Zebrafish mylipb attenuates antiviral innate immunity through two synergistic mechanisms targeting transcription factor irf3.

IFN regulatory factor 3 (IRF3) is the transcription factor crucial for the production of type I IFN in viral defence and inflammatory responses. The activity of IRF3 is strictly modulated by post-translational modifications (PTMs) to effectively protect the host from infection while avoiding excessive immunopathology. Here, we report that zebrafish myosin-regulated light chain interacting protein b (mylipb) inhibits virus-induced type I IFN production via two synergistic mechanisms: induction of autophagic degradation of irf3 and reduction of irf3 phosphorylation. In vivo, mylipb-null zebrafish exhibit reduced lethality and viral mRNA levels compared to controls. At the cellular level, overexpression of mylipb significantly reduces cellular antiviral capacity, and promotes viral proliferation. Mechanistically, mylipb associates with irf3 and targets Lys 352 to increase K6-linked polyubiquitination, dependent on its E3 ubiquitin ligase activity, leading to autophagic degradation of irf3. Meanwhile, mylipb acts as a decoy substrate for the phosphokinase tbk1 to attenuate irf3 phosphorylation and cellular antiviral responses independent of its enzymatic activity. These findings support a critical role for zebrafish mylipb in the limitation of antiviral innate immunity through two synergistic mechanisms targeting irf3.

HGTphyloDetect: facilitating the identification and phylogenetic analysis of horizontal gene transfer.

BACKGROUND: Horizontal gene transfer (HGT) is an important driver in genome evolution, gain-of-function, and metabolic adaptation to environmental niches. Genome-wide identification of putative HGT events has become increasingly practical, given the rapid growth of genomic data. However, existing HGT analysis toolboxes are not widely used, limited by their inability to perform phylogenetic reconstruction to explore potential donors, and the detection of HGT from both evolutionarily distant and closely related species. RESULTS: In this study, we have developed HGTphyloDetect, which is a versatile computational toolbox that combines high-throughput analysis with phylogenetic inference, to facilitate comprehensive investigation of HGT events. Two case studies with Saccharomyces cerevisiae and Candida versatilis demonstrate the ability of HGTphyloDetect to identify horizontally acquired genes with high accuracy. In addition, HGTphyloDetect enables phylogenetic analysis to illustrate a likely path of gene transmission among the evolutionarily distant or closely related species. CONCLUSIONS: The HGTphyloDetect computational toolbox is designed for ease of use and can accurately find HGT events with a very low false discovery rate in a high-throughput manner. The HGTphyloDetect toolbox and its related user tutorial are freely available at https://github.com/SysBioChalmers/HGTphyloDetect.

Differential expression and co-localization of transcriptional factors during callus transition to differentiation for shoot organogenesis in the water fern Ceratopteris richardii.

BACKGROUND AND AIMS: In flowering plants, regeneration can be achieved by a variety of approaches, and different sets of transcriptional factors are involved in these processes. However, regeneration in taxa other than flowering plants remains a mystery. Ceratopteris richardii is a representative fern capable of both direct and indirect organogenesis, and we aimed to investigate the genetics underlying the transition from callus proliferation to differentiation. METHODS: Morphological and histological analyses were used to determine the type of regeneration involved. RNA sequencing and differential gene expression were used to investigate how the callus switches from proliferation to differentiation. Phylogenetic analysis and RNA in situ hybridization were used to understand whether transcriptional factors are involved in this transition. KEY RESULTS: The callus formed on nascent leaves and subsequently developed the shoot pro-meristem and shoot meristem, thus completing indirect de novo shoot organogenesis in C. richardii. Genes were differentially expressed during the callus transition from proliferation to differentiation, indicating a role for photosynthesis, stimulus response and transmembrane signalling in this transition and the involvement of almost all cell layers that make up the callus. Transcriptional factors were either downregulated or upregulated, which were generally in many-to-many orthology with genes known to be involved in callus development in flowering plants, suggesting that the genetics of fern callus development are both conserved and divergent. Among them, an STM-like, a PLT-like and an ethylene- and salt-inducible ERF gene3-like gene were expressed simultaneously in the vasculature but not in the other parts of the callus, indicating that the vasculature played a role in the callus transition from proliferation to differentiation. CONCLUSIONS: Indirect de novo shoot organogenesis could occur in ferns, and the callus transition from proliferation to differentiation required physiological changes, differential expression of transcriptional factors and involvement of the vasculature.

Molecular characterization and expression analyses of five genes involved in the MyD88-dependent pathway of yellow catfish (Pelteobagrus fulvidraco) responding to challenge of Aeromonas hydrophila.

MyD88-dependent pathway mediated by Toll-like receptor is one of the vital ways activating immune responses. In order to identify the role of MyD88-dependent signaling pathway in yellow catfish, the Pf_MyD88, Pf_IRAK4, Pf_IRAK1, Pf_TRAF6 and Pf_NFκB1 (p105) (Pf: abbreviation of Pelteobagrus fulvidraco) were cloned and characterized respectively. The Pf_MyD88, Pf_IRAK4, Pf_IRAK1 and Pf_TRAF6 were all highly conserved among species and showed the highest homology to that of Pangasianodon hypophthalmus. Pf_NFκB1 showed the highest homology to that of Ictalurus punetaus. All of the five genes showed similar expression patterns in various tissues, with the highest expression level in the liver. These genes also showed similar expression levels in different embryonic development stages, except Pf_IRAK4. The higher expression level was detected from fertilized eggs to 1 day post hatching (dph), lower expression from 3 dph to 30 dph. After stimulation of inactivated Aeromonas hydrophila, the mRNA expressions of Pf_MyD88, Pf_IRAK4, Pf_IRAK1, Pf_TRAF6 and Pf_NFκB1 were significantly increased at 24 h in the liver, spleen, head kidney and trunk kidney, suggesting that all the five genes were involved in the innate immune response of yellow catfish. These results showed that MyD88-dependent signaling pathway plays important roles for disease defensing in the innate immune response. Meanwhile, inactivated A. hydrophila can cause strong innate immune response, which provides theoretical bases for the application of inactivated vaccines in defense against bacterial diseases of teleost.

Transcriptomes of Zebrafish in Early Stages of Multiple Viral Invasions Reveal the Role of Sterols in Innate Immune Switch-On.

Although it is widely accepted that in the early stages of virus infection, fish pattern recognition receptors are the first to identify viruses and initiate innate immune responses, this process has never been thoroughly investigated. In this study, we infected larval zebrafish with four different viruses and analyzed whole-fish expression profiles from five groups of fish, including controls, at 10 h after infection. At this early stage of virus infection, 60.28% of the differentially expressed genes displayed the same expression pattern across all viruses, with the majority of immune-related genes downregulated and genes associated with protein synthesis and sterol synthesis upregulated. Furthermore, these protein synthesis- and sterol synthesis-related genes were strongly positively correlated in the expression pattern of the rare key upregulated immune genes, IRF3 and IRF7, which were not positively correlated with any known pattern recognition receptor gene. We hypothesize that viral infection triggered a large amount of protein synthesis that stressed the endoplasmic reticulum and the organism responded to this stress by suppressing the body's immune system while also mediating an increase in steroids. The increase in sterols then participates the activation of IRF3 and IRF7 and triggers the fish's innate immunological response to the virus infection.

Immobilization of antimony in soil and groundwater using ferro-magnesium bimetallic organic frameworks.

Sb(III) is often detected in contaminated soil and groundwater. Hence, high-efficiency technology is needed. In this study, bimetallic organic frameworks were used for the first time to immobilize Sb(III) from contaminated soil and groundwater. The materials were synthesized by the hydrothermal method. Both ends of the prepared material were hexagonal tip rods, and the length became shorter as the ratio of Fe/Mg decreased. The bimetallic organic framework with a Fe/Mg feeding ratio of 0.5 was the optimum material for Sb(III) removal, which could effectively immobilize Sb(III). The adsorption isotherm was fitted well with the Freundlich model, and the optimal adsorption capacity can reach 106.97 mg/g. The adsorption capacity of 84% can be completed in 10 min, which conformed to the pseudo-second-order kinetics. The Fe3+ could enhance the stability of the material, and the Mg2+ was conducive to freeing up adsorption sites for binding Sb(III) and forming stable chemical adsorption. Ion exchange is the predominant mechanism to remove Sb(III). After 14 days of remediation of Sb(III) contaminated soil, the Toxicity Characteristic Leaching Procedure (TCLP)-leached concentrations of Sb(III) were reduced by 86%, 91% and 94% when the material dosages were 1%, 2% and 3%, respectively. Immobilization of Sb(III) in soil resulted in a conversion of antimony speciation from more easily bioavailable species to less bioavailable species, further contributing to reduce the environmental risk of antimony. The results indicate that ferro-magnesium bimetallic organic frameworks may serve as a kind of promising materials for the immobilization of Sb(III) in contaminated soil and groundwater.

Data-driven rational biosynthesis design: from molecules to cell factories.

A proliferation of chemical, reaction and enzyme databases, new computational methods and software tools for data-driven rational biosynthesis design have emerged in recent years. With the coming of the era of big data, particularly in the bio-medical field, data-driven rational biosynthesis design could potentially be useful to construct target-oriented chassis organisms. Engineering the complicated metabolic systems of chassis organisms to biosynthesize target molecules from inexpensive biomass is the main goal of cell factory design. The process of data-driven cell factory design could be divided into several parts: (1) target molecule selection; (2) metabolic reaction and pathway design; (3) prediction of novel enzymes based on protein domain and structure transformation of biosynthetic reactions; (4) construction of large-scale DNA for metabolic pathways; and (5) DNA assembly methods and visualization tools. The construction of a one-stop cell factory system could achieve automated design from the molecule level to the chassis level. In this article, we outline data-driven rational biosynthesis design steps and provide an overview of related tools in individual steps.

ChemHub: a knowledgebase of functional chemicals for synthetic biology studies.

SUMMARY: The field of synthetic biology lacks a comprehensive knowledgebase for selecting synthetic target molecules according to their functions, economic applications and known biosynthetic pathways. We implemented ChemHub, a knowledgebase containing >90 000 chemicals and their functions, along with related biosynthesis information for these chemicals that was manually extracted from >600 000 published studies by more than 100 people over the past 10 years. AVAILABILITY AND IMPLEMENTATION: Multiple algorithms were implemented to enable biosynthetic pathway design and precursor discovery, which can support investigation of the biosynthetic potential of these functional chemicals. ChemHub is freely available at: http://www.rxnfinder.org/chemhub/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Yeast metabolic innovations emerged via expanded metabolic network and gene positive selection.

Yeasts are known to have versatile metabolic traits, while how these metabolic traits have evolved has not been elucidated systematically. We performed integrative evolution analysis to investigate how genomic evolution determines trait generation by reconstructing genome-scale metabolic models (GEMs) for 332 yeasts. These GEMs could comprehensively characterize trait diversity and predict enzyme functionality, thereby signifying that sequence-level evolution has shaped reaction networks towards new metabolic functions. Strikingly, using GEMs, we can mechanistically map different evolutionary events, e.g. horizontal gene transfer and gene duplication, onto relevant subpathways to explain metabolic plasticity. This demonstrates that gene family expansion and enzyme promiscuity are prominent mechanisms for metabolic trait gains, while GEM simulations reveal that additional factors, such as gene loss from distant pathways, contribute to trait losses. Furthermore, our analysis could pinpoint to specific genes and pathways that have been under positive selection and relevant for the formulation of complex metabolic traits, i.e. thermotolerance and the Crabtree effect. Our findings illustrate how multidimensional evolution in both metabolic network structure and individual enzymes drives phenotypic variations.

Spatial Resolved Surface Ozone with Urban and Rural Differentiation during 1990-2019: A Space-Time Bayesian Neural Network Downscaler.

Long-term exposure to ambient ozone (O3) can lead to a series of chronic diseases and associated premature deaths, and thus population-level environmental health studies hanker after the high-resolution surface O3 concentration database. In response to this demand, we innovatively construct a space-time Bayesian neural network parametric regressor to fuse TOAR historical observations, CMIP6 multimodel simulation ensemble, population distributions, land cover properties, and emission inventories altogether and downscale to 10 km × 10 km spatial resolution with high methodological reliability (R2 = 0.89-0.97, RMSE = 1.97-3.42 ppbV), fair prediction accuracy (R2 = 0.69-0.77, RMSE = 5.63-7.97 ppbV), and commendable spatiotemporal extrapolation capabilities (R2 = 0.62-0.76, RMSE = 5.38-11.7 ppbV). Based on our predictions in 8-h maximum daily average metric, the rural-site surface O3 are 15.1±7.4 ppbV higher than urban globally averaged across 30 historical years during 1990-2019, with developing countries being of the most evident differences. The globe-wide urban surface O3 are climbing by 1.9±2.3 ppbV per decade, except for the decreasing trends in eastern United States. On the other hand, the global rural surface O3 tend to be relatively stable, except for the rising tendencies in China and India. Using CMIP6 model simulations directly without urban-rural differentiation will lead to underestimations of population O3 exposure by 2.0±0.8 ppbV averaged over each historical year. Our original Bayesian neural network framework contributes to the deep-learning-driven environmental studies methodologically by providing a brand-new feasible way to realize data fusion and downscaling, which maintains high interpretability by conforming to the principles of spatial statistics without compromising the prediction accuracy. Moreover, the 30-year highly spatial resolved monthly surface O3 database with multiple metrics fills in the literature gap for long-term surface O3 exposure tracing.

novoPathFinder: a webserver of designing novel-pathway with integrating GEM-model.

To increase the number of value-added chemicals that can be produced by metabolic engineering and synthetic biology, constructing metabolic space with novel reactions/pathways is crucial. However, with the large number of reactions that existed in the metabolic space and complicated metabolisms within hosts, identifying novel pathways linking two molecules or heterologous pathways when engineering a host to produce a target molecule is an arduous task. Hence, we built a user-friendly web server, novoPathFinder, which has several features: (i) enumerate novel pathways between two specified molecules without considering hosts; (ii) construct heterologous pathways with known or putative reactions for producing target molecule within Escherichia coli or yeast without giving precursor; (iii) estimate novel pathways with considering several categories, including enzyme promiscuity, Synthetic Complex Score (SCScore) and LD50 of intermediates, overall stoichiometric conversions, pathway length, theoretical yields and thermodynamic feasibility. According to the results, novoPathFinder is more capable to recover experimentally validated pathways when comparing other rule-based web server tools. Besides, more efficient pathways with novel reactions could also be retrieved for further experimental exploration. novoPathFinder is available at http://design.rxnfinder.org/novopathfinder/.

Passive Smart Thermal Control Coatings Incorporating CaF2/VO2 Core-Shell Microsphere Structures.

Existing smart radiation devices suffer from numerous disadvantages such as large thicknesses, limited dimensions, or requirements for sustained electrical power. The present study addresses these issues by proposing a smart thermal control coating based on CaF2/VO2 core-shell (CaF2@VO2) structured microspheres prepared by a solvent/hydrothermal-calcination method and distributed within an easily applied polymer matrix. Here, the dielectric-to-metallic transition property of the VO2 shell material with increasing temperature is used to regulate the optical scattering and absorption characteristics of the CaF2@VO2 core-shell microspheres to realize a positive and reversible increase in the emissivity of the coating from 0.47 at 30 °C to 0.83 at 90 °C. The mechanisms behind this effect are investigated by theoretical analyses and numerical simulations. The present work can expect to promote the further research and development of new coating materials for smart thermal control applications.

Bio2Rxn: sequence-based enzymatic reaction predictions by a consensus strategy.

SUMMARY: The development of sequencing technologies has generated large amounts of protein sequence data. The automated prediction of the enzymatic reactions of uncharacterized proteins is a major challenge in the field of bioinformatics. Here, we present Bio2Rxn as a web-based tool to provide putative enzymatic reaction predictions for uncharacterized protein sequences. Bio2Rxn adopts a consensus strategy by incorporating six types of enzyme prediction tools. It allows for the efficient integration of these computational resources to maximize the accuracy and comprehensiveness of enzymatic reaction predictions, which facilitates the characterization of the functional roles of target proteins in metabolism. Bio2Rxn further links the enzyme function prediction with more than 300 000 enzymatic reactions, which were manually curated by more than 100 people over the past 9 years from more than 580 000 publications. AVAILABILITY AND IMPLEMENTATION: Bio2Rxn is available at: http://design.rxnfinder.org/bio2rxn/. CONTACT: qnhu@sibs.ac.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

BCSExplorer: a customized biosynthetic chemical space explorer with multifunctional objective function analysis.

SUMMARY: The biosynthetic ability of living organisms has important applications in producing bulk chemicals, biofuels and natural products. Based on the most comprehensive biosynthesis knowledgebase, a computational system, BCSExplorer, is proposed to discover the unexplored chemical space using nature's biosynthetic potential. BCSExplorer first integrates the most comprehensive biosynthetic reaction database with 280 000 biochemical reactions and 60 000 chemicals biosynthesized globally over the past 130 years. Second, in this study, a biosynthesis tree is computed for a starting chemical molecule based on a comprehensive biotransformation rule library covering almost all biosynthetic possibilities, in which redundant rules are removed using a new algorithm. Moreover, biosynthesis feasibility, drug-likeness and toxicity analysis of a new generation of compounds will be pursued in further studies to meet various needs. BCSExplorer represents a novel method to explore biosynthetically available chemical space. AVAILABILITY AND IMPLEMENTATION: BCSExplorer is available at: http://www.rxnfinder.org/bcsexplorer/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Microcystin-LR induces ovarian injury and apoptosis in mice via activating apoptosis signal-regulating kinase 1-mediated P38/JNK pathway.

As an emerging pollutant in the aquatic environment, microcystin-LR (MC-LR) can enter the body through multiple pathways, and then induce apoptosis and gonadal damage, affecting reproductive function. Previous studies focused on male reproductive toxicity induced by MC-LR neglecting its effects on females. The apoptotic signal-regulated kinase 1 (ASK1) is an upstream protein of P38/JNK pathway, closely associated with apoptosis and organ damage. However, the role of ASK1 in MC-LR-induced reproductive toxicity is unclear. Therefore, this study investigated the role of ASK1 in mouse ovarian injury and apoptosis induced by MC-LR. After MC-LR exposure, ASK1 expression in mouse ovarian granulosa cells was increased at the protein and mRNA levels, and decreased following pretreatment by antioxidant N-acetylcysteine, suggesting that MC-LR-induced oxidative stress has a regulatory role in ASK1 expression. Inhibition of ASK1 expression with siASK1 and NQDI-1 could effectively alleviate MC-LR-induced mitochondrial membrane potential damage and apoptosis in ovarian granulosa cells, as well as pathological damage, apoptosis and the decreased gonadal index in ovaries of C57BL/6 mice. Moreover, the P38/JNK pathway and downstream apoptosis-related proteins (P-P38, P-JNK, P-P53, Fas) and genes (MKK4, MKK3, Ddit3, Mef2c) were activated in vivo and vitro, but their activation was restrained after ASK1 inhibition. Data presented herein suggest that the ASK1-mediated P38/JNK pathway is involved in ovarian injury and apoptosis induced by MC-LR in mice. It is confirmed that ASK1 has an important role in MC-LR-induced ovarian injury, which provides new insights for preventing MCs-induced reproductive toxicity in females.

PrecursorFinder: a customized biosynthetic precursor explorer.

SUMMARY: Synthetic biology has a great potential to produce high value pharmaceuticals, commodities or bulk chemicals. However, many biosynthetic target molecules have no defined or predicted biosynthetic pathways. Biosynthetic precursors are crucial to create biosynthetic pathways. Thus computer-assisted tools for precursor identification are urgently needed to develop novel metabolic pathways. To this end, we present PrecursorFinder, a computational tool that explores biosynthetic precursors for the query target molecules using chemical structure, similarity as well as MCS (maximum common substructure). This platform comprises more than 60 000 compounds biosynthesized for being promising precursors, which are extracted from >500 000 scientific literatures and manually curated by more than 100 people over the past 8 years. The PrecursorFinder could speed up the process of biosynthesis research and make synthetic biology or metabolic engineering more efficient. AVAILABILITY AND IMPLEMENTATION: PrecursorFinder is available at: http://www.rxnfinder.org/precursorfinder/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Role of microRNA-122 in microcystin-leucine arginine-induced dysregulation of hepatic iron homeostasis in mice.

Microcystin-leucine arginine (MC-LR) is a cyclic heptapeptide hepatotoxin produced by cyanobacteria. MicroRNA-122 (miR-122) is specifically expressed in the liver. This study focuses on the role of miR-122 in MC-LR-induced dysregulation of hepatic iron homeostasis in C57BL/6 mice. The thirty mice were randomly divided into five groups (Control, 12.5 µg/kg·BW MC-LR, 25 µg/kg·BW MC-LR, Negative control agomir and 25 µg/kg·BW MC-LR + miR-122 agomir). The results show that MC-LR decreases the expressions of miR-122, Hamp, and its related regulators, while increasing the content of hepatic iron and the expressions of FPN1 and Tmprss6. Furthermore, miR-122 agomir pretreatment improves MC-LR induced dysregulation of hepatic iron homeostasis by arousing the related regulators and reducing the expression of Tmprss6. These results suggest that miR-122 agomir can prevent the accumulation of hepatic iron induced by MC-LR, which may be related to the regulation of hepcidin by BMP/SMAD and IL-6/STAT signaling pathways.

Epigenetic modification of H3K4 and oxidative stress are involved in MC-LR-induced apoptosis in testicular cells of SD rats.

Microcystin-leucine arginine (MC-LR) is a cyclic heptapeptide, produced by aquatic cyanobacteria such as microcystis, with strong reproductive toxicity which poses greater threat to the reproductive abilities of humans and animals. By exploring the role of trimethylation of histone H3 at lysine 4 (H3K4me3) and the role of oxidative stress in MC-LR-induced apoptosis in testicular Sertoli cells in Sprague-Dawley (SD) rats, this study indicated that MC-LR increased the expression levels of apoptosis-related genes by raising the levels of H3K4me3. 5'-Deoxy-5'-methylthioadenosine (MTA), the inhibitor of H3K4me3, reduced apoptosis, indicating for the first time that epigenetic modification is closely related to the testicular reproductive toxicity induced by MC-LR. MC-LR also induced oxidative stress by stimulating the generation of reactive oxygen species (ROS), and subsequently triggering mitochondria-mediated apoptotic pathway by decreasing mitochondrial membrane potential and increasing the levels of Bax, Bcl-2, Caspase-3, and so on. MC-LR-induced apoptosis of testicular cells could be decreased after pretreatment with oxidative stress inhibitor N-acetyl-cysteine (NAC). Furthermore, the pathological damage to mitochondria and testes were observed in SD rats. These results show that MC-LR can induce apoptosis by raising the levels of H3K4me3, and pretreatment with MTA can ameliorate the MC-LR-induced apoptosis of cocultured cells by lowering the levels of H3K4me3. Furthermore, NAC has a protective effect on MC-LR-induced apoptosis of testicular cells in SD rats by inhibiting the oxidative stress.

Work engagement as a mediator between organizational commitment and job satisfaction among community health-care workers in China: a cross-sectional study.

The purpose of this study was to explore levels of organizational commitment, job satisfaction and work engagement among community health-care workers in China, and to examine spatial relationships of variables. Data were collected by Organizational Commitment Scale, Job Satisfaction Scale and Utrecht Work Engagement Scale from 1404 community health-care workers in Guangzhou and Shenzhen cities. Structural equation model was used to analyze relationships among three variables. Medium levels of organizational commitment, job satisfaction and work engagement were found among community health-care workers. Organizational commitment was positively correlated to work engagement (r = 0.564) and job satisfaction (r = 0.550). The path analysis indicated that total effect (ß = 0.598) of organizational commitment on job satisfaction (R2 = 0.52) consisted of a direct effect (ß = 0.264) and an indirect effect (ß = 0.334), which was mediated positively by work engagement. Improvement in work engagement may lead to higher level of job satisfaction and organizational commitment.

The adverse health effects of bisphenol A and related toxicity mechanisms.

Bisphenol A (BPA) is an industrial component commonly used in synthesis of polycarbonate plastics, epoxy resin and other polymer materials. Due to its mass productions and widespread applications, the presence of BPA is ubiquitous in the environment. BPA can enter the body via different ways such as digestive tract, respiratory tract and dermal tract. As an endocrine disruptor, BPA has estrogen-like and anti-androgen effects causing damages to different tissues and organs, including reproductive system, immune system and neuroendocrine system, etc. Recently, it has been shown that BPA could induce carcinogenesis and mutagenesis in animal models. Here, the underlying mechanisms of BPA-induced multi-organ toxicity were well summarized, involving the receptor pathways, disruption of neuroendocrine system, inhibition of enzymes, modulation of immune and inflammatory responses, as well as genotoxic and epigenetic mechanisms. The aim of this review is to compile the available current research data regarding BPA and provide an overview of the current status of BPA exposure and relevant health effects covering reproductive, developmental, metabolic, immuno, respiratory, hepatic and renal toxicity and carcinogenesis of BPA. This review provides comprehensive data of BPA toxicity on human health and related mechanisms. We also identify any missing data which should be addressed by further studies.