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Article ; Online: Mapping Interindividual Variability of Toxicodynamics Using High-Throughput Transcriptomics and Primary Human Hepatocytes from Fifty Donors.

Niemeijer, Marije / Więcek, Witold / Fu, Shuai / Huppelschoten, Suzanna / Bouwman, Peter / Baze, Audrey / Parmentier, Céline / Richert, Lysiane / Paules, Richard S / Bois, Frederic Y / van de Water, Bob

Environmental health perspectives

2024 Volume 132, Issue 3, Page(s) 37005

Abstract: Background: Understanding the variability across the human population with respect to toxicodynamic responses after exposure to chemicals, such as environmental toxicants or drugs, is essential to define safety factors for risk assessment to protect the ...

Abstract	Background: Understanding the variability across the human population with respect to toxicodynamic responses after exposure to chemicals, such as environmental toxicants or drugs, is essential to define safety factors for risk assessment to protect the entire population. Activation of cellular stress response pathways are early adverse outcome pathway (AOP) key events of chemical-induced toxicity and would elucidate the estimation of population variability of toxicodynamic responses. Objectives: We aimed to map the variability in cellular stress response activation in a large panel of primary human hepatocyte (PHH) donors to aid in the quantification of toxicodynamic interindividual variability to derive safety uncertainty factors. Methods: High-throughput transcriptomics of over 8,000 samples in total was performed covering a panel of 50 individual PHH donors upon 8 to 24 h exposure to broad concentration ranges of four different toxicological relevant stimuli: tunicamycin for the unfolded protein response (UPR), diethyl maleate for the oxidative stress response (OSR), cisplatin for the DNA damage response (DDR), and tumor necrosis factor alpha ( Results: Transcriptome mapping allowed the investigation of the interindividual variability in concentration-dependent stress response activation, where the average of BMCs had a maximum difference of 864-, 13-, 13-, and 259-fold between different PHHs for UPR, OSR, DDR, and Discussion: Overall, by combining high-throughput transcriptomics and population modeling, improved understanding of interindividual variability in chemical-induced activation of toxicity relevant stress pathways across the human population using a large panel of plated cryopreserved PHHs was established, thereby contributing toward increasing the confidence of
MeSH term(s)	Humans ; Hepatocytes ; Gene Expression Profiling ; Transcriptome ; Oxidative Stress
Language	English
Publishing date	2024-03-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	195189-0
ISSN	1552-9924 ; 0091-6765 ; 1078-0475
ISSN (online)	1552-9924
ISSN	0091-6765 ; 1078-0475
DOI	10.1289/EHP11891
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Article: A Comparison of the TempO-Seq S1500+ Platform to RNA-Seq and Microarray Using Rat Liver Mode of Action Samples.

Bushel, Pierre R / Paules, Richard S / Auerbach, Scott S

Frontiers in genetics

2018 Volume 9, Page(s) 485

Abstract: The TempO- ... ...

Abstract	The TempO-Seq
Language	English
Publishing date	2018-10-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2018.00485
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Article: Comparison of Normalization Methods for Analysis of TempO-Seq Targeted RNA Sequencing Data.

Bushel, Pierre R / Ferguson, Stephen S / Ramaiahgari, Sreenivasa C / Paules, Richard S / Auerbach, Scott S

Frontiers in genetics

2020 Volume 11, Page(s) 594

Abstract: Analysis of bulk RNA sequencing (RNA-Seq) data is a valuable tool to understand transcription at the genome scale. Targeted sequencing of RNA has emerged as a practical means of assessing the majority of the transcriptomic space with less reliance on ... ...

Abstract	Analysis of bulk RNA sequencing (RNA-Seq) data is a valuable tool to understand transcription at the genome scale. Targeted sequencing of RNA has emerged as a practical means of assessing the majority of the transcriptomic space with less reliance on large resources for consumables and bioinformatics. TempO-Seq is a templated, multiplexed RNA-Seq platform that interrogates a panel of sentinel genes representative of genome-wide transcription. Nuances of the technology require proper preprocessing of the data. Various methods have been proposed and compared for normalizing bulk RNA-Seq data, but there has been little to no investigation of how the methods perform on TempO-Seq data. We simulated count data into two groups (treated vs. untreated) at seven-fold change (FC) levels (including no change) using control samples from human HepaRG cells run on TempO-Seq and normalized the data using seven normalization methods. Upper Quartile (UQ) performed the best with regard to maintaining FC levels as detected by a limma contrast between treated vs. untreated groups. For all FC levels, specificity of the UQ normalization was greater than 0.84 and sensitivity greater than 0.90 except for the no change and +1.5 levels. Furthermore, K-means clustering of the simulated genes normalized by UQ agreed the most with the FC assignments [adjusted Rand index (ARI) = 0.67]. Despite having an assumption of the majority of genes being unchanged, the DESeq2 scaling factors normalization method performed reasonably well as did simple normalization procedures counts per million (CPM) and total counts (TCs). These results suggest that for two class comparisons of TempO-Seq data, UQ, CPM, TC, or DESeq2 normalization should provide reasonably reliable results at absolute FC levels ≥2.0. These findings will help guide researchers to normalize TempO-Seq gene expression data for more reliable results.
Language	English
Publishing date	2020-06-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606823-0
ISSN	1664-8021
ISSN	1664-8021
DOI	10.3389/fgene.2020.00594
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Article: Intersection of toxicogenomics and high throughput screening in the Tox21 program: an NIEHS perspective.

Merrick, B Alex / Paules, Richard S / Tice, Raymond R

International journal of biotechnology

2016 Volume 14, Issue 1, Page(s) 7–27

Abstract: Humans are exposed to thousands of chemicals with inadequate toxicological data. Advances in computational toxicology, robotic high throughput screening (HTS), and genome-wide expression have been integrated into the Tox21 program to better predict the ... ...

Abstract	Humans are exposed to thousands of chemicals with inadequate toxicological data. Advances in computational toxicology, robotic high throughput screening (HTS), and genome-wide expression have been integrated into the Tox21 program to better predict the toxicological effects of chemicals. Tox21 is a collaboration among US government agencies initiated in 2008 that aims to shift chemical hazard assessment from traditional animal toxicology to target-specific, mechanism-based, biological observations using
Language	English
Publishing date	2016-04-28
Publishing country	England
Document type	Journal Article
ISSN	0963-6048
ISSN	0963-6048
DOI	10.1504/IJBT.2015.074797
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Article ; Online: Use of transcriptomics in understanding mechanisms of drug-induced toxicity.

Cui, Yuxia / Paules, Richard S

Pharmacogenomics

2010 Volume 11, Issue 4, Page(s) 573–585

Abstract: Adverse drug reactions (ADRs) are an important clinical issue and a serious public health risk. Understanding the underlying mechanisms is critical for clinical diagnosis and management of different ADRs. Toxicogenomics can reveal impacts on biological ... ...

Abstract	Adverse drug reactions (ADRs) are an important clinical issue and a serious public health risk. Understanding the underlying mechanisms is critical for clinical diagnosis and management of different ADRs. Toxicogenomics can reveal impacts on biological pathways and processes that had not previously been considered to be involved in a drug response. Mechanistic hypotheses can be generated that can then be experimentally tested using the full arsenal of pharmacology, toxicology, molecular biology and genetics. Recent transcriptomic studies on drug-induced toxicity, which have provided valuable mechanistic insights into various ADRs, have been reviewed with a focus on nephrotoxicity and hepatotoxicity. Related issues have been discussed, including extrapolation of mechanistic findings from experimental model systems to humans using blood as a surrogate tissue for organ damage and comparative systems biology approaches.
MeSH term(s)	Animals ; Chemical and Drug Induced Liver Injury/genetics ; Drug-Related Side Effects and Adverse Reactions/genetics ; Gene Expression Profiling ; Humans ; Kidney Diseases/chemically induced ; Kidney Diseases/genetics ; Toxicogenetics/methods
Language	English
Publishing date	2010-04-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Intramural ; Review
ZDB-ID	2019513-8
ISSN	1744-8042 ; 1462-2416
ISSN (online)	1744-8042
ISSN	1462-2416
DOI	10.2217/pgs.10.37
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Zs.A 5247: Show issues

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Article ; Online: DNA damage responses in murine Pre-B cells with genetic deficiencies in damage response genes.

Innes, Cynthia L / Hesse, Jill E / Morales, Abigail J / Helmink, Beth A / Schurman, Shepherd H / Sleckman, Barry P / Paules, Richard S

Cell cycle (Georgetown, Tex.)

2019 Volume 19, Issue 1, Page(s) 67–83

Abstract: DNA damage can be generated in multiple ways from genotoxic and physiologic sources. Genotoxic damage is known to disrupt cellular functions and is lethal if not repaired properly. We compare the transcriptional programs activated in response to ... ...

Abstract	DNA damage can be generated in multiple ways from genotoxic and physiologic sources. Genotoxic damage is known to disrupt cellular functions and is lethal if not repaired properly. We compare the transcriptional programs activated in response to genotoxic DNA damage induced by ionizing radiation (IR) in abl pre-B cells from mice deficient in DNA damage response (DDR) genes
MeSH term(s)	Animals ; Cell Cycle/genetics ; Cell Cycle/radiation effects ; Cell Cycle Checkpoints/genetics ; DNA Damage/genetics ; Gene Expression Regulation/radiation effects ; Genotype ; Mice ; Precursor Cells, B-Lymphoid/immunology ; Precursor Cells, B-Lymphoid/metabolism ; Precursor Cells, B-Lymphoid/radiation effects ; Radiation, Ionizing ; Signal Transduction ; Transcription, Genetic/radiation effects
Language	English
Publishing date	2019-11-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.1080/15384101.2019.1693118
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Zs.A 5881: Show issues

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Article ; Online: Depletion of ATR selectively sensitizes ATM-deficient human mammary epithelial cells to ionizing radiation and DNA-damaging agents.

Cui, Yuxia / Palii, Stela S / Innes, Cynthia L / Paules, Richard S

Cell cycle (Georgetown, Tex.)

2014 Volume 13, Issue 22, Page(s) 3541–3550

Abstract: DNA damage response (DDR) to double strand breaks is coordinated by 3 phosphatidylinositol 3-kinase-related kinase (PIKK) family members: the ataxia-telangiectasia mutated kinase (ATM), the ATM and Rad3-related (ATR) kinase and the catalytic subunit of ... ...

Abstract	DNA damage response (DDR) to double strand breaks is coordinated by 3 phosphatidylinositol 3-kinase-related kinase (PIKK) family members: the ataxia-telangiectasia mutated kinase (ATM), the ATM and Rad3-related (ATR) kinase and the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs). ATM and ATR are central players in activating cell cycle checkpoints and function as an active barrier against genome instability and tumorigenesis in replicating cells. Loss of ATM function is frequently reported in various types of tumors, thus placing more reliance on ATR for checkpoint arrest and cell survival following DNA damage. To investigate the role of ATR in the G2/M checkpoint regulation in response to ionizing radiation (IR), particularly when ATM is deficient, cell lines deficient of ATM, ATR, or both were generated using a doxycycline-inducible lentiviral system. Our data suggests that while depletion of ATR or ATM alone in wild-type human mammary epithelial cell cultures (HME-CCs) has little effect on radiosensitivity or IR-induced G2/M checkpoint arrest, depletion of ATR in ATM-deficient cells causes synthetic lethality following IR, which correlates with severe G2/M checkpoint attenuation. ATR depletion also inhibits IR-induced autophagy, regardless of the ATM status, and enhances IR-induced apoptosis particularly when ATM is deficient. Collectively, our results clearly demonstrate that ATR function is required for the IR-induced G2/M checkpoint activation and subsequent survival of cells with ATM deficiency. The synthetic lethal interaction between ATM and ATR in response to IR supports ATR as a therapeutic target for improved anti-cancer regimens, especially in tumors with a dysfunctional ATM pathway.
MeSH term(s)	Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors ; Ataxia Telangiectasia Mutated Proteins/deficiency ; Ataxia Telangiectasia Mutated Proteins/genetics ; Ataxia Telangiectasia Mutated Proteins/metabolism ; DNA Breaks, Double-Stranded ; DNA Damage/genetics ; DNA Damage/radiation effects ; G2 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Mammary Glands, Human/metabolism ; Mammary Glands, Human/pathology ; Mammary Glands, Human/radiation effects ; Radiation Tolerance/genetics ; Radiation, Ionizing ; Signal Transduction/radiation effects
Chemical Substances	ATM protein, human (EC 2.7.11.1) ; ATR protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1)
Language	English
Publishing date	2014-12-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/15384101.2014.960729
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Article ; Online: Detection and Prioritization of Developmentally Neurotoxic and/or Neurotoxic Compounds Using Zebrafish.

Quevedo, Celia / Behl, Mamta / Ryan, Kristen / Paules, Richard S / Alday, Aintzane / Muriana, Arantza / Alzualde, Ainhoa

Toxicological sciences : an official journal of the Society of Toxicology

2018 Volume 168, Issue 1, Page(s) 225–240

Abstract: The standard methods for toxicity testing using rodent models cannot keep pace with the increasing number of chemicals in our environment due to time and resource limitations. Hence, there is an unmet need for fast, sensitive, and cost-effective ... ...

Abstract	The standard methods for toxicity testing using rodent models cannot keep pace with the increasing number of chemicals in our environment due to time and resource limitations. Hence, there is an unmet need for fast, sensitive, and cost-effective alternate models to reliably predict toxicity. As part of Tox21 Phase III's effort, a 90-compound library was created and made available to researchers to screen for neurotoxicants using novel technology and models. The chemical library was evaluated in zebrafish in a dose-range finding test for embryo-toxicity (ie, mortality or morphological alterations induced by each chemical). In addition, embryos exposed to the lowest effect level and nonobservable effect level were used to measure the internal concentration of the chemicals within the embryos by bioanalysis. Finally, considering the lowest effect level as the highest testing concentration, a functional assay was performed based on locomotor activity alteration in response to light-dark changes. The quality control chemicals included in the library, ie, negative controls and replicated chemicals, indicate that the assays performed were reliable. The use of analytical chemistry pointed out the importance of measuring chemical concentration inside embryos, and in particular, in the case of negative chemicals to avoid false negative classification. Overall, the proposed approach presented a good sensitivity and supports the inclusion of zebrafish assays as a reliable, relevant, and efficient screening tool to identify, prioritize, and evaluate chemical toxicity.
MeSH term(s)	Animals ; Biological Assay ; Embryo, Nonmammalian/drug effects ; Flame Retardants/toxicity ; Larva/drug effects ; Motor Activity/drug effects ; Neurotoxicity Syndromes ; Pesticides/toxicity ; Pharmaceutical Preparations ; Small Molecule Libraries ; Swimming ; Toxicity Tests/methods ; Zebrafish/growth & development
Chemical Substances	Flame Retardants ; Pesticides ; Pharmaceutical Preparations ; Small Molecule Libraries
Language	English
Publishing date	2018-12-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfy291
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Zs.A 1709: Show issues

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Article ; Online: Toxicity profiling of flame retardants in zebrafish embryos using a battery of assays for developmental toxicity, neurotoxicity, cardiotoxicity and hepatotoxicity toward human relevance.

Alzualde, Ainhoa / Behl, Mamta / Sipes, Nisha S / Hsieh, Jui-Hua / Alday, Aintzane / Tice, Raymond R / Paules, Richard S / Muriana, Arantza / Quevedo, Celia

Neurotoxicology and teratology

2018 Volume 70, Page(s) 40–50

Abstract: Following the voluntary phase-out of brominated flame retardants (BFRs) due to their environmental persistence and toxicity, the organophosphorus flame retardants (OPFRs) are emerging replacements. However, there is limited information on the potential ... ...

Abstract	Following the voluntary phase-out of brominated flame retardants (BFRs) due to their environmental persistence and toxicity, the organophosphorus flame retardants (OPFRs) are emerging replacements. However, there is limited information on the potential human health effects of the OPFRs. Zebrafish embryos are a viable vertebrate model organism with many advantages for high throughput testing toward human hazard assessment. We utilized zebrafish embryos to assess developmental toxicity, neurotoxicity, cardiotoxicity and hepatotoxicity, of eight replacement OPFRs: (triphenyl phosphate [TPHP], isopropylated phenyl phosphate [IPP], 2-ethylhexyl diphenyl phosphate [EHDP], tert-butylated phenyl diphenyl phosphate [BPDP], trimethyl phenyl phosphate [TMPP], isodecyl diphenyl phosphate [IDDP], tris(1,3-dichloroisopropyl) phosphate [TDCIPP], and tris(2-chloroethyl) phosphate [TCEP]) and two BFRs (3,3',5,5'- tetrabromobisphenol A [TBBPA] and 2,2'4,4'-brominated diphenyl ether [BDE-47]). To determine potential effects on teratogenicity, embryos were exposed to flame retardants (FRs) at 4 h post fertilization (hpf) to 4 days post fertilization (dpf) and morphological alterations and corresponding survival were evaluated at 2 and 4 dpf. Internal concentrations were measured in larvae used in this assay by liquid chromatography-mass spectrometry. Locomotor activity was assessed in larvae treated for 48 h (from 3 dpf to 5 dpf), followed by hepatotoxicity evaluation. Finally, alterations in heart rate and rhythmicity were assessed to determine cardiotoxicity in 48 hpf embryos exposed to compounds for 3 h. Results suggest that several OPFRs (BPDP, EHDP; IPP, TMPP; TPHP and TDCIPP) produced adverse effects in multiple target organs at concentrations comparable to the two BFRs. As these OPFRs have the capacity to disrupt an integrated vertebrate model, they potentially have the capacity to affect mammalian biology. Then, we compared the lowest effective levels (LEL) in zebrafish with estimated or measured human plasma concentrations using biomonitoring data (human plasma, breast milk, handwipe samples and house dust) and a high throughput toxicokinetic (HTTK) model. Results indicate that for some compounds, the nominal LELs were within the range of human exposures, while internal LELs in zebrafish are above internal exposures in humans. These findings demonstrate the value of the zebrafish model as a relevant screening tool and support the need for further hazard characterization of the OPFRs.
MeSH term(s)	Animals ; Cardiotoxicity/etiology ; Embryonic Development/drug effects ; Flame Retardants/toxicity ; Humans ; Neurotoxicity Syndromes/etiology ; Organophosphates/pharmacology ; Organophosphates/toxicity ; Organophosphorus Compounds/toxicity ; Zebrafish
Chemical Substances	Flame Retardants ; Organophosphates ; Organophosphorus Compounds ; triphenyl phosphate (YZE19Z66EA) ; trimethyl phosphate (Z1E45TMW1Z)
Language	English
Publishing date	2018-10-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	639165-5
ISSN	1872-9738 ; 0892-0362
ISSN (online)	1872-9738
ISSN	0892-0362
DOI	10.1016/j.ntt.2018.10.002
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Article: The US Federal Tox21 Program: A strategic and operational plan for continued leadership.

Thomas, Russell S / Paules, Richard S / Simeonov, Anton / Fitzpatrick, Suzanne C / Crofton, Kevin M / Casey, Warren M / Mendrick, Donna L

ALTEX

2018 Volume 35, Issue 2, Page(s) 163–168

Abstract: The traditional approaches to toxicity testing have posed multiple challenges for evaluating the safety of commercial chemicals, pesticides, food additives/contaminants, and medical products.The challenges include number of chemicals that need to be ... ...

Abstract	The traditional approaches to toxicity testing have posed multiple challenges for evaluating the safety of commercial chemicals, pesticides, food additives/contaminants, and medical products.The challenges include number of chemicals that need to be tested, time and resource intensive nature of traditional toxicity tests, and unexpected adverse effects that occur in pharmaceutical clinical trials despite the extensive toxicological testing.Over a decade ago, the U.S. Environmental Protection Agency (EPA), National Toxicology Program (NTP), National Center for Advancing Translational Sciences (NCATS), and the Food and Drug Administration (FDA) formed a federal consortium for "Toxicology in the 21st Century" (Tox21) with a focus on developing and evaluating in vitro high-throughput screening (HTS) methods for hazard identification and providing mechanistic insights.The Tox21 consortium generated data on thousands of pharmaceuticals and datapoor chemicals, developed better understanding of the limits and applications of in vitro methods, and enabled incorporation of HTS data into regulatory decisions. To more broadly address the challenges in toxicology, Tox21 has developed a new strategic and operational plan that expands the focus of its research activities. The new focus areas include developing an expanded portfolio of alternative test systems, addressing technical limitations of in vitrotest systems, curating legacy in vivo toxicity testing data, establishing scientific confidence in the in vitrotest systems, and refining alternative methods for characterizing pharmacokinetics and in vitro assay disposition.The new Tox21 strategic and operational plan addresses key challenges to advance toxicology testing and will benefit both the organizations involved and the toxicology community.
MeSH term(s)	Animal Testing Alternatives ; Animals ; Cooperative Behavior ; High-Throughput Screening Assays ; Humans ; In Vitro Techniques ; Leadership ; Pharmacokinetics ; Toxicity Tests/methods ; United States ; United States Environmental Protection Agency/organization & administration ; United States Food and Drug Administration/organization & administration
Language	English
Publishing date	2018-03-08
Publishing country	Germany
Document type	Journal Article
ZDB-ID	165707-0
ISSN	1868-596X ; 1018-4562 ; 0946-7785
ISSN	1868-596X ; 1018-4562 ; 0946-7785
DOI	10.14573/altex.1803011
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