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Poster presented to the Society of Toxicology 62nd Annual Meeting and ToxExpo March 2023 Search for CCTE records in EPA’s Science Inventory by typing in the title at this link. https://cfpub.epa.gov/si/si_public_search_results.cfm?advSearch=true&showCriteria=2&keyword=CCTE&TIMSType=&TIMSSubTypeID=&epaNumber=&ombCat=Any&dateBeginPublishedPresented=07/01/2017&dateEndPublishedPresented=&dateBeginUpdated=&dateEndUpdated=&DEID=&personName=&personID=&role=Any&journalName=&journalID=&publisherName=&publisherID=&sortBy=pubDate&count=25

Adaptive stress response pathways (SRPs) restore cellular homeostasis after chemical exposure. SRPs also activate terminal programs if cellular disruption exceeds adaptive thresholds and are implicated in various diseases (e.g., type II diabetes and neurodegeneration). To investigate SRP activity from high-throughput data, we developed a text-mining pipeline for annotating hundreds of chemicals associated with canonical SRPs. First, we identified 129 candidate reference chemicals used in published biomarker studies and annotated them based on consensus with six SRPs, including DNA damage (DDR), heat shock (HSR), hypoxia (HPX), metal stress (MSR), oxidative stress (OSR), and unfolded protein (UPR). Second, we used information retrieval from PubMed to find 123,696 abstracts containing cooccurrences of terms for 129 chemicals and six SRPs. Since term cooccurrence frequency is not a reliable proxy for biological relationships, we calculated pairwise mutual information (PMI), an information-theoretic measure, for finding relevant chemical-SRP relationships. The area under the receiver operator curve (AUROC) performance of PMI for classifying the 129 chemicals to the expert-assigned SRP classes was: 0.91/DDR, 0.83/HPX 0.96/HSR,0.93/MSR, 0.86/OSR and 0.82/UPR, with a mean AUROC of 0.88. The maximum PMI score correctly classified the expert-curated SRP annotation for 82% of chemicals, while the top two PMI scores matched 96% of annotations. We also identified PMI score thresholds for classifying cooccurrences found in PubMed abstracts as relevant chemical-SRP relationships. Fourth, we applied this text-mining pipeline to 4,671 chemicals from the Library of Integrated Network-based Cellular Signatures (LINCS) and found 1,206 chemicals with putative SRP relationships (based on PMI scores exceeding the thresholds from the candidate reference chemicals). An independent analysis of the L1000 transcriptomic profiles shows that the 1,206 chemicals in LINCS cluster by putative SRP class. Our findings suggest that text mining based on PMI scores for chemical and SRP term cooccurrences in PubMed abstracts is a powerful approach for building high-quality annotated data sets to solve computational toxicology problems. This abstract does not reflect US EPA policy.

Poster presented to the Society of Toxicology 61st Annual Meeting and ToxExpo March 2022Search for CCTE records in EPA���s Science Inventory by typing in the title at this link.https://cfpub.epa.gov/si/si_public_search_results.cfm?advSearch=true&showCriteria=2&keyword=CCTE&TIMSType=&TIMSSubTypeID=&epaNumber=&ombCat=Any&dateBeginPublishedPresented=07/01/2017&dateEndPublishedPresented=&dateBeginUpdated=&dateEndUpdated=&DEID=&personName=&personID=&role=Any&journalName=&journalID=&publisherName=&publisherID=&sortBy=pubDate&count=25

Presentation to the Society of Toxicology 61st Annual Meeting and ToxExpo March 2022 Search for CCTE records in EPA’s Science Inventory by typing in the title at this link. https://cfpub.epa.gov/si/si_public_search_results.cfm?advSearch=true&showCriteria=2&keyword=CCTE&TIMSType=&TIMSSubTypeID=&epaNumber=&ombCat=Any&dateBeginPublishedPresented=07/01/2017&dateEndPublishedPresented=&dateBeginUpdated=&dateEndUpdated=&DEID=&personName=&personID=&role=Any&journalName=&journalID=&publisherName=&publisherID=&sortBy=pubDate&count=25

Poster presented to the Society of Toxicology 61st Annual Meeting and ToxExpo March 2022 Search for CCTE records in EPA’s Science Inventory by typing in the title at this link. https://cfpub.epa.gov/si/si_public_search_results.cfm?advSearch=true&showCriteria=2&keyword=CCTE&TIMSType=&TIMSSubTypeID=&epaNumber=&ombCat=Any&dateBeginPublishedPresented=07/01/2017&dateEndPublishedPresented=&dateBeginUpdated=&dateEndUpdated=&DEID=&personName=&personID=&role=Any&journalName=&journalID=&publisherName=&publisherID=&sortBy=pubDate&count=25

Presentation to the Society of Toxicology 2021 Virtual Annual Meeting (March 2021)Search for CCTE records in EPA���s Science Inventory by typing in the title at this link.https://cfpub.epa.gov/si/si_public_search_results.cfm?advSearch=true&showCriteria=2&keyword=CCTE&TIMSType=&TIMSSubTypeID=&epaNumber=&ombCat=Any&dateBeginPublishedPresented=07/01/2017&dateEndPublishedPresented=&dateBeginUpdated=&dateEndUpdated=&DEID=&personName=&personID=&role=Any&journalName=&journalID=&publisherName=&publisherID=&sortBy=pubDate&count=25

Presentation to the Carolina Society of Environmental Toxicology and Chemistry (CSETAC) 2022 Annual Meeting April 2022 Search for CCTE records in EPA’s Science Inventory by typing in the title at this link. https://cfpub.epa.gov/si/si_public_search_results.cfm?advSearch=true&showCriteria=2&keyword=CCTE&TIMSType=&TIMSSubTypeID=&epaNumber=&ombCat=Any&dateBeginPublishedPresented=07/01/2017&dateEndPublishedPresented=&dateBeginUpdated=&dateEndUpdated=&DEID=&personName=&personID=&role=Any&journalName=&journalID=&publisherName=&publisherID=&sortBy=pubDate&count=25

Presentation to the QSAR 2021 International Workshop on QSAR in Environmental and Health Sciences June 2021Search for CCTE records in EPA’s Science Inventory by typing in the title at this link.https://cfpub.epa.gov/si/si_public_search_results.cfm?advSearch=true&showCriteria=2&keyword=CCTE&TIMSType=&TIMSSubTypeID=&epaNumber=&ombCat=Any&dateBeginPublishedPresented=07/01/2017&dateEndPublishedPresented=&dateBeginUpdated=&dateEndUpdated=&DEID=&personName=&personID=&role=Any&journalName=&journalID=&publisherName=&publisherID=&sortBy=pubDate&count=25

Presentation to the Society of Toxicology 2021 Virtual Annual Meeting March 2021Search for CCTE records in EPA���s Science Inventory by typing in the title at this link.https://cfpub.epa.gov/si/si_public_search_results.cfm?advSearch=true&showCriteria=2&keyword=CCTE&TIMSType=&TIMSSubTypeID=&epaNumber=&ombCat=Any&dateBeginPublishedPresented=07/01/2017&dateEndPublishedPresented=&dateBeginUpdated=&dateEndUpdated=&DEID=&personName=&personID=&role=Any&journalName=&journalID=&publisherName=&publisherID=&sortBy=pubDate&count=25

Presentation to the EPA Systematic Review - Communities of Practice November 2021Search for CCTE records in EPA���s Science Inventory by typing in the title at this link.https://cfpub.epa.gov/si/si_public_search_results.cfm?advSearch=true&showCriteria=2&keyword=CCTE&TIMSType=&TIMSSubTypeID=&epaNumber=&ombCat=Any&dateBeginPublishedPresented=07/01/2017&dateEndPublishedPresented=&dateBeginUpdated=&dateEndUpdated=&DEID=&personName=&personID=&role=Any&journalName=&journalID=&publisherName=&publisherID=&sortBy=pubDate&count=25

Presentation to the Society for Risk Analysis Dose Response Specialty Group (DRSG) May 2020

Presentation given to the OpenTox 2020 Virtual Conference held September 2020

Control of microbial growth is key to proper function of engineered systems and human health. Combating biological contamination in engineered processes is complicated due to the limited number of materials that are both able to impede microbial growth and are benign with respect to human and environmental health. Silver nanoparticles (AgNPs) have emerged as a novel biocide, reducing biological fouling in consumer goods and health care materials. Their almost ubiquitous usage is primarily due to their microbial cytotoxicity, limited human toxicity, and their ability to be incorporated into a wide variety of materials. The use of AgNPs is not without challenges; microbial toxicity varies by exposure methodology, and studies have shown that AgNPs have the potential to disrupt engineered biological processes either as nanoparticles or through the dissolution of aqueous silver (Ag([subscript aq])). The use of AgNPs is further complicated by their mechanisms of action; there is significant overlap of their biological targets with the targets of antibiotics. Thus, antibiotic resistance might result from AgNP exposure through the processes of co- and cross-resistance, in which one chemical selects for microbial resistance to a second (unrelated) chemical. In this work, the impact of AgNP aggregation and dissolution on toxicity to Escherichia coli was examined. Data indicate that conditions promoting high fractal dimension promote greater toxicity and induce an oxidative stress response. Subsequent studies on the opportunistic human pathogen Pseudomonas aeruginosa were directed at elucidating the mechanisms of action of AgNPs and the microbial response. Transcriptomic and proteomic studies focused on defining a model of bacterial AgNP interaction and isolated mechanisms of toxicity of AgNPs. Further these data provided the first evidence of AgNP exposure resulting in antibiotic resistance through the expression of multidrug efflux pumps. Transcriptomic data indicated that the stress response systems activated as a result of AgNP exposure were localized to the periplasm while the stress response systems activated as a result of Ag([subscript aq]) exposure were localized to the cytoplasm, which supports a surface attachment model of bacterial AgNP interaction distinct from that of Ag([subscript aq]). Transcriptomic studies revealed that key antibiotic resistance systems, including mexGHI and mexPQ, were stimulated by AgNP exposure. P. aeruginosa cells that were pre-exposed to a sublethal concentration of AgNPs demonstrated increased resistance in subsequent antibiotic challenges, demonstrating that antibiotic resistance can be induced by AgNPs. The findings of this study are an important contribution to our understanding of the impacts of co- and cross-resistance induced by AgNP exposure and will ultimately help inform decisions related to human and environmental health