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Article ; Online: Low-calorie sweeteners and health outcomes: an evaluation of rapid versus traditional evidence mapping.

Lam, Juleen / Elmore, Rebecca / Howard, Brian / Shah, Ruchir R

2022 Volume 15, Issue 1, Page(s) 65

Abstract: Objective: Scientific evidence related to environmental exposures continues to mount. Tools such as evidence mapping support decision making, but can be resource- and time-intensive. We explored "rapid evidence mapping" to efficiently map scientific ... ...

Abstract	Objective: Scientific evidence related to environmental exposures continues to mount. Tools such as evidence mapping support decision making, but can be resource- and time-intensive. We explored "rapid evidence mapping" to efficiently map scientific evidence using rigorous and transparent methodologies. We undertook a proof-of-concept case study on the topic of low-calorie sweeteners. Our intent was to conduct a traditional evidence map based on the same evidence base from a prior rapid evidence map case study to compare approaches, findings, and conclusions. We searched the literature, screened full text of studies, manually tagged and categorized articles, and created visualizations to map the evidence. Results: We conducted full-text screening of studies from the prior rapid evidence map and identified 255 relevant studies. Our findings corroborated those of the rapid evidence map, identifying most studies as short-term conducted in healthy individuals studying outcomes of appetite, energy sensing and body weight. We identified gaps in research areas related to outcomes of appetite and dietary intake, particularly in study populations with diabetes. Our findings illustrate the promise of rapid evidence mapping as a rigorous approach that can summarize scientific evidence, identify knowledge gaps, and identify areas for a future systematic review in a time-efficient manner.
MeSH term(s)	Appetite ; Body Weight ; Energy Intake ; Health Status ; Humans ; Sweetening Agents
Chemical Substances	Sweetening Agents
Language	English
Publishing date	2022-02-19
Publishing country	England
Document type	Journal Article
ZDB-ID	2413336-X
ISSN	1756-0500 ; 1756-0500
ISSN (online)	1756-0500
ISSN	1756-0500
DOI	10.1186/s13104-022-05926-3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Impact of Aligner, Normalization Method, and Sequencing Depth on TempO-seq Accuracy.

Everett, Logan J / Mav, Deepak / Phadke, Dhiral P / Balik-Meisner, Michele R / Shah, Ruchir R

Bioinformatics and biology insights

2022 Volume 16, Page(s) 11779322221095216

Abstract: High-throughput transcriptomics has advanced through the introduction of TempO-seq, a targeted alternative to traditional RNA-seq. TempO-seq platforms use 50 nucleotide probes, each specifically designed to target a known transcript, thus allowing for ... ...

Abstract	High-throughput transcriptomics has advanced through the introduction of TempO-seq, a targeted alternative to traditional RNA-seq. TempO-seq platforms use 50 nucleotide probes, each specifically designed to target a known transcript, thus allowing for reduced sequencing depth per sample compared with RNA-seq without compromising the accuracy of results. Thus far, studies using the TempO-seq method have relied on existing tools for processing the resulting short read data. However, these tools were originally designed for other data types. While they have been used for processing of early TempO-seq data, they have not been systematically assessed for accuracy or compared to determine an optimal framework for processing and analyzing TempO-seq data. In this work, we re-analyze several publicly available TempO-seq data sets covering a range of experimental designs and use corresponding RNA-seq data sets as a gold standard to rigorously assess accuracy at multiple levels. We compare 6 aligners and 5 normalization methods across various accuracy and performance metrics. Our results demonstrate the overall robust accuracy of the TempO-seq platform, independent of data processing methods. Complex aligners and advanced normalization methods do not appear to have any general advantage over simpler methods when it comes to analyzing TempO-seq data. The reduced complexity of the sequencing space, and the fact that TempO-seq probes are all equal length, appears to reduce the need for elaborate bioinformatic or statistical methods used to address these factors in RNA-seq data.
Language	English
Publishing date	2022-04-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	2423808-9
ISSN	1177-9322
ISSN	1177-9322
DOI	10.1177/11779322221095216
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Article ; Online: Hazard and risk characterization of 56 structurally diverse PFAS using a targeted battery of broad coverage assays using six human cell types.

Ford, Lucie C / Lin, Hsing-Chieh / Tsai, Han-Hsuan D / Zhou, Yi-Hui / Wright, Fred A / Sedykh, Alexander / Shah, Ruchir R / Chiu, Weihsueh A / Rusyn, Ivan

Toxicology

2024 Volume 503, Page(s) 153763

Abstract: Per- and poly-fluoroalkyl substances (PFAS) are extensively used in commerce leading to their prevalence in the environment. Due to their chemical stability, PFAS are considered to be persistent and bioaccumulative; they are frequently detected in both ... ...

Abstract	Per- and poly-fluoroalkyl substances (PFAS) are extensively used in commerce leading to their prevalence in the environment. Due to their chemical stability, PFAS are considered to be persistent and bioaccumulative; they are frequently detected in both the environment and humans. Because of this, PFAS as a class (composed of hundreds to thousands of chemicals) are contaminants of very high concern. Little information is available for the vast majority of PFAS, and regulatory agencies lack safety data to determine whether exposure limits or restrictions are needed. Cell-based assays are a pragmatic approach to inform decision-makers on potential health hazards; therefore, we hypothesized that a targeted battery of human in vitro assays can be used to determine whether there are structure-bioactivity relationships for PFAS, and to characterize potential risks by comparing bioactivity (points of departure) to exposure estimates. We tested 56 PFAS from 8 structure-based subclasses in concentration response (0.1-100 μM) using six human cell types selected from target organs with suggested adverse effects of PFAS - human induced pluripotent stem cell (iPSC)-derived hepatocytes, neurons, and cardiomyocytes, primary human hepatocytes, endothelial and HepG2 cells. While many compounds were without effect; certain PFAS demonstrated cell-specific activity highlighting the necessity of using a compendium of in vitro models to identify potential hazards. No class-specific groupings were evident except for some chain length- and structure-related trends. In addition, margins of exposure (MOE) were derived using empirical and predicted exposure data. Conservative MOE calculations showed that most tested PFAS had a MOE in the 1-100 range; ∼20% of PFAS had MOE<1, providing tiered priorities for further studies. Overall, we show that a compendium of human cell-based models can be used to derive bioactivity estimates for a range of PFAS, enabling comparisons with human biomonitoring data. Furthermore, we emphasize that establishing structure-bioactivity relationships may be challenging for the tested PFAS.
MeSH term(s)	Humans ; Induced Pluripotent Stem Cells ; Biological Monitoring ; Fluorocarbons/chemistry
Chemical Substances	Fluorocarbons
Language	English
Publishing date	2024-02-27
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	184557-3
ISSN	1879-3185 ; 0300-483X
ISSN (online)	1879-3185
ISSN	0300-483X
DOI	10.1016/j.tox.2024.153763
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Article ; Online: Single nucleotide polymorphism patterns associated with a cancer resistant phenotype.

Dunnick, June K / Pandiri, Arun R / Shockley, Keith R / Herbert, Ronald / Mav, Deepak / Phadke, Dhiral / Shah, Ruchir R / Merrick, B Alex

Experimental and molecular pathology

2022 Volume 128, Page(s) 104812

Abstract: Background and aims: In this study ten mouse strains representing ~90% of genetic diversity in laboratory mice (B6C3F1/J, C57BL/6J, C3H/HeJ, A/J, NOD.B1oSnH2/J, NZO/HILtJ, 129S1/SvImJ, WSB/EiJ, PWK/PhJ, CAST/EiJ) were examined to identify the mouse ... ...

Abstract	Background and aims: In this study ten mouse strains representing ~90% of genetic diversity in laboratory mice (B6C3F1/J, C57BL/6J, C3H/HeJ, A/J, NOD.B1oSnH2/J, NZO/HILtJ, 129S1/SvImJ, WSB/EiJ, PWK/PhJ, CAST/EiJ) were examined to identify the mouse strain with the lowest incidence of cancer. The unique single polymorphisms (SNPs) associated with this low cancer incidence are reported. Methods: Evaluations of cancer incidence in the 10 mouse strains were based on gross and microscopic diagnosis of tumors. Single nucleotide polymorphisms (SNPs) in the coding regions of the genome were derived from the respective mouse strains located in the Sanger mouse sequencing database and the B6C3F1/N genome from the National Toxicology Program (NTP). Results: The WSB strain had an overall lower incidence of both benign and malignant tumors compared to the other mouse strains. At 2 years, the incidence of total malignant tumors (Poly-3 incidence rate) ranged from 2% (WSB) to 92% (C3H) in males, and 14% (WSB) to 93% (NZO) in females, and the total incidence of benign and malignant tumor incidence ranged from 13% (WSB) to 99% (C3H) in males and 25% (WSB) to 96% (NOD) in females. Single nucleotide polymorphism (SNP) patterns were examined in the following strains: B6C3F1/N, C57BL/6J, C3H/HeJ, 129S1/SvImJ, A/J, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ. We identified 7519 SNPs (involving 5751 Ensembl transcripts of 3453 Ensembl Genes) that resulted in a unique amino acid change in the coding region of the WSB strain. Conclusions: The inherited genetic patterns in the WSB cancer-resistant mouse strain occurred in genes involved in multiple cell functions including mitochondria, metabolic, immune, and membrane-related cell functions. The unique SNP patterns in a cancer resistant mouse strain provides insights for understanding and developing strategies for cancer prevention.
MeSH term(s)	Male ; Female ; Mice ; Animals ; Polymorphism, Single Nucleotide/genetics ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, Inbred C3H ; Phenotype ; Mice, Inbred Strains ; Neoplasms/genetics ; Amino Acids/genetics
Chemical Substances	Amino Acids
Language	English
Publishing date	2022-07-21
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Research Support, N.I.H., Extramural
ZDB-ID	207655-x
ISSN	1096-0945 ; 0014-4800
ISSN (online)	1096-0945
ISSN	0014-4800
DOI	10.1016/j.yexmp.2022.104812
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Article ; Online: Low-calorie sweeteners and health outcomes: A demonstration of rapid evidence mapping (rEM).

Lam, Juleen / Howard, Brian E / Thayer, Kristina / Shah, Ruchir R

Environment international

2019 Volume 123, Page(s) 451–458

Abstract: Background: "Evidence Mapping" is an emerging tool that is increasingly being used to systematically identify, review, organize, quantify, and summarize the literature. It can be used as an effective method for identifying well-studied topic areas ... ...

Abstract	Background: "Evidence Mapping" is an emerging tool that is increasingly being used to systematically identify, review, organize, quantify, and summarize the literature. It can be used as an effective method for identifying well-studied topic areas relevant to a broad research question along with any important literature gaps. However, because the procedure can be significantly resource-intensive, approaches that can increase the speed and reproducibility of evidence mapping are in great demand. Methods: We propose an alternative process called "rapid Evidence Mapping" (rEM) to map the scientific evidence in a time-efficient manner, while still utilizing rigorous, transparent and explicit methodological approaches. To illustrate its application, we have conducted a proof-of-concept case study on the topic of low-calorie sweeteners (LCS) with respect to human dietary exposures and health outcomes. During this process, we developed and made publicly available our study protocol, established a PECO (Participants, Exposure, Comparator, and Outcomes) statement, searched the literature, screened titles and abstracts to identify potentially relevant studies, and applied semi-automated machine learning approaches to tag and categorize the included articles. We created various visualizations including bubble plots and frequency tables to map the evidence and research gaps according to comparison type, population baseline health status, outcome group, and study sample size. We compared our results with a traditional evidence mapping of the same topic published in 2016 (Wang et al., 2016). Results: We conducted an rEM of LCS, for which we identified 8122 records from a PubMed search (January 1, 1946-May 1, 2014) and then utilized machine learning (SWIFT-Active Screener) to prioritize relevant records. After screening 2267 (28%) of the total set of titles and abstracts to achieve 95% estimated recall, we ultimately included 297 relevant studies. Overall, our findings corroborated those of Wang et al. (2016) and identified that most studies were acute or short-term in healthy individuals, and studied the outcomes of appetite, energy sensing and body weight. We also identified a lack of studies assessing appetite and dietary intake related outcomes in people with diabetes. The rEM approach required approximately 100 person-hours conducted over 7 calendar months. Conclusion: Rapid Evidence Mapping is an expeditious approach based on rigorous methodology that can be used to quickly summarize the available body of evidence relevant to a research question, identify gaps in the literature to inform future research, and contextualize the design of a systematic review within the broader scientific literature, significantly reducing human effort while yielding results comparable to those from traditional methods. The potential time savings of this approach in comparison to the traditional evidence mapping process make it a potentially powerful tool for rapidly translating knowledge to inform science-based decision-making.
MeSH term(s)	Body Weight ; Health Status ; Humans ; Reproducibility of Results ; Review Literature as Topic ; Sweetening Agents
Chemical Substances	Sweetening Agents
Language	English
Publishing date	2019-01-05
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	554791-x
ISSN	1873-6750 ; 0160-4120
ISSN (online)	1873-6750
ISSN	0160-4120
DOI	10.1016/j.envint.2018.11.070
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Saagar

Sedykh, Alexander Y / Shah, Ruchir R / Kleinstreuer, Nicole C / Auerbach, Scott S / Gombar, Vijay K

Chemical research in toxicology

2020 Volume 34, Issue 2, Page(s) 634–640

Abstract: Molecular structure-based predictive models provide a proven alternative to costly and inefficient animal testing. However, due to a lack of interpretability of predictive models built with abstract molecular descriptors they have earned the notoriety of ...

Abstract	Molecular structure-based predictive models provide a proven alternative to costly and inefficient animal testing. However, due to a lack of interpretability of predictive models built with abstract molecular descriptors they have earned the notoriety of being black boxes. Interpretable models require interpretable descriptors to provide chemistry-backed predictive reasoning and facilitate intelligent molecular design. We developed a novel set of extensible chemistry-aware substructures,
MeSH term(s)	Animals ; Anthraquinones/chemistry ; Databases, Factual ; Models, Molecular ; Molecular Structure ; Quantitative Structure-Activity Relationship
Chemical Substances	Anthraquinones
Language	English
Publishing date	2020-12-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.0c00464
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Article: Low-calorie sweeteners and health outcomes: A demonstration of rapid evidence mapping (rEM)

Lam, Juleen / Howard, Brian E / Shah, Ruchir R / Thayer, Kristina

Environment international. 2019 Feb., v. 123

2019

Abstract: Evidence Mapping” is an emerging tool that is increasingly being used to systematically identify, review, organize, quantify, and summarize the literature. It can be used as an effective method for identifying well-studied topic areas relevant to a ... ...

Abstract	“Evidence Mapping” is an emerging tool that is increasingly being used to systematically identify, review, organize, quantify, and summarize the literature. It can be used as an effective method for identifying well-studied topic areas relevant to a broad research question along with any important literature gaps. However, because the procedure can be significantly resource-intensive, approaches that can increase the speed and reproducibility of evidence mapping are in great demand.We propose an alternative process called “rapid Evidence Mapping” (rEM) to map the scientific evidence in a time-efficient manner, while still utilizing rigorous, transparent and explicit methodological approaches. To illustrate its application, we have conducted a proof-of-concept case study on the topic of low-calorie sweeteners (LCS) with respect to human dietary exposures and health outcomes. During this process, we developed and made publicly available our study protocol, established a PECO (Participants, Exposure, Comparator, and Outcomes) statement, searched the literature, screened titles and abstracts to identify potentially relevant studies, and applied semi-automated machine learning approaches to tag and categorize the included articles. We created various visualizations including bubble plots and frequency tables to map the evidence and research gaps according to comparison type, population baseline health status, outcome group, and study sample size. We compared our results with a traditional evidence mapping of the same topic published in 2016 (Wang et al., 2016).We conducted an rEM of LCS, for which we identified 8122 records from a PubMed search (January 1, 1946–May 1, 2014) and then utilized machine learning (SWIFT-Active Screener) to prioritize relevant records. After screening 2267 (28%) of the total set of titles and abstracts to achieve 95% estimated recall, we ultimately included 297 relevant studies. Overall, our findings corroborated those of Wang et al. (2016) and identified that most studies were acute or short-term in healthy individuals, and studied the outcomes of appetite, energy sensing and body weight. We also identified a lack of studies assessing appetite and dietary intake related outcomes in people with diabetes. The rEM approach required approximately 100 person-hours conducted over 7 calendar months.Rapid Evidence Mapping is an expeditious approach based on rigorous methodology that can be used to quickly summarize the available body of evidence relevant to a research question, identify gaps in the literature to inform future research, and contextualize the design of a systematic review within the broader scientific literature, significantly reducing human effort while yielding results comparable to those from traditional methods. The potential time savings of this approach in comparison to the traditional evidence mapping process make it a potentially powerful tool for rapidly translating knowledge to inform science-based decision-making.
Keywords	appetite ; artificial intelligence ; body weight ; case studies ; decision making ; diabetes ; energy ; food intake ; health status ; humans ; people ; screening ; sweeteners ; systematic review
Language	English
Dates of publication	2019-02
Size	p. 451-458.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	554791-x
ISSN	1873-6750 ; 0160-4120
ISSN (online)	1873-6750
ISSN	0160-4120
DOI	10.1016/j.envint.2018.11.070
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Transcriptional pathways linked to fetal and maternal hepatic dysfunction caused by gestational exposure to perfluorooctanoic acid (PFOA) or hexafluoropropylene oxide-dimer acid (HFPO-DA or GenX) in CD-1 mice.

Blake, Bevin E / Miller, Colette N / Nguyen, Helen / Chappell, Vesna A / Phan, Trina P / Phadke, Dhiral P / Balik-Meisner, Michele R / Mav, Deepak / Shah, Ruchir R / Fenton, Suzanne E

Ecotoxicology and environmental safety

2022 Volume 248, Page(s) 114314

Abstract: Per- and polyfluoroalkyl substances (PFAS) comprise a diverse class of chemicals used in industrial processes, consumer products, and fire-fighting foams which have become environmental pollutants of concern due to their persistence, ubiquity, and ... ...

Abstract	Per- and polyfluoroalkyl substances (PFAS) comprise a diverse class of chemicals used in industrial processes, consumer products, and fire-fighting foams which have become environmental pollutants of concern due to their persistence, ubiquity, and associations with adverse human health outcomes, including in pregnant persons and their offspring. Multiple PFAS are associated with adverse liver outcomes in adult humans and toxicological models, but effects on the developing liver are not fully described. Here we performed transcriptomic analyses in the mouse to investigate the molecular mechanisms of hepatic toxicity in the dam and its fetus after exposure to two different PFAS, perfluorooctanoic acid (PFOA) and its replacement, hexafluoropropylene oxide-dimer acid (HFPO-DA, known as GenX). Pregnant CD-1 mice were exposed via oral gavage from embryonic day (E) 1.5-17.5 to PFOA (0, 1, or 5 mg/kg-d) or GenX (0, 2, or 10 mg/kg-d). Maternal and fetal liver RNA was isolated (N = 5 per dose/group) and the transcriptome analyzed by Affymetrix Array. Differentially expressed genes (DEG) and differentially enriched pathways (DEP) were obtained. DEG patterns were similar in maternal liver for 5 mg/kg PFOA, 2 mg/kg GenX, and 10 mg/kg GenX (R
MeSH term(s)	Adult ; Humans ; Female ; Pregnancy ; Mice ; Animals ; Fluorocarbons/toxicity ; Oxides ; Caprylates/toxicity ; Fetus ; Polymers
Chemical Substances	perfluorooctanoic acid (947VD76D3L) ; Fluorocarbons ; Oxides ; Caprylates ; Polymers
Language	English
Publishing date	2022-11-24
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	436536-7
ISSN	1090-2414 ; 0147-6513
ISSN (online)	1090-2414
ISSN	0147-6513
DOI	10.1016/j.ecoenv.2022.114314
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Article ; Online: Whole genome sequencing of low input circulating cell-free DNA obtained from normal human subjects.

Foley, Julie F / Elgart, Brian / Alex Merrick, B / Phadke, Dhiral P / Cook, Molly E / Malphurs, Jason A / Solomon, Gregory G / Shah, Ruchir R / Fessler, Michael B / Miller, Frederick W / Gerrish, Kevin E

Physiological reports

2021 Volume 9, Issue 15, Page(s) e14993

Abstract: Cell-free DNA circulates in plasma at low levels as a normal by-product of cellular apoptosis. Multiple clinical pathologies, as well as environmental stressors can lead to increased circulating cell-free DNA (ccfDNA) levels. Plasma DNA studies ... ...

Abstract	Cell-free DNA circulates in plasma at low levels as a normal by-product of cellular apoptosis. Multiple clinical pathologies, as well as environmental stressors can lead to increased circulating cell-free DNA (ccfDNA) levels. Plasma DNA studies frequently employ targeted amplicon deep sequencing platforms due to limited concentrations (ng/ml) of ccfDNA in the blood. Here, we report whole genome sequencing (WGS) and read distribution across chromosomes of ccfDNA extracted from two human plasma samples from normal, healthy subjects, representative of limited clinical samples at <1 ml. Amplification was sufficiently robust with ~90% of the reference genome (GRCh38.p2) exhibiting 10X coverage. Chromosome read coverage was uniform and directly proportional to the number of reads for each chromosome across both samples. Almost 99% of the identified genomic sequence variants were known annotated dbSNP variants in the hg38 reference genome. A high prevalence of C>T and T>C mutations was present along with a strong concordance of variants shared between the germline genome databases; gnomAD (81.1%) and the 1000 Genome Project (93.6%). This study demonstrates isolation and amplification procedures from low input ccfDNA samples that can detect sequence variants across the whole genome from amplified human plasma ccfDNA that can translate to multiple clinical research disciplines.
MeSH term(s)	Cell-Free Nucleic Acids/blood ; Cell-Free Nucleic Acids/genetics ; Chromosomes, Human/genetics ; Genome, Human ; Humans ; Mutation ; Whole Genome Sequencing/methods
Chemical Substances	Cell-Free Nucleic Acids
Language	English
Publishing date	2021-07-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2724325-4
ISSN	2051-817X ; 2051-817X
ISSN (online)	2051-817X
ISSN	2051-817X
DOI	10.14814/phy2.14993
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Genome-wide promoter DNA methylation profiling of hepatocellular carcinomas arising either spontaneously or due to chronic exposure to Ginkgo biloba extract (GBE) in B6C3F1/N mice.

Kovi, Ramesh C / Bhusari, Sachin / Mav, Deepak / Shah, Ruchir R / Ton, Thai Vu / Hoenerhoff, Mark J / Sills, Robert C / Pandiri, Arun R

Archives of toxicology

2019 Volume 93, Issue 8, Page(s) 2219–2235

Abstract: Epigenetic modifications, such as DNA methylation, play an important role in carcinogenesis. In a recent NTP study, chronic exposure of B6C3F1/N mice to Ginkgo biloba extract (GBE) resulted in a high incidence of hepatocellular carcinomas (HCC). Genome- ... ...

Abstract	Epigenetic modifications, such as DNA methylation, play an important role in carcinogenesis. In a recent NTP study, chronic exposure of B6C3F1/N mice to Ginkgo biloba extract (GBE) resulted in a high incidence of hepatocellular carcinomas (HCC). Genome-wide promoter methylation profiling on GBE-exposed HCC (2000 mg/kg group), spontaneous HCC (vehicle-control group), and age-matched vehicle control liver was performed to identify differentially methylated genes in GBE-exposed HCC and spontaneous HCC. DNA methylation alterations were correlated to the corresponding global gene expression changes. Compared to control liver, 1296 gene promoters (719 hypermethylated, 577 hypomethylated) in GBE-exposed HCC and 738 (427 hypermethylated, 311 hypomethylated) gene promoters in spontaneous HCC were significantly differentially methylated, suggesting an impact of methylation on GBE-exposed HCC. Differential methylation of promoter regions in relevant cancer genes (cMyc, Spry2, Dusp5) and their corresponding differential gene expression was validated by quantitative pyrosequencing and qRT-PCR, respectively. In conclusion, we have identified differentially methylated promoter regions of relevant cancer genes altered in GBE-exposed HCC compared to spontaneous HCC. Further study of unique sets of differentially methylated genes in chemical-exposed mouse HCC could potentially be used to differentiate treatment-related tumors from spontaneous-tumors in cancer bioassays and provide additional understanding of the underlying epigenetic mechanisms of chemical carcinogenesis.
MeSH term(s)	Animals ; Carcinoma, Hepatocellular/chemically induced ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/metabolism ; DNA Methylation/drug effects ; Epigenesis, Genetic/drug effects ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Genome-Wide Association Study ; Liver Neoplasms/chemically induced ; Liver Neoplasms/genetics ; Liver Neoplasms/metabolism ; Male ; Mice, Inbred Strains ; Plant Extracts/administration & dosage ; Plant Extracts/adverse effects ; Promoter Regions, Genetic ; Reproducibility of Results ; Toxicity Tests, Chronic
Chemical Substances	Plant Extracts ; Ginkgo biloba extract (19FUJ2C58T)
Language	English
Publishing date	2019-07-05
Publishing country	Germany
Document type	Journal Article
ZDB-ID	124992-7
ISSN	1432-0738 ; 0340-5761
ISSN (online)	1432-0738
ISSN	0340-5761
DOI	10.1007/s00204-019-02505-7
Database	MEDical Literature Analysis and Retrieval System OnLINE

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