Toxicological Sciences最新文献

{"title":"Acute particulate hexavalent chromium exposure induces DNA double-strand breaks and activates homologous recombination repair in rat lung tissue.","authors":"Haiyan Lu, Sandra S Wise, Rachel M Speer, Tayler J Croom-Perez, Jennifer H Toyoda, Idoia Meaza, Aggie Williams, John Pierce Wise, J Calvin Kouokam, Jamie Young Wise, Gary W Hoyle, Cairong Zhu, Abdul-Mehdi Ali, John Pierce Wise","doi":"10.1093/toxsci/kfae076","DOIUrl":"10.1093/toxsci/kfae076","url":null,"abstract":"<p><p>Hexavalent chromium [Cr(VI)] is an established human lung carcinogen, but the carcinogenesis mechanism is poorly understood. Chromosome instability, a hallmark of lung cancer, is considered a major driver of Cr(VI)-induced lung cancer. Unrepaired DNA double-strand breaks are the underlying cause, and homologous recombination repair is the primary mechanism preventing Cr(VI)-induced DNA breaks from causing chromosome instability. Cell culture studies show acute Cr(VI) exposure causes DNA double-strand breaks and increases homologous recombination repair activity. However, the ability of Cr(VI)-induced DNA breaks and repair impact has only been reported in cell culture studies. Therefore, we investigated whether acute Cr(VI) exposure could induce breaks and homologous recombination repair in rat lungs. Male and female Wistar rats were acutely exposed to either zinc chromate particles in a saline solution or saline alone by oropharyngeal aspiration. This exposure route resulted in increased Cr levels in each lobe of the lung. We found Cr(VI) induced DNA double-strand breaks in a concentration-dependent manner, with females being more susceptible than males, and induced homologous recombination repair at similar levels in both sexes. Thus, these data show this driving mechanism discovered in cell culture indeed translates to lung tissue in vivo.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"1-13"},"PeriodicalIF":3.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11347773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141311770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mucus matters: pollution alters mucus pathophysiology.","authors":"Kaitlyn R Rouillard, Ilona Jaspers, David B Hill","doi":"10.1093/toxsci/kfae082","DOIUrl":"https://doi.org/10.1093/toxsci/kfae082","url":null,"abstract":"","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142112254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Steatotic liver disease induced by TCPOBOP-activated hepatic constitutive androstane receptor: primary and secondary gene responses with links to disease progression.","authors":"Ravi Sonkar, Hong Ma, David J Waxman","doi":"10.1093/toxsci/kfae057","DOIUrl":"10.1093/toxsci/kfae057","url":null,"abstract":"<p><p>Constitutive androstane receptor (CAR, Nr1i3), a liver nuclear receptor and xenobiotic sensor, induces drug, steroid, and lipid metabolizing enzymes, stimulates liver hypertrophy and hyperplasia, and ultimately, hepatocellular carcinogenesis. The mechanisms linking early CAR responses to later disease development are poorly understood. Here we show that exposure of CD-1 mice to TCPOBOP (1,4-bis[2-(3,5-dichloropyridyloxy)]benzene), a halogenated xenochemical and selective CAR agonist ligand, induces pericentral steatosis marked by hepatic accumulation of cholesterol and neutral lipid, and elevated circulating alanine aminotransferase, indicating hepatocyte damage. TCPOBOP-induced steatosis was weaker in the pericentral region but stronger in the periportal region in females compared with males. Early (1 day) TCPOBOP transcriptional responses were enriched for CAR-bound primary response genes, and for lipogenesis and xenobiotic metabolism and oxidative stress protection pathways; late (2 weeks) TCPOBOP responses included many CAR binding-independent secondary response genes, with enrichment for macrophage activation, immune response, and cytokine and reactive oxygen species production. Late upstream regulators specific to TCPOBOP-exposed male liver were linked to proinflammatory responses and hepatocellular carcinoma progression. TCPOBOP administered weekly to male mice using a high corn oil vehicle induced carbohydrate-responsive transcription factor (MLXIPL)-regulated target genes, dysregulated mitochondrial respiratory and translation regulatory pathways, and induced more advanced liver pathology. Overall, TCPOBOP exposure recapitulates histological and gene expression changes characteristic of emerging steatotic liver disease, including secondary gene responses in liver nonparenchymal cells indicative of transition to a more advanced disease state. Upstream regulators of both the early and late TCPOBOP response genes include novel biomarkers for foreign chemical-induced metabolic dysfunction-associated steatotic liver disease.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"324-345"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140851340","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross study analyses of SEND data: toxicity profile classification.","authors":"Mark A Carfagna, Cm Sabbir Ahmed, Susan Butler, Tamio Fukushima, William Houser, Nikolai Jensen, Brianna Paisley, Stephanie Leuenroth-Quinn, Kevin Snyder, Saurabh Vispute, Wenxian Wang, Md Yousuf Ali","doi":"10.1093/toxsci/kfae072","DOIUrl":"10.1093/toxsci/kfae072","url":null,"abstract":"<p><p>A SEND toxicology data transformation, harmonization, and analysis platform were created to improve the identification of unique findings related to the intended target, species, and duration of dosing using data from multiple studies. The lack of a standardized digital format for data analysis had impeded large-scale analysis of in vivo toxicology studies. The CDISC SEND standard enables the analysis of data from multiple studies performed by different laboratories. This work describes methods to analyze data and automate cross-study analysis of toxicology studies. Cross-study analysis can be used to understand a single compound's toxicity profile across all studies performed and/or to evaluate on-target versus off-target toxicity for multiple compounds intended for the same pharmacological target. This work involved development of data harmonization/transformation strategies to enable cross-study analysis of both numerical and categorical SEND data. Four de-identified SEND datasets from the BioCelerate database were used for the analyses. Toxicity profiles for key organ systems were developed for liver, kidney, male reproductive tract, endocrine system, and hematopoietic system using SEND domains. A cross-study analysis dashboard with a built-in user-defined scoring system was created for custom analyses, including visualizations to evaluate data at the organ system level and drill down into individual animal data. This data analysis provides the tools for scientists to compare toxicity profiles across multiple studies using SEND. A cross-study analysis of 2 different compounds intended for the same pharmacological target is described and the analyses indicate potential on-target effects to liver, kidney, and hematopoietic systems.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"277-286"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141293759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microplastic presence in dog and human testis and its potential association with sperm count and weights of testis and epididymis.","authors":"Chelin Jamie Hu, Marcus A Garcia, Alexander Nihart, Rui Liu, Lei Yin, Natalie Adolphi, Daniel F Gallego, Huining Kang, Matthew J Campen, Xiaozhong Yu","doi":"10.1093/toxsci/kfae060","DOIUrl":"10.1093/toxsci/kfae060","url":null,"abstract":"<p><p>The ubiquitous existence of microplastics and nanoplastics raises concerns about their potential impact on the human reproductive system. Limited data exists on microplastics within the human reproductive system and their potential consequences on sperm quality. Our objectives were to quantify and characterize the prevalence and composition of microplastics within both canine and human testes and investigate potential associations with the sperm count, and weights of testis and epididymis. Using advanced sensitive pyrolysis-gas chromatography/mass spectrometry, we quantified 12 types of microplastics within 47 canine and 23 human testes. Data on reproductive organ weights, and sperm count in dogs were collected. Statistical analyses, including descriptive analysis, correlational analysis, and multivariate linear regression analyses were applied to investigate the association of microplastics with reproductive functions. Our study revealed the presence of microplastics in all canine and human testes, with significant inter-individual variability. Mean total microplastic levels were 122.63 µg/g in dogs and 328.44 µg/g in humans. Both humans and canines exhibit relatively similar proportions of the major polymer types, with PE being dominant. Furthermore, a negative correlation between specific polymers such as PVC and PET and the normalized weight of the testis was observed. These findings highlight the pervasive presence of microplastics in the male reproductive system in both canine and human testes, with potential consequences on male fertility.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"235-240"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of ozone exposure on lung injury, inflammation, and oxidative stress in a murine model of nonpneumonic endotoxemia.","authors":"Jared Radbel, Jaclynn A Meshanni, Kinal N Vayas, Oahn Le-Hoang, Elena Abramova, Peihong Zhou, Laurie B Joseph, Jeffrey D Laskin, Andrew J Gow, Debra L Laskin","doi":"10.1093/toxsci/kfae062","DOIUrl":"10.1093/toxsci/kfae062","url":null,"abstract":"<p><p>Recent studies have identified exposure to environmental levels of ozone as a risk factor for the development of acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI) that can develop in humans with sepsis. The aim of this study was to develop a murine model of ALI to mechanistically explore the impact of ozone exposure on ARDS development. Mice were exposed to ozone (0.8 ppm, 3 h) or air control followed 24 h later by intravenous administration of 3 mg/kg lipopolysaccharide (LPS) or PBS. Exposure of mice to ozone + LPS caused alveolar hyperplasia; increased BAL levels of albumin, IgM, phospholipids, and proinflammatory mediators including surfactant protein D and soluble receptor for advanced glycation end products were also detected in BAL, along with markers of oxidative and nitrosative stress. Administration of ozone + LPS resulted in an increase in neutrophils and anti-inflammatory macrophages in the lung, with no effects on proinflammatory macrophages. Conversely, the numbers of resident alveolar macrophages decreased after ozone + LPS; however, expression of Nos2, Arg1, Cxcl1, Cxcl2, Ccl2 by these cells increased, indicating that they are activated. These findings demonstrate that ozone sensitizes the lung to respond to endotoxin, resulting in ALI, oxidative stress, and exacerbated pulmonary inflammation, and provide support for the epidemiologic association between ozone exposure and ARDS incidence.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"299-311"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140946031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of hepatic xenosensor function by HNF4alpha.","authors":"Manasi Kotulkar, Diego Paine-Cabrera, Dakota R Robarts, Udayan Apte","doi":"10.1093/toxsci/kfae069","DOIUrl":"10.1093/toxsci/kfae069","url":null,"abstract":"<p><p>Nuclear receptors such as constitutive androstane receptor (CAR), pregnane X receptor (PXR), and peroxisome proliferator-activated receptor-alpha (PPARα), and transcription factors with nuclear receptor type activity such as aryl hydrocarbon receptor (AhR) function as xenobiotic sensors. Hepatocyte nuclear factor 4alpha (HNF4α) is a highly conserved orphan nuclear receptor essential for liver function. We tested the hypothesis that HNF4α is essential for the function of these 4 major xenosensors. Wild-type (WT) and hepatocyte-specific Hnf4a null (HNF4α-KO) mice were treated with the mouse-specific activators of AhR (TCDD, 30 µg/kg), CAR (TCPOBOP, 2.5 µg/g), PXR, (PCN, 100 µg/g), and PPARα (WY-14643, 1 mg/kg). Blood and liver tissue samples were collected to study receptor activation. TCDD (AhR agonist) treatment did not affect the liver-to-body weight ratio (LW/BW) in either WT or HNF4α-KO mice. Further, TCDD activated AhR in both WT and HNF4α-KO mice, confirmed by increase in expression of AhR target genes. TCPOBOP (CAR agonist) significantly increased the LW/BW ratio and CAR target gene expression in WT mice, but not in HNF4α-KO mice. PCN (a mouse PXR agonist) significantly increased LW/BW ratio in both WT and HNF4α-KO mice however, failed to induce PXR target genes in HNF4α-KO mice. The treatment of WY-14643 (PPARα agonist) increased LW/BW ratio and PPARα target gene expression in WT mice but not in HNF4α-KO mice. Together, these data indicate that the function of CAR, PXR, and PPARα but not of AhR was disrupted in HNF4α-KO mice. These results demonstrate that HNF4α function is critical for the activation of hepatic xenosensors, which are critical for toxicological responses.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"346-356"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141176419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative toxicological assessment of 2 bisphenols using a systems approach: evaluation of the behavioral and transcriptomic responses of Danio rerio to bisphenol A and tetrabromobisphenol A.","authors":"Michael G Morash, Morgan W Kirzinger, John C Achenbach, Ananda B Venkatachalam, Jessica Nixon, Susanne Penny, Joëlle Pinsonnault Cooper, Deborah E Ratzlaff, Cindy L A Woodland, Lee D Ellis","doi":"10.1093/toxsci/kfae063","DOIUrl":"10.1093/toxsci/kfae063","url":null,"abstract":"<p><p>The zebrafish (Danio rerio) is becoming a critical component of new approach methods (NAMs) in chemical risk assessment. As a whole organism in vitro NAM, the zebrafish model offers significant advantages over individual cell-line testing, including toxicokinetic and toxicodynamic competencies. A transcriptomic approach not only allows for insight into mechanism of action for both apical endpoints and unobservable adverse outcomes, but also changes in gene expression induced by lower, environmentally relevant concentrations. In this study, we used a larval zebrafish model to assess the behavioral and transcriptomic alterations caused by subphenotypic concentrations of 2 chemicals with the same structural backbone, the endocrine-disrupting chemicals bisphenol A and tetrabromobisphenol A. Following assessment of behavioral toxicity, we used a transcriptomic approach to identify molecular pathways associated with previously described phenotypes. We also determined the transcriptomic point of departure for each chemical by modeling gene expression changes as continuous systems which allows for the identification of a single concentration at which toxic effects can be predicted. This can then be investigated with confirmatory cell-based testing in an integrated approach to testing and assessment to determine risk to human health and the environment with greater confidence. This paper demonstrates the impact of using a multi-faceted approach for evaluating the physiological and neurotoxic effects of exposure to structurally related chemicals. By comparing phenotypic effects with transcriptomic outcomes, we were able to differentiate, characterize, and rank the toxicities of related bisphenols, which demonstrates methodological advantages unique to the larval zebrafish NAM.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"394-403"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140909041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PFAS and their association with the increased risk of cardiovascular disease in postmenopausal women.","authors":"Alicia Arredondo Eve, Elif Tunc, Dhruv Mehta, Jin Young Yoo, Huriye Erbak Yilmaz, Sadık Volkan Emren, Filiz Akyıldız Akçay, Zeynep Madak Erdogan","doi":"10.1093/toxsci/kfae065","DOIUrl":"10.1093/toxsci/kfae065","url":null,"abstract":"<p><p>Cardiovascular diseases (CVDs) are one of the major causes of death globally. In addition to traditional risk factors such as unhealthy lifestyles (smoking, obesity, sedentary) and genetics, common environmental exposures, including persistent environmental contaminants, may also influence CVD risk. Per- and polyfluoroalkyl substances (PFASs) are a class of highly fluorinated chemicals used in household consumer and industrial products known to persist in our environment for years, causing health concerns that are now linked to endocrine disruptions and related outcomes in women, including interference of the cardiovascular and reproductive systems. In postmenopausal women, higher levels of PFAS are observed than in premenopausal women due to the cessation of menstruation, which is crucial for PFAS excretion. Because of these findings, we explored the association between perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), and perfluorobutanesulfonic acid in postmenopausal women from our previously established CVD study. We used liquid chromatography with tandem mass spectrometry, supported by machine learning approaches, and the detection and quantification of serum metabolites and proteins. Here, we show that PFOS can be a good predictor of coronary artery disease, whereas PFOA can be an intermediate predictor of coronary microvascular disease. We also found that the PFAS levels in our study are significantly associated with inflammation-related proteins. Our findings may provide new insight into the potential mechanisms underlying the PFAS-induced risk of CVDs in this population. This study shows that exposure to PFOA and PFOS is associated with an increased risk of cardiovascular disease in postmenopausal women. PFOS and PFOA levels correlate with amino acids and proteins related to inflammation. These circulating biomarkers contribute to the etiology of CVD and potentially implicate a mechanistic relationship between PFAS exposure and increased risk of cardiovascular events in this population.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"312-323"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140959689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of PFAS on human liver transporters: implications for health outcomes.","authors":"Ena Vujic, Stephen S Ferguson, Kim L R Brouwer","doi":"10.1093/toxsci/kfae061","DOIUrl":"10.1093/toxsci/kfae061","url":null,"abstract":"<p><p>Per- and polyfluoroalkyl substances (PFAS) have become internationally recognized over the past three decades as persistent organic pollutants used in the production of various consumer and industrial goods. Research efforts continue to gauge the risk that historically used, and newly produced, PFAS may cause to human health. Numerous studies report toxic effects of PFAS on the human liver as well as increased serum cholesterol levels in adults. A major concern with PFAS, also dubbed \"forever chemicals,\" is that they accumulate in the liver and kidney and persist in serum. The mechanisms responsible for their disposition and excretion in humans are poorly understood. A better understanding of the interaction of PFAS with liver transporters, as it pertains to the disposition of PFAS and other xenobiotics, could provide mechanistic insight into human health effects and guide efforts toward risk assessment of compounds in development. This review summarizes the current state of the literature on the emerging relationships (eg, substrates, inhibitors, modulators of gene expression) between PFAS and specific hepatic transporters. The adaptive and toxicological responses of hepatocytes to PFAS that reveal linkages to pathologies and epidemiological findings are highlighted. The evidence suggests that our understanding of the molecular landscape of PFAS must improve to determine their impact on the expression and function of hepatocyte transporters that play a key role in PFAS or other xenobiotic disposition. From here, we can assess what role these changes may have in documented human health outcomes.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"213-227"},"PeriodicalIF":3.4,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11285162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140899598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}