Epistemic_Statements  

CORD-19:1fe201bcf1ed66856f693846cb0d07ce48051ec1 JSONTXT 9 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T1 0-166 Epistemic_statement denotes Toxicology Gene expression profiling to identify potentially relevant disease outcomes and support human health risk assessment for carbon black nanoparticle exposure
T2 177-277 Epistemic_statement denotes New approaches are urgently needed to evaluate potential hazards posed by exposure to nanomaterials.
T3 756-965 Epistemic_statement denotes Analysis of CBNP-perturbed pathways, networks and transcription factors revealed concomitant changes in predicted phenotypes (e.g., pulmonary inflammation and genotoxicity), that correlated with dose and time.
T4 1495-1728 Epistemic_statement denotes Our synthesis demonstrates how toxicogenomic profiles may be used in human health risk assessment of nanoparticles and constitutes an important step forward in the ultimate recognition of toxicogenomic endpoints in human health risk.
T5 1985-1990 Epistemic_statement denotes Crown
T6 1992-2371 Epistemic_statement denotes Chronic inhalation of fine and ultrafine particulate matter has been associated with adverse pulmonary effects including fibrosis and cancer, as well as exacerbation of existing conditions such as asthma, bronchitis and chronic obstructive pulmonary disorder (Bonner, 2007; Knaapen et al., 2004) , in addition to cardiovascular disease (Dockery et al., 1993; Pope et al., 2004) .
T7 2372-2672 Epistemic_statement denotes Human exposure to manufactured nanomaterials (NMs), which have at least one size dimension that is less than 100 nm, may constitute an increased risk of adverse effects especially following inhalation exposure, and their potential to induce toxic effects is poorly understood (Handy and Shaw, 2007) .
T8 2673-2780 Epistemic_statement denotes Moreover, the human health risks associated with inhalation exposure have not been adequately investigated.
T9 2781-2992 Epistemic_statement denotes Methods that can be effective in screening for NM toxicities are paramount, due to the countless variations in physical and chemical properties of NMs in terms of size, shape, agglomeration and surface coatings.
T10 3441-3638 Epistemic_statement denotes However, some of these assays, such as those based on chronic animal exposures at the maximum tolerated dose, are time and resource intensive, thus limiting broad application (Suter et al., 2004) .
T11 3639-3942 Epistemic_statement denotes Recent discussions have identified gene expression profiling as a potentially rapid and cost-effective approach for identifying and assessing prospective hazard, characterizing chemical (or particle) mode of action, and assessing human relevance in support of HHRA (National Academy of Sciences, 2007) .
T12 3943-4295 Epistemic_statement denotes In order for gene expression data to become accepted for routine use in HHRA, it is necessary to demonstrate that mRNA/protein expression profiles can effectively predict the modes of action and biological outcomes of exposure at relevant doses, and to confirm that these data can be used to strengthen the foundation for HHRA and regulatory decisions.
T13 4296-4588 Epistemic_statement denotes In this regard, it has been hypothesized that gene expression profiling will be extremely useful in identifying effects at low doses, and moreover, useful for distinguishing between doses that elicit an adaptive response vs. those that yield adverse effects (Boverhof and Zacharewski, 2006) .
T14 4589-4812 Epistemic_statement denotes To date, the application of gene expression profiling in regulatory toxicology has largely focused on qualitative identification of chemical modes of action and transcription biomarkers that can predict specific toxicities.
T15 4813-4975 Epistemic_statement denotes However, the utility of gene expression profiling in quantitative determination of threshold values (e.g., benchmark doses) has not yet been rigorously explored .
T16 4976-5295 Epistemic_statement denotes In the present study we investigate the utility of gene expression profiles derived from mice exposed to Printex 90 carbon black nanoparticles (CBNPs) by intratracheal installation to identify potential hazards, modes of action, and doses above which adverse effects may be expected for specific toxicological outcomes.
T17 5437-5571 Epistemic_statement denotes We employ Printex 90 as a model NM due to the rich database of traditional toxicity information on which our findings can be anchored.
T18 5572-6034 Epistemic_statement denotes Briefly, Printex 90 consists almost entirely of carbon, with very low levels of impurities in terms of polycyclic aromatic hydrocarbons and endotoxins (Bourdon et al., 2012b; Jacobsen et al., 2008; Saber et al., 2011) They generate reactive oxygen species (Jacobsen et al., 2008) , induce DNA strand breaks in vitro and in vivo (Jacobsen et al., 2009; Saber et al., 2005) and mutations in vitro (Jacobsen et al., 2007) that are associated with oxidative stress .
T19 6322-6597 Epistemic_statement denotes We previously characterized widespread changes in gene expression involving acute phase response and inflammation, supported by concomitant influxes of pulmonary bronchoalveolar lavage cells (BAL) and increases in tissue-specific DNA strand breaks (Bourdon et al., 2012a,b) .
T20 6598-6929 Epistemic_statement denotes In addition to the examination of BMDs and BMDLs, we compare CBNP-modified gene expression profiles to various models of lung disease in mice and humans reported in the literature, in order to explore the utility of our data in predicting the potential risk of adverse health outcomes and the human relevance of expression changes.
T21 6930-7129 Epistemic_statement denotes The work demonstrates one approach by which gene expression profiling may be integrated into HHRA to support or predict apical toxicological endpoints, dose-response, and relevance to human diseases.
T22 7439-7684 Epistemic_statement denotes The intratracheal instillation route of exposure allows for deposition of known doses directly in the lungs of the mice, and controls for potential dermal-and ingestion-related CBNP exposure that can occur during whole body inhalation exposures.
T23 8135-8216 Epistemic_statement denotes Very limited filtration of CBNPs from the nose is expected during human exposure.
T24 8217-8567 Epistemic_statement denotes Printex 90 CBNPs were characterized and displayed the following properties: 14 nm primary particle size, 295-338 m 2 /g Brunauer Emmett and Teller (BET) surface area, 74.2 g/g PAHs, 142 EU/g endotoxin, polydispersity index of 1, −10.7 mV zeta potential, 2.6 m peak hydrodynamic number and 3.1 m peak volume-size-distribution (Bourdon et al., 2012b) .
T25 12386-12686 Epistemic_statement denotes To determine the correlation between gene expression profiles of mice exposed to CBNPs with those of mouse pulmonary disease models, a prediction analysis for microarrays (PAM) (Tibshirani et al., 2002) was conducted in R (R Development Core Team, 2011) using the PAMR library (Hastie et al., 2011) .
T26 14714-14863 Epistemic_statement denotes DAVID Biological functions with enrichment scores > 1.3 were considered significant, in accordance with DAVID recommendations (Huang et al., 2009a) .
T27 16971-17040 Epistemic_statement denotes However, the number of significant pathways increased with dose (Fig.
T28 18383-18535 Epistemic_statement denotes However, minimum BMDs, representing the most sensitive gene for each relevant pathway, were much more comparable to BMDs of apical endpoints (Table 2) .
T29 19095-19261 Epistemic_statement denotes Two CBNP exposure conditions (day 28 low and medium doses) did not cluster with other CBNP exposure condition or other disease models, likely due to lack of response.
T30 19352-19461 Epistemic_statement denotes PAM analysis revealed an association between CBNP exposure, Th2 responses and lung injury/fibrotic responses.
T31 19462-19820 Epistemic_statement denotes Although Th2 response and lung injury/fibrotic responses were more closely associated with one another than with CBNP exposure, PAM analysis revealed that CBNP exposure was more closely related to lung injury/fibrotic responses than to Th2 responses, which is also supported by probability statistics comparing CBNP exposure with each disease sub-group (Fig.
T32 20665-20824 Epistemic_statement denotes However, CBNP responses were more similar to bleomycin-induced lung injury as shown by the high degree of overlapping biological functions on day 3 (Table 3) .
T33 20825-20942 Epistemic_statement denotes CBNPs triggered an adaptive immune response on day 28 that was also only apparent in lung injury and fibrosis models.
T34 21488-21618 Epistemic_statement denotes adenomatoid malformation, and injury of lung, were identified as the top three respiratory diseases associated with CBNP exposure.
T35 21619-21803 Epistemic_statement denotes Interestingly, fibrosis was identified as a predicted disease outcome of CBNP exposure that increased considerably with time (e.g., score of 14 on day 1, 35 on day 3 and 45 on day 28).
T36 21804-22005 Epistemic_statement denotes In order to examine the molecular mechanisms that may be involved in fibrosis in more detail, a meta-analysis was completed using curated studies within NextBio that identified fibrosis as a phenotype.
T37 22274-22527 Epistemic_statement denotes Meta-analysis using CBNP gene expression profiles in mouse ranked 473 canonical pathways and 21,277 genes present in at least one of the studies on select models of pulmonary fibrosis and lung injury (identified in NextBio disease correlation profiles).
T38 23040-23188 Epistemic_statement denotes Interestingly, comparison of fold-ranks between the mouse and human analysis revealed that the most affected pathways were the same in both species.
T39 23189-23487 Epistemic_statement denotes However, the genes that were most perturbed during fibrotic responses were considerably different in CBNP-exposed mice compared to human diseases, with the exception of glycerol-3-phosphate dehydrogenase (GDP1), kruppel-like factor 4 (KLF4), secreted phosphoprotein 1 (SPP1) and ceruloplasmin (CP).
T40 23733-23970 Epistemic_statement denotes It is hypothesized that toxicogenomic profiling can be used as a screening tool to prioritize the specific assays that should be conducted from the standard battery of tests, thus minimizing animal use, cost and time (Dix et al., 2007) .
T41 23971-24182 Epistemic_statement denotes Moreover, global analyses of transcriptional changes provide a wealth of information that can be used to identify putative modes of action and to query relevance to human adverse health outcomes (Currie, 2012) .
T42 24351-24649 Epistemic_statement denotes However, substantive work demonstrating the ability of gene expression profiles to identify hazards, to assess risk of exposure via quantitative dose-response analysis, and to identify adverse outcomes associated with specific modes of action is required before these endpoints can be used in HHRA.
T43 24650-24864 Epistemic_statement denotes The present study applies pathway-and network-based approaches, BMD modelling, and disease prediction tools to gene expression data to explore the relationship between apical endpoints and transcriptional profiles.
T44 24865-25147 Epistemic_statement denotes The work investigates the potential utility of gene expression profiling in determining hazard and mode of action of NPs, in characterizing dose-response relationships and in predicting the relevance of these findings to potential disease-outcomes and human health effects for HHRA.
T45 25148-25380 Epistemic_statement denotes The utility of gene expression profiling in hazard identification has been examined for a limited number of chemicals, including dibutyl phthalate and acetaminophen (Euling et al., 2011; Kienhuis et al., 2011; Makris et al., 2010) .
T46 25856-25993 Epistemic_statement denotes Our data demonstrate that gene expression profiles can also be viewed as effective predictors of the biological effects of CBNP exposure.
T47 26502-26967 Epistemic_statement denotes In addition, observed transcriptomic changes associated with perturbations of cell cycle networks, alterations of non-homologous end-joining, and p53 signalling support the sustained genotoxicity observed in the mice, although dose and time correlations were not as apparent (e.g., levels of DNA strand breaks remained relatively constant at the two highest exposure doses (Bourdon et al., 2012b) whereas induction of DNA repair genes decreased with dose and time).
T48 26968-27230 Epistemic_statement denotes The transcriptomic changes associated with alterations in glutathione metabolism and free radical scavenging correlate with induction of DNA formamidopyrimidine DNA glycoslase (FPG) sensitive sites (an indicator of oxidative DNA damage) early after the exposure.
T49 27351-27633 Epistemic_statement denotes Interestingly, CBNP-induced alterations in gene expression profiles also revealed a pulmonary acute phase response and unexpected changes in lipid homeostasis, which were subsequently supported by measured decreases in plasma high density lipoprotein (HDL) (Bourdon et al., 2012a) .
T50 27634-27897 Epistemic_statement denotes The strong association between CBNPinduced gene expression profiles and apical endpoints collectively support the use of toxicogenomics for hazard identification of Table 4 Meta-analyses in NextBio using mouse and human profiles in which fibrosis was a phenotype.
T51 27977-28111 Epistemic_statement denotes Rank 1 (rank 2) Pathway Rank 1 (rank 2) Gene (symbol) NMs, and perhaps more importantly, for highlighting unexpected adverse outcomes.
T52 28112-28398 Epistemic_statement denotes Moreover, ongoing work within the Organization for Economic Co-operation and Development (OECD) is actively developing adverse outcome pathways (AOP) approaches that are expected to provide tangible methods by which systems biology endpoints can be used in human health risk assessment.
T53 28399-28567 Epistemic_statement denotes Toxicogenomics data that examine responses over dose and time in a variety of tissues can be very useful for such applications, as illustrated for CBNP exposure in Fig.
T54 28572-28753 Epistemic_statement denotes Overall, our data suggest that gene expression profiles can be effectively used to identify putative mode(s) of action and hazards of NP exposure, in the absence of phenotypic data.
T55 28754-28992 Epistemic_statement denotes In addition to identification of hazard, it has been suggested that gene expression profiles may be useful for quantitative assessment (e.g., establishment of reference doses) of responses related to both cancer and non-cancer endpoints .
T56 28993-29212 Epistemic_statement denotes Benchmark doses are generally considered more informative than the no observable adverse effect level (NOAEL) in deriving reference doses as they are based on the entire dose-response relationship (Crump et al., 1995) .
T57 29213-29486 Epistemic_statement denotes Because alterations in gene expression can be initiated in the absence of biological effects (e.g., adaptive or stress response pathways effective in mitigating toxic effects), it is expected that reference doses for genomics endpoints may be too sensitive for use in HHRA.
T58 29487-29836 Epistemic_statement denotes However, previous analyses of 5 chemicals (i.e., 1,4-dichlorobenzene, propylene glycol mono-t-butyl ether, 1,2,3-trichloropropane, methylene chloride and naphthalene) showed that median BMD and BMDLs for the most sensitive pathways and GO categories were highly correlated with BMD and BMDLs of cancer and non-cancer endpoints (Thomas et al., 2011 .
T59 30280-30535 Epistemic_statement denotes However, the mean of the minimum BMDs and BMDLs across all the pathways that we assigned as relevant to the apical endpoints (i.e., corresponding to the most sensitive genes within the relevant pathways) were similar to those of relevant apical endpoints.
T60 30536-30714 Epistemic_statement denotes Median BMDs and BMDLs for the most sensitive pathways also correlate more closely with apical endpoints even though the pathways were not necessarily relevant to these endpoints.
T61 30715-30863 Epistemic_statement denotes This finding supports previous examples demonstrating a 1:1 correlation between BMDs for gene expression and apical endpoints (Thomas et al., 2011 .
T62 30864-30990 Epistemic_statement denotes These data indicate the potential utility of using gene expression profiles in determining acceptable exposure limits for NPs.
T63 31209-31507 Epistemic_statement denotes Perhaps the principal motivation for including gene expression profiling in HHRA is the wealth of information that can be used to identify key events that are correlated with adverse outcomes that are relevant to human disease, and moreover can be used to predict the likelihood of a human disease.
T64 31508-31810 Epistemic_statement denotes Identification of key events at the transcriptional level can facilitate the identification of processes that are critical for disease initiation and progression, thus allowing information from animal experiments to be queried and used for extrapolation to human scenarios (Edwards and Preston, 2008) .
T65 31811-32061 Epistemic_statement denotes Comparison of our data with specific models of lung disease, including bacterial infection, airway hypersensitivity and lung injury revealed that CBNPs induced responses that were more closely related to lung injury and fibrosis than to other models.
T66 32392-32661 Epistemic_statement denotes Although it is unclear if CBNP exposure would result in the same gene expression profile in humans, similar pathways including many involved in fibrotic responses were found in both mice and humans (52% of the top 50 pathways found were common between mouse and human).
T67 32662-32759 Epistemic_statement denotes Despite concordance of pathways, the top ranked genes differed considerably between both species.
T68 32760-33099 Epistemic_statement denotes However, many of the genes found in mice and humans had similar functions, including inflammatory and acute phase responses (e.g., Saa3, Socs3 and Mt2 in mice and CP, VNN2 and CXCL10 in humans), cell cycle progression (Cdkn1a in mice and KLF4 in humans) and bone and tissue modelling (Mmp14, Timp1, Eln and Ogn in mice and SPP1 in humans).
T69 33100-33335 Epistemic_statement denotes Thus, despite discordance in the gene expression profiles between species, the similar functions of top ranked genes and concordance between pathways supports the likelihood of similar responses in the event of CBNP exposure in humans.
T70 33336-33668 Epistemic_statement denotes In addition, fibrosis has been identified as an outcome of exposure to various particles and NPs in animals (Bermudez et al., 2004; Shvedova et al., 2008) , including Printex 90 (e.g., 28-day nose only inhalation in Wistar WU rats) (Bellmann et al., 2009) , as well as in humans (Lkhasuren et al., 2007; Wang and Christiani, 2003) .
T71 33669-33785 Epistemic_statement denotes The process of pulmonary fibrosis is closely related to progression of carcinogenic outcome (Hubbard et al., 2000) .
T72 34252-34353 Epistemic_statement denotes First, transcriptional profiles can effectively predict the biological effects of chemical exposures.
T73 34354-34581 Epistemic_statement denotes Specifically, in the absence of data for any apical endpoints, our data would have suggested that mice exposed to CBNPs exhibit an inflammatory response, oxidative stress, DNA damage and perturbations in cholesterol metabolism.
T74 34760-35048 Epistemic_statement denotes Third, that expression profiles can be fairly easily mined to identify potential adverse outcomes (i.e., diseases) that are relevant to humans, and might reasonably be expected to occur in humans exposed to substances that elicit specific gene expression patterns in experimental animals.
T75 35049-35209 Epistemic_statement denotes We believe that our work constitutes a significant step towards the ultimate recognition of toxicogenomic endpoints for routine assessment of human health risk.
T76 35210-35319 Epistemic_statement denotes Gene expression profiling offers a promising approach to decipher the largely unknown hazards of NP exposure.
T77 35320-35605 Epistemic_statement denotes Due to the unique properties of NPs, powerful technologies that can assess a multitude of adverse outcome possibilities will be required to elucidate their modes of action and potential impacts on human health within a time-frame that is suitable for prompt regulatory decision making.
T78 35606-35724 Epistemic_statement denotes This same premise should hold true for any new chemical products, for which toxicity is largely or completely unknown.