolism, butanoate/propanoate metabolism and glucose metabolism were discovered in TCPP-exposed male mussels, and more DEPs (with multiple interactions) functioned in TCA cycle and pyruvate/glyoxylate/dicarboxylate metabolism were found in TCCP-exposed female mussels. Taken together, TCPP induced gender-specific toxicological effects in mussels, which may shed new lights on further understanding the toxicological mechanisms of TCPP in aquatic organisms., Competing Interests: Declaration of competing interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Triphenyl phosphate (TPP) has been found in various environmental media and in biota suggesting widespread human exposure. However, there is still insufficient information on the hepatotoxicity mechanisms of health risk exposed to TPP. In this study, TPP could induce human normal liver cell (L02) apoptosis, injury cell ultrastructure and elevate the levels of reactive oxygen species (ROS). The integrated multi-omic (transcriptomic, proteomic, and metabolomic) analysis was used to further investigate the mechanisms. Transcriptomic analysis revealed that TPP exposure markedly affected cell apoptosis, oncogene activation, REDOX homeostasis, DNA damage and repair. Additionally, proteomic analysis found that the related proteins associated with apoptosis, oxidative stress, metabolism and membrane structure were affected. And metabolomic analysis verified that the related metabolic pathways, such as glycolysis, citrate cycle, oxidative phosphorylation, lipid and protein metabolism, were also significantly disrupted. Based on the multi-omic results, a hypothesized network was constructed to discover the key molecular events in response to TPP and illustrate the mechanism of TPP-induced hepatotoxicity in L02 cells. Therefore, molecular responses could be elucidated at multiple biological levels, and multi-omic analysis could provide scientific tools for exploring potential mechanisms of toxicity and chemical risk assessment., (Copyright © 2020 Elsevier Inc. All rights reserved.)