Publications by authors named "Doug Crump"

91 Publications

Metabolomic profiles in relation to benchmark polycyclic aromatic compounds (PACs) and trace elements in two seabird species from Arctic Canada.

Environ Res 2021 Sep 8;204(Pt B):112022. Epub 2021 Sep 8.

Science and Technology Branch, Environment and Climate Change Canada, Ottawa, ON, Canada. Electronic address:

While exposure of birds to oil-related contaminants has been documented, the related adverse effects this exposure has on Arctic marine birds remain unexplored. Metabolomics can play an important role to explore biologically relevant metabolite biomarkers in relation to different stressors, even at benchmark levels of contamination. The aim of this study was to characterize the metabolomics profiles in relation to polycyclic aromatic compounds (PACs) and trace elements in the liver of two seabird species in the Canadian Arctic. In July 2018, black guillemots (Cepphus grylle) and thick-billed murres (Uria lomvia) were collected by hunters from a region where natural oil seeps occur in the seabed near Qikiqtarjuaq, Nunavut, Canada. A total of 121 metabolites were identified in liver tissue samples using reversed phase and hydrophilic interaction liquid chromatography coupled to high resolution mass spectrometry platforms to detect non-polar and polar metabolites, respectively. Sixty-nine metabolites showed excellent repeatability and linearity and were used to examine possible effects of oil-related contaminants exposure (PACs and trace elements). Metabolites including 3-hydroxy anthranilic acid, adenine, adenosine, adenosine mono-phosphate, ascorbic acid, butyrylcarnitine, cholic acid, guanosine, guanosine mono-phosphate, inosine, norepinephrine and threonine showed significant differences (more than two fold) between the two species. Elevated adenine and adenosine, along with decreased reduced/oxidized glutathione ratio, highlighted the potential for oxidative stress in murres. Lipid peroxidation and superoxide dismutase activity assays also confirmed these metabolomic findings. These results will help to characterize the baseline metabolomic profiles of Arctic seabird species with different foraging behaviour and trace element burden.
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http://dx.doi.org/10.1016/j.envres.2021.112022DOI Listing
September 2021

Using Transcriptomics and Metabolomics to Understand Species Differences in Sensitivity to Chlorpyrifos in Japanese Quail and Double-Crested Cormorant Embryos.

Environ Toxicol Chem 2021 Jul 22. Epub 2021 Jul 22.

Ecotoxicology and Wildlife Health Division, Environment Canada, National Wildlife Research Centre, Carleton University, Ottawa, Ontario, Canada.

Modern 21st-century toxicity testing makes use of omics technologies to address critical questions in toxicology and chemical management. Of interest are questions relating to chemical mechanisms of toxicity, differences in species sensitivity, and translation of molecular effects to observable apical endpoints. Our study addressed these questions by comparing apical outcomes and multiple omics responses in early-life stage exposure studies with Japanese quail (Coturnix japonica) and double-crested cormorant (Phalacrocorax auritus), representing a model and ecological species, respectively. Specifically, we investigated the dose-dependent response of apical outcomes as well as transcriptomics and metabolomics in the liver of each species exposed to chlorpyrifos, a widely used organophosphate pesticide. Our results revealed a clear pattern of dose-dependent disruption of gene expression and metabolic profiles in Japanese quail but not double-crested cormorant at similar chlorpyrifos exposure concentrations. The difference in sensitivity between species was likely due to higher metabolic transformation of chlorpyrifos in Japanese quail compared to double-crested cormorant. The most impacted biological pathways after chlorpyrifos exposure in Japanese quail included hepatic metabolism, oxidative stress, endocrine disruption (steroid and nonsteroid hormones), and metabolic disease (lipid and fatty acid metabolism). Importantly, we show consistent responses across biological scales, suggesting that significant disruption at the level of gene expression and metabolite profiles leads to observable apical responses at the organism level. Our study demonstrates the utility of evaluating effects at multiple biological levels of organization to understand how modern toxicity testing relates to outcomes of regulatory relevance, while also highlighting important, yet poorly understood, species differences in sensitivity to chemical exposure. Environ Toxicol Chem 2021;00:1-15. © 2021 SETAC.
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http://dx.doi.org/10.1002/etc.5174DOI Listing
July 2021

Assessing the Toxicity of 17α-Ethinylestradiol in Rainbow Trout Using a 4-Day Transcriptomics Benchmark Dose (BMD) Embryo Assay.

Environ Sci Technol 2021 08 22;55(15):10608-10618. Epub 2021 Jul 22.

Toxicology Centre, University of Saskatchewan, Saskatoon, Saskatchewan, Canada S7N 5B3.

There is an urgent demand for more efficient and ethical approaches in ecological risk assessment. Using 17α-ethinylestradiol (EE2) as a model compound, this study established an embryo benchmark dose (BMD) assay for rainbow trout (RBT; ) to derive transcriptomic points-of-departure (tPODs) as an alternative to live-animal tests. Embryos were exposed to graded concentrations of EE2 (measured: 0, 1.13, 1.57, 6.22, 16.3, 55.1, and 169 ng/L) from hatch to 4 and up to 60 days post-hatch (dph) to assess molecular and apical responses, respectively. Whole proteome analyses of alevins did not show clear estrogenic effects. In contrast, transcriptomics revealed responses that were in agreement with apical effects, including excessive accumulation of intravascular and hepatic proteinaceous fluid and significant increases in mortality at 55.1 and 169 ng/L EE2 at later time points. Transcriptomic BMD analysis estimated the median of the 20th lowest geneBMD to be 0.18 ng/L, the most sensitive tPOD. Other estimates (0.78, 3.64, and 1.63 ng/L for the 10th percentile geneBMD, first peak geneBMD distribution, and median geneBMD of the most sensitive over-represented pathway, respectively) were within the same order of magnitude as empirically derived apical PODs for EE2 in the literature. This 4-day alternative RBT embryonic assay was effective in deriving tPODs that are protective of chronic effects of EE2.
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http://dx.doi.org/10.1021/acs.est.1c02401DOI Listing
August 2021

Cross-Model Comparison of Transcriptomic Dose-Response of Short-Chain Chlorinated Paraffins.

Environ Sci Technol 2021 06 26;55(12):8149-8158. Epub 2021 May 26.

State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, P. R. China.

Short-chain chlorinated paraffins (SCCPs) have attracted attention because of their toxicological potential in humans and wildlife at environmentally relevant doses. However, limited information is available regarding mechanistic differences across species in terms of the biological pathways that are impacted by SCCP exposure. Here, a concentration-dependent reduced human transcriptome (RHT) approach was conducted to evaluate 15 SCCPs in HepG2 cells and compared with our previous results using a reduced zebrafish transcriptome (RZT) approach in zebrafish embryos (ZFEs). Generally, SCCPs induced a broader suite of biological pathways in ZFEs than HepG2 cells, and all of the 15 SCCPs were more potent in HepG2 cells compared to ZFEs. Despite these general differences, the transcriptional potency of SCCPs in both model systems showed a significant linear relationship ( = 0.0017, = 0.57), and the average ratios of transcriptional potency for each SCCP in RZT to that in RHT were ∼100,000. CHCl was the most potent SCCP, while CHCl was the least potent in both ZFEs and HepG2 cells. An adverse outcome pathway network-based analysis demonstrated model-specific responses, such as xenobiotic metabolism that may be mediated by different nuclear receptor-mediated pathways between HepG2 cells (, CAR and AhR activation) and ZFEs (, PXR activation). Moreover, induced transcriptional changes in ZFEs associated with pathways and molecular initiating events (, activation of nicotinic acetylcholine receptor) suggest that SCCPs may disrupt neural development processes. The cross-model comparison of concentration-dependent transcriptomics represents a promising approach to assess and prioritize SCCPs.
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http://dx.doi.org/10.1021/acs.est.1c00975DOI Listing
June 2021

Polychlorinated Diphenyl Sulfides: An Emerging Class of Persistent, Bioaccumulative, and Toxic Substances in the Environment.

Environ Toxicol Chem 2021 May 18. Epub 2021 May 18.

State Key Laboratory of Pollution Control and Resources Reuse, School of the Environment, Nanjing University, Nanjing, China.

Polychlorinated diphenyl sulfides (PCDPSs) have recently attracted increasing attention due to their potential adverse effects on human and ecosystem health. We present a review regarding their environmental occurrence, persistence, bioaccumulation, toxicity, and biotransformation. The existing literature demonstrates that PCDPSs are ubiquitous in various environmental matrices, are persistent in the environment, and have long-range transport potential. In addition, the high bioaccumulation potential of these emerging pollutants, especially the low chlorinated PCDPS congeners, has been confirmed based on both theoretical calculations and experimental investigations. Moreover, a spectrum of adverse effects, such as acute liver injury, retardation of development, reproductive disorders, and increased mortality have been widely reported in vertebrates. These adverse outcomes were associated with oxidative stress and activation of aryl hydrocarbon receptors. Given these findings, PCDPSs represent candidate persistent, bioaccumulative, and toxic substances and thus deserve further research to fully elucidate their environmental behavior and fate, and evaluate the risks to human and ecosystem health. Environ Toxicol Chem 2021;00:1-10. © 2021 SETAC.
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http://dx.doi.org/10.1002/etc.5120DOI Listing
May 2021

ToxChip PCR Arrays for Two Arctic-Breeding Seabirds: Applications for Regional Environmental Assessments.

Environ Sci Technol 2021 06 13;55(11):7521-7530. Epub 2021 May 13.

National Wildlife Research Centre, Environment and Climate Change Canada, 1125 Colonel By Dr., Ottawa, ON ON K1S, Canada.

Increasing pollution in the Arctic poses challenges in terms of geographical and ecological monitoring. The Baffin Bay-Davis Strait (BBDS) region in the Canadian Arctic Archipelago is of particular concern due to the potential for increased shipping traffic and oil exploration. However, data on background contaminants associated with oil exploration/spills/natural seeps (e.g., polycyclic aromatic compounds [PAC]) and measures of potential effects for Arctic birds are limited. We developed a toxicogenomics approach to investigate the background gene expression profiles for two Arctic-breeding seabirds, the thick-billed murre () and the black guillemot (), which will aid effects-based monitoring efforts. Chemical burdens (53 PACs and 5 trace elements) and transcriptomic profiles (31 genes using a ToxChip PCR array) were examined in liver tissues ( = 30) of each species collected from the Qaqulluit and Akpait National Wildlife Areas in the BBDS region. While chemical and transcriptomic profiles demonstrated low variability across individuals for each species, gene expression signatures were able to distinguish guillemots collected from two distinct colonies. This toxicogenomics approach provides benchmark data for two Arctic seabirds and is promising for future monitoring efforts and strategic environmental assessments in this sensitive ecosystem and areas elsewhere in the circumpolar Arctic that are undergoing change.
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http://dx.doi.org/10.1021/acs.est.1c00229DOI Listing
June 2021

Concentration- and time-dependent induction of Cyp1a and DNA damage response by benzo(a)pyrene in LMH three-dimensional spheroids.

Environ Mol Mutagen 2021 Jun 1;62(5):319-327. Epub 2021 Jun 1.

Environment and Climate Change Canada, National Wildlife Research Centre, Ottawa, Ontario, Canada.

In vitro liver toxicity tests performed using cell lines cultured as two-dimensional (2D) monolayer have limited CYP450 activity and may be inadequate for screening chemicals that require activation to exert toxicity. Metabolic competence is greatly improved using three-dimensional (3D) cell culture. In this study, Cyp1a induction, and subsequent DNA damage response induced by benzo(a)pyrene (BaP) were compared in 2D monolayer cells and 3D spheroids of the chicken hepatic cell line, LMH. Cells were exposed to BaP (0.1-100 μM) for different durations: 8, 24, 35, or 48 hr. Cyp1a activity, mRNA expression of Cyp1a and DNA damage response (DDR) genes, and phosphorylation of H2AX (γH2AX) were determined using the EROD assay, a customized PCR array, and flow cytometry, respectively. EROD activity was induced at 8 hr and achieved maximal induction at 24 hr in spheroids; earlier time points than for monolayer cells. In spheroids, BaP exposure resulted in a concentration-dependent increase in Cyp1a4 mRNA expression at 8 hr followed by upregulation of DDR genes at 24 hr, whereas Cyp1a4 mRNA induction was only observed at 48 hr in monolayer cells. Cyp1a5 mRNA was induced at 8 hr in monolayer cells but maximum induction was greater in spheroids. An increase in γH2AX was observed at 24 hr in spheroids; this endpoint was not evaluated in monolayer cells. These results suggest that BaP metabolism precedes the DNA damage response and occurs earlier in 3D spheroids. This study demonstrates that LMH 3D spheroids could be a suitable metabolically-competent in vitro model to measure genotoxicity of chemicals that require metabolic activation by Cyp1a.
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http://dx.doi.org/10.1002/em.22433DOI Listing
June 2021

Polycyclic Aromatic Hydrocarbons Alter the Hepatic Expression of Genes Involved in Sanderling (Calidris alba) Pre-migratory Fueling.

Environ Toxicol Chem 2021 Jul 1;40(7):1983-1991. Epub 2021 Jun 1.

Department of Biology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Polycyclic aromatic hydrocarbons (PAHs) impaired pre-migratory fueling in 49 orally dosed Sanderling (Calidris alba). In the present study, 8 genes related to fat deposition and PAH exposure were measured in liver subsamples from these same shorebirds. At the highest dose (1260 µg total PAH [tPAH]/kg body wt/day), PAH exposure decreased liver basic fatty acid binding protein 1 (Lbfabp) and hepatic lipase (Lipc) expression. The present study reveals candidate molecular-level pathways for observed avian pre-migratory refueling impairment. Environ Toxicol Chem 2021;40:1983-1991. © 2021 SETAC.
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http://dx.doi.org/10.1002/etc.5056DOI Listing
July 2021

Development of a Comprehensive Toxicity Pathway Model for 17α-Ethinylestradiol in Early Life Stage Fathead Minnows ().

Environ Sci Technol 2021 04 23;55(8):5024-5036. Epub 2021 Mar 23.

Toxicology Centre, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B3, Canada.

There is increasing pressure to develop alternative ecotoxicological risk assessment approaches that do not rely on expensive, time-consuming, and ethically questionable live animal testing. This study aimed to develop a comprehensive early life stage toxicity pathway model for the exposure of fish to estrogenic chemicals that is rooted in mechanistic toxicology. Embryo-larval fathead minnows (FHM; ) were exposed to graded concentrations of 17α-ethinylestradiol (water control, 0.01% DMSO, 4, 20, and 100 ng/L) for 32 days. Fish were assessed for transcriptomic and proteomic responses at 4 days post-hatch (dph), and for histological and apical end points at 28 dph. Molecular analyses revealed core responses that were indicative of observed apical outcomes, including biological processes resulting in overproduction of vitellogenin and impairment of visual development. Histological observations indicated accumulation of proteinaceous fluid in liver and kidney tissues, energy depletion, and delayed or suppressed gonad development. Additionally, fish in the 100 ng/L treatment group were smaller than controls. Integration of omics data improved the interpretation of perturbations in early life stage FHM, providing evidence of conservation of toxicity pathways across levels of biological organization. Overall, the mechanism-based embryo-larval FHM model showed promise as a replacement for standard adult live animal tests.
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http://dx.doi.org/10.1021/acs.est.0c05942DOI Listing
April 2021

Extracts from Dated Lake Sediment Cores in the Athabasca Oil Sands Region Alter Ethoxyresorufin-O-deethylase Activity and Gene Expression in Avian Hepatocytes.

Environ Toxicol Chem 2021 Jul 4;40(7):1883-1893. Epub 2021 May 4.

Ecotoxicology and Wildlife Health Division, Environment and Climate Change Canada, National Wildlife Research Centre, Carleton University, Ottawa, Ontario, Canada.

Increases in oil sands mining operations in the Athabasca oil sands region have resulted in increased concentrations of polycyclic aromatic compounds (PACs) and heavy metals in aquatic systems located near surface mining operations. In the present study, sediment cores were collected from 3 lakes with varying proximity to surface mining operations to determine the differences in PAC concentrations. Sediment cores were separated into 2 sections-current mining (top; 2000-2017) and premining (bottom; pre-1945)-and extracts were prepared for in vitro screening using a well-established chicken embryonic hepatocyte (CEH) assay. Concentrations and composition of PACs varied between sites, with the highest ∑PACs in Saline Lake, 5 km from an active oil sands mine site. The proportion of alkylated PACs was greater than that of parent PACs in the top sediment sections compared with the bottom. Ethoxyresorufin-O-deethylase activity in CEH permitted the ranking of lake sites/core sections based on an aryl hydrocarbon receptor-mediated end point; mean median effect concentration values were lowest for the top cores from Saline Lake and another near-mining operations lake, referred to as WF1. A ToxChip polymerase chain reaction (PCR) array was used to evaluate gene expression changes across 43 target genes associated with numerous toxicological pathways following exposure to top and bottom sediment core extracts. The 2 study sites with the greatest ∑PAC concentrations (Saline Lake and WF1) had the highest gene expression alterations on the ToxChip PCR array (19 [top] and 17 [bottom]/43), compared with a reference site (13 [top] and 7 [bottom]/43). The avian in vitro bioassay was useful for identifying the toxicity of complex PAC extracts associated with variably contaminated sediment cores, supporting its potential use for hotspot identification and complex mixture screening. EnvironToxicol Chem 2021;40:1883-1893. © 2021 SETAC.
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http://dx.doi.org/10.1002/etc.5040DOI Listing
July 2021

Ultrafast functional profiling of RNA-seq data for nonmodel organisms.

Genome Res 2021 Apr 17;31(4):713-720. Epub 2021 Mar 17.

Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec H9X 3V9, Canada.

Computational time and cost remain a major bottleneck for RNA-seq data analysis of nonmodel organisms without reference genomes. To address this challenge, we have developed Seq2Fun, a novel, all-in-one, ultrafast tool to directly perform functional quantification of RNA-seq reads without transcriptome de novo assembly. The pipeline starts with raw read quality control: sequencing error correction, removing poly(A) tails, and joining overlapped paired-end reads. It then conducts a DNA-to-protein search by translating each read into all possible amino acid fragments and subsequently identifies possible homologous sequences in a well-curated protein database. Finally, the pipeline generates several informative outputs including gene abundance tables, pathway and species hit tables, an HTML report to visualize the results, and an output of clean reads annotated with mapped genes ready for downstream analysis. Seq2Fun does not have any intermediate steps of file writing and loading, making I/O very efficient. Seq2Fun is written in C++ and can run on a personal computer with a limited number of CPUs and memory. It can process >2,000,000 reads/min and is >120 times faster than conventional workflows based on de novo assembly, while maintaining high accuracy in our various test data sets.
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http://dx.doi.org/10.1101/gr.269894.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015844PMC
April 2021

Effects of two Bisphenol A replacement compounds, 1,7-bis (4-hydroxyphenylthio)-3,5-dioxaheptane and Bisphenol AF, on development and mRNA expression in chicken embryos.

Ecotoxicol Environ Saf 2021 Jun 14;215:112140. Epub 2021 Mar 14.

Environment and Climate Change Canada, National Wildlife Research Centre, Ottawa, Ontario K1S 5B6, Canada.

Concerns about the estrogenic properties of Bisphenol A (BPA) have led to increased efforts to find BPA replacements. 1,7-bis(4-Hydroxyphenylthio)-3,5-dioxaheptane (DD-70) and 4,4'-(hexafluoroisopropylidene) diphenol (bisphenol AF, BPAF) are two potential chemical substitutes for BPA; however, toxicity data for these chemicals in avian species are limited. To determine effects on avian embryonic viability, development, and hepatic mRNA expression at two distinct developmental periods (mid-incubation [day 11] and term [day 20]), two egg injection studies were performed. Test chemicals were injected into the air cell of unincubated, fertilized chicken eggs at concentrations ranging from 0-88.2 µg/g for DD-70 and 0-114 µg/g egg for BPAF. Embryonic concentrations of DD-70 and BPAF decreased at mid-incubation and term compared to injected concentrations suggesting embryonic metabolism. Exposure to DD-70 (40.9 and 88.2 µg/g) and BPAF (114 µg/g) significantly decreased embryonic viability at mid-incubation. Exposure to DD-70 (88.2 µg/g) decreased embryo mass and increased gallbladder mass, while 114 µg/g BPAF resulted in increased gallbladder mass in term embryos. Expression of hepatic genes related to xenobiotic metabolism, lipid homeostasis, and response to estrogen were altered at both developmental stages. Given the importance of identifying suitable BPA replacements, the present study provides novel, whole animal avian toxicological data for two replacement compounds, DD-70 and BPAF. DATA AVAILABILITY: Data, associated metadata, and calculation tools are available from the corresponding author ([email protected]).
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http://dx.doi.org/10.1016/j.ecoenv.2021.112140DOI Listing
June 2021

In Vitro Screening of 21 Bisphenol A Replacement Alternatives: Compared with Bisphenol A, the Majority of Alternatives Are More Cytotoxic and Dysregulate More Genes in Avian Hepatocytes.

Environ Toxicol Chem 2021 Jul 29;40(7):2026-2033. Epub 2021 Apr 29.

Environment and Climate Change Canada, National Wildlife Research Centre, Ottawa, Ontario, Canada.

An avian in vitro screening approach was used to determine the effects of 21 bisphenol A (BPA) alternatives. Cytotoxicity and dysregulation of genes associated with estrogen response and other toxicologically relevant pathways evoked by these alternatives were compared with BPA. Most of the BPA alternatives (15/21) were equally or more cytotoxic than BPA in chicken embryonic hepatocytes; variability in cell viability was associated with chemical structure and the log octanol-water partition coefficient (logP) values. A negative linear relationship (r  = 0.745; p = 0.49 ; n = 18) was observed between logP and the log median lethal concentration (logLC50) values. The least cytotoxic BPA alternatives elicited the greatest gene dysregulation and, overall, most of the alternatives altered more genes than BPA (measured with a custom polymerase chain reaction array). This overall approach shows promise for use as a screen for hazard-based prioritization of BPA replacement alternatives and to ideally identify those that may be less harmful and/or require additional toxicity testing. Environ Toxicol Chem 2021;40:2026-2033. © 2021 Her Majesty the Queen in Right of Canada Environmental Toxicology and Chemistry © 2021 SETAC. Reproduced with the permission of the Minister of Environment and Climate Change Canada.
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http://dx.doi.org/10.1002/etc.5032DOI Listing
July 2021

Toxicity Screening of Bisphenol A Replacement Compounds: Cytotoxicity and mRNA Expression in Primary Hepatocytes of Chicken and Double-Crested Cormorant.

Environ Toxicol Chem 2021 May 23;40(5):1368-1378. Epub 2021 Mar 23.

Environment and Climate Change Canada, National Wildlife Research Centre, Ottawa, Ontario, Canada.

A market for bisphenol A (BPA) replacement compounds has emerged as a result of restrictions on the use of BPA. Some of these compounds have been detected in the environment; however, little is known about their toxicological properties. In the present study, an avian in vitro toxicogenomic approach was used to compare the effects of 5 BPA alternatives. Cell viability and mRNA expression were compared in primary embryonic hepatocytes of chicken (CEH) and double-crested cormorant (DCEH) exposed to 4,4'-(propane-2,2-diyl) diphenol (BPA), bis (4-hydroxyphenyl) methane (BPF), bis (3-allyl-4-hydroxyphenyl) sulfone (TGSH), 7-bis (4-hydroxyphenylthio)-3,5-dioxaheptane (DD-70), 2,2-bis (4-hydroxyphenyl) hexafluoropropane (BPAF), and 4-hydroxyphenyl 4-isoprooxyphenylsulfone (BPSIP). Changes in gene expression were determined using 2 polymerase chain reaction (PCR) arrays: 1) species-specific ToxChips that contain genes representing toxicologically relevant pathways, and 2) chicken-specific AestroChip that measures estrogen responsive genes. In CEH and DCEH, BPA alternatives TGSH, DD-70, and BPAF were most cytotoxic. Some of the replacement compounds changed the expression of genes related to xenobiotic metabolism, bile acid, and cholesterol regulation. The rank order based on the number of genes altered on the chicken ToxChip array was TGSH > DD-70 > BPAF = BPF > 17β estradiol (E2) > BPSIP > BPA. On the cormorant ToxChip array, BPSIP altered the greatest number of genes. Based on the chicken AestroChip data, BPSIP and BPF were slightly estrogenic. These results suggest that the replacement compounds have comparable or even greater toxicity than BPA and act via different mechanisms. Environ Toxicol Chem 2021;40:1368-1378. © 2021 Her Majesty the Queen in Right of Canada. Reproduced with the permission of the Minister of Environment and Climate Change Canada.
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http://dx.doi.org/10.1002/etc.4985DOI Listing
May 2021

Effects on Apical Outcomes of Regulatory Relevance of Early-Life Stage Exposure of Double-Crested Cormorant Embryos to 4 Environmental Chemicals.

Environ Toxicol Chem 2021 02 18;40(2):390-401. Epub 2020 Dec 18.

Department of Natural Resource Sciences, McGill University, Montreal, Quebec, Canada.

Environmental risk assessment is often challenged by a lack of toxicity data for ecological species. The overall goal of the present study was to employ an avian early-life stage toxicity test to determine the effects of 4 chemicals (benzo[a]pyrene [BaP], chlorpyrifos, fluoxetine hydrochloride [FLX], and ethinyl estradiol [EE2]) on an ecologically relevant avian species, the double-crested cormorant (Phalacrocorax auritus), and to compare our results with those we previously reported for a laboratory model species, Japanese quail. Chemicals were dissolved in dimethyl sulfoxide and administered via air cell injection to fertilized, unincubated double-crested cormorant eggs at 3 nominal concentrations, the highest selected to approximate the 20% lethal dose. Of the 4 chemicals, only chlorpyrifos and FLX were detected in liver tissue of embryos at midincubation (day 14) and termination (day 26; 1-2 d prior to hatch); EE2 and BaP were not detectable, suggesting embryonic clearance/metabolism. No apical effects were observed in double-crested cormorant embryos up to the highest concentrations of chlorpyrifos (no-observed-effect level [NOEL] = 25 µg/g) or FLX (NOEL = 18 µg/g). Exposure to EE2 reduced embryonic viability and increased deformities at a concentration of 2.3 µg/g (NOEL = 0.18 µg/g), and BaP decreased embryonic viability (median lethal dose = 0.015 µg/g; NOEL = 0.0027 µg/g). Compared with Japanese quail, double-crested cormorant were more sensitive with regard to embryolethality and deformities for EE2 and embryolethality for BaP, whereas they were less sensitive to embryonic deformities associated with chlorpyrifos exposure. These data reinforce the idea that standardized toxicity tests using a laboratory model species may not always be protective of wild birds, and thus they stress the importance of developing such alternative testing strategies (e.g., the EcoToxChip Project) for ecologically relevant species to augment risk assessment efforts. Environ Toxicol Chem 2021;40:390-401. © 2020 SETAC.
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http://dx.doi.org/10.1002/etc.4922DOI Listing
February 2021

Drivers of and Obstacles to the Adoption of Toxicogenomics for Chemical Risk Assessment: Insights from Social Science Perspectives.

Environ Health Perspect 2020 10 28;128(10):105002. Epub 2020 Oct 28.

University of Sydney Business School and University of Sydney Nano Institute, Sydney, New South Wales, Australia; Department of Chemistry, Faculty of Science, McGill University, Montreal, Quebec, Canada.

Background: Some 20 y ago, scientific and regulatory communities identified the potential of omics sciences (genomics, transcriptomics, proteomics, metabolomics) to improve chemical risk assessment through development of toxicogenomics. Recognizing that regulators adopt new scientific methods cautiously given accountability to diverse stakeholders, the scope and pace of adoption of toxicogenomics tools and data have nonetheless not met the ambitious, early expectations of omics proponents.

Objective: Our objective was, therefore, to inventory, investigate, and derive insights into drivers of and obstacles to adoption of toxicogenomics in chemical risk assessment. By invoking established social science frameworks conceptualizing innovation adoption, we also aimed to develop recommendations for proponents of toxicogenomics and other new approach methodologies (NAMs).

Methods: We report findings from an analysis of 56 scientific and regulatory publications from 1998 through 2017 that address the adoption of toxicogenomics for chemical risk assessment. From this purposeful sample of toxicogenomics discourse, we identified major categories of drivers of and obstacles to adoption of toxicogenomics tools and data sets. We then mapped these categories onto social science frameworks for conceptualizing innovation adoption to generate actionable insights for proponents of toxicogenomics.

Discussion: We identify the most salient drivers and obstacles. From 1998 through 2017, adoption of toxicogenomics was understood to be helped by drivers such as those we labeled , , and but hindered by obstacles such as those we labeled , , and . Leveraging social science frameworks, we find that arguments for adoption that draw on the most salient drivers, which emphasize superior and novel functionality of omics as rationales, overlook potential adopters' key concerns: simplicity of use and compatibility with existing practices. We also identify two perspectives-innovation-centric and adopter-centric-on omics adoption and explain how overreliance on the former may be undermining efforts to promote toxicogenomics. https://doi.org/10.1289/EHP6500.
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http://dx.doi.org/10.1289/EHP6500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592882PMC
October 2020

Polycyclic aromatic compounds (PACs) and trace elements in four marine bird species from northern Canada in a region of natural marine oil and gas seeps.

Sci Total Environ 2020 Nov 15;744:140959. Epub 2020 Jul 15.

Department of Biology, Acadia University, Wolfville, NS, Canada.

There is a growing understanding of how oil pollution can affect aquatic ecosystems, including physical and chemical effects. One of the biggest challenges with detecting the effects of oil-related contaminants on biota from resource development is understanding the background levels and potential effects of the exposure of biota to contaminants from various natural and anthropogenic sources prior to large scale oil and gas operations. Seabirds are effective indicators of pollution, and can be useful for tracking oil-related contaminants in the marine environment. We sampled four seabird species (black guillemot, Cepphus grylle; thick-billed murre, Uria lomvia; black-legged kittiwake, Rissa tridactyla; and northern fulmar, Fulmarus glacialis) in the Baffin Bay-Davis Strait region of the Northwest Atlantic and Arctic oceans, an area where natural oil and gas seeps are present but lacking any large-scale oil and gas projects. We found detectable levels of PACs and several trace elements in all species examined. Alkylated PAC levels were higher than parent compounds in all four seabird species examined, with fulmars and murres having the highest levels detected; mean hepatic concentrations of ∑PAC were 99.05, 46.42, 12.78 and 9.57 ng/g lw, respectively, for guillemots, murres, fulmars and kittiwakes. Overall, PAC concentrations in the seabird species examined were similar to PAC concentrations measured in other bird species in regions with more industrialization. These findings provide data which can be used to assess the current oil-related contaminant exposure of biota in the region. As well, they provide background levels for the region at a time when shipping activity is relatively low, which can used for future comparisons following expected increases in shipping and oil and gas activities in the region.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140959DOI Listing
November 2020

Toxicogenomic Assessment of Complex Chemical Signatures in Double-Crested Cormorant Embryos from Variably Contaminated Great Lakes Sites.

Environ Sci Technol 2020 06 5;54(12):7504-7512. Epub 2020 Jun 5.

National Wildlife Research Centre, Environment and Climate Change Canada, Ottawa K1A 0H3, Ontario, Canada.

Using omics approaches to monitor complex environmental mixtures is challenging. Previously, we evaluated transcriptomic effects of complex organic extracts derived from avian eggs. However, there is a lack of studies using wild species that are naturally exposed to contaminant mixtures. Here, we examined polychlorinated biphenyl (PCB) and polybrominated diphenyl ether (PBDE) residues and gene expression in embryonic liver tissue of double-crested cormorants () collected from six variably contaminated colonies. Colonies near industrialized areas were distinguished from less contaminated sites based on their PCB and PBDE concentrations. The most variably expressed genes between sites were involved in pathways including, xenobiotic metabolism (e.g., ), lipid/bile acid homeostasis (e.g., ), and oxidative stress (e.g., ). Hierarchical clustering, based on relative gene expression, revealed a grouping pattern similar to chemical residue concentrations. Further, partial least squares regression analysis was used to estimate chemical concentrations from transcriptomics data. PCB 155 and BDE 47 showed the highest slopes (0.77 and 0.69, respectively) fitted by linear regression of measured and estimated chemical concentrations. The application of transcriptomics to a wild avian species, naturally exposed to complex chemical mixtures and other stressors, represents a promising means to distinguish and prioritize variably contaminated sites.
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http://dx.doi.org/10.1021/acs.est.0c02725DOI Listing
June 2020

Evaluation of the Aryl Hydrocarbon Receptor Response in LMH 3D Spheroids.

Environ Toxicol Chem 2020 09 1;39(9):1693-1701. Epub 2020 Jul 1.

National Wildlife Research Centre, Environment and Climate Change Canada, Ottawa, Ontario, Canada.

In the present study, we investigated whether the immortalized chicken hepatocellular carcinoma cell line, leghorn male hepatoma (LMH), had a comparable aryl hydrocarbon receptor (AhR) response to primary chicken embryonic hepatocytes (CEHs) when used in a well-established assay for chemical screening and prioritization. The LMH cells were grown as 2-dimensional (2D) confluent cells and 3D spheroids to determine the optimal cell culture states for chemical screening. Cytochrome P450 1A4 and 1A5 (CYP1A) activity and gene expression were compared between CEHs and LMH cells grown in 2 culture states following exposure to the dioxin-like compound 3,3',4,4',5-pentachlorobiphenyl (PCB-126). The CYP1A activity was measured using the ethoxyresorufin-O-deethylase (EROD) assay, and changes in mRNA expression associated with the AhR pathway were determined using a custom-designed polymerase chain reaction array. Among LMH cell culture states (i.e., 2D vs 3D), EROD induction was observed only in 3D LMH spheroids. Similarly, 3D spheroids had the greatest number of changes in AhR-related genes compared with confluent cells. Overall, these results suggest that LMH cells grown as 3D spheroids have a metabolic and gene expression profile that is comparable to that of CEH, and may represent a suitable animal-free alternative for in vitro screening of chemicals. Environ Toxicol Chem 2020;39:1693-1701. © 2020 SETAC.
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http://dx.doi.org/10.1002/etc.4783DOI Listing
September 2020

EcoToxModules: Custom Gene Sets to Organize and Analyze Toxicogenomics Data from Ecological Species.

Environ Sci Technol 2020 04 10;54(7):4376-4387. Epub 2020 Mar 10.

Faculty of Agricultural and Environmental Sciences, McGill University, Sainte-Anne-de-Bellevue H9X 3V9, Canada.

Traditional results from toxicogenomics studies are complex lists of significantly impacted genes or gene sets, which are challenging to synthesize down to actionable results with a clear interpretation. Here, we defined two sets of 21 custom gene sets, called the functional and statistical EcoToxModules, in fathead minnow () to (1) re-cast predefined molecular pathways into a toxicological framework and (2) provide a data-driven, unsupervised grouping of genes impacted by exposure to environmental contaminants. The functional EcoToxModules were identified by re-organizing KEGG pathways into biological processes that are more relevant to ecotoxicology based on the input from expert scientists and regulators. The statistical EcoToxModules were identified using co-expression analysis of publicly available microarray data ( = 303 profiles) measured in livers of fathead minnows after exposure to 38 different conditions. Potential applications of the EcoToxModules were demonstrated with two case studies that represent exposure to a pure chemical and to environmental wastewater samples. In comparisons to differential expression and gene set analysis, we found that EcoToxModule responses were consistent with these traditional results. Additionally, they were easier to visualize and quantitatively compare across different conditions, which facilitated drawing conclusions about the relative toxicity of the exposures within each case study.
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http://dx.doi.org/10.1021/acs.est.9b06607DOI Listing
April 2020

Factors Affecting the Perception of New Approach Methodologies (NAMs) in the Ecotoxicology Community.

Integr Environ Assess Manag 2020 Mar 24;16(2):269-281. Epub 2020 Feb 24.

McGill University, Natural Resource Sciences, Ste Anne de Bellevue, Canada.

Given current legislative mandates to assess the safety of thousands of chemicals and the slow pace at which conventional testing proceeds, there is a need to accelerate chemical risk assessment. Governments and businesses are increasingly interested in new approach methodologies (NAMs) that promise to reduce costs and delays. We explore 5 sociological factors within the ecotoxicology community that can influence the perception of NAMs: 1) professional profile (educational cohort, employer), 2) internal science communication within professional forums, 3) concern for "error cost," 4) collaboration across stakeholders, and 5) fundamental beliefs regarding toxicology. We conducted an online survey (n = 171; 2018) asking participants about their experiences and perspectives at events of the Society of Environmental Toxicology and Chemistry (SETAC) to assess 1) how NAMs are discussed compared to conventional testing and 2) how respondents perceive their viability. We developed ordered logistic regression (OLR) models to understand the influence of exploratory variables (cohort, core views on toxicology, frequency of collaboration) on respondents' evaluation of the viability of different NAMs. Our results showed that 1) NAMs were more likely than conventional methods to be challenged in forum discussions, which may be fueled by concerns for error costs in regulatory decision making; 2) perceptions of the viability of NAMs tended to follow a "pattern of familiarity," whereby respondents that were more knowledgeable about a test method tended to find it more viable; 3) respondents who agreed with the Paracelsus maxim had a greater likelihood of finding conventional testing viable; and 4) the more a respondent reported collaborating with industry on alternative testing strategies, the more likely she or he was to report that NAMs were less viable. These results suggest that there are professional and organizational barriers to greater acceptance of NAMs that can be addressed through a social learning process within the professional community. Integr Environ Assess Manag 2020;16:269-281. © 2020 SETAC.
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http://dx.doi.org/10.1002/ieam.4244DOI Listing
March 2020

Computational evaluation of interactions between organophosphate esters and nuclear hormone receptors.

Environ Res 2020 03 4;182:108982. Epub 2019 Dec 4.

Environment and Climate Change Canada, National Wildlife Research Centre, 1125 Colonel By Drive, K1A 0H3, Ottawa, Canada.

Organophosphate esters (OPEs) have gained considerable interest from many environmental chemists and toxicologists due to their frequent detection in the environment and potential adverse effects on health. Nuclear hormone receptors (NHRs) were found to mediate many of their adverse effects. However, our knowledge regarding the direct binding and interaction between OPEs and NHRs is limited. In this study, Endocrine Disruptome, an online computational tool based on the technique of inverse docking, was used to calculate the binding affinity score of 25 individual OPEs with 12 different human NHRs. Results showed that 20% of potential binding interactions between the OPEs and NHRs had medium-to-high probabilities. The accuracy, sensitivity and specificity of the predictions were 78.8, 60.0 and 80.9%, respectively. OPEs with a benzene ring were more active than those without, among which, tri-o-tolyl phosphate and tri-m-tolyl phosphate displayed the highest activities, suggesting that they might pose the greatest potential risks for interference with endocrine functions. In addition, the antagonistic conformations of androgen receptor and estrogen receptor β were found to be the two most vulnerable NHR conformations. Our findings can further the understanding about the health risk(s) of OPEs.
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http://dx.doi.org/10.1016/j.envres.2019.108982DOI Listing
March 2020

Persistent, bioaccumulative, and toxic properties of liquid crystal monomers and their detection in indoor residential dust.

Proc Natl Acad Sci U S A 2019 Dec 9. Epub 2019 Dec 9.

Jiangsu Key Laboratory of Chemical Pollution Control and Resources Reuse, School of Environmental and Biological Engineering, Nanjing University of Science and Technology, 210094 Nanjing, People's Republic of China;

Liquid crystal monomers (LCMs) are used widely in liquid crystal displays (LCDs), which are dramatically changing the world due to the provision of convenient communication. However, there are essentially no published reports on the fate and/or effects of LCMs in the environment. Of 362 currently produced LCMs, 87 were identified as persistent and bioaccumulative (P&B) chemicals, which indicated that these chemicals would exhibit resistance to degradation and exhibit mobility after entering the environment. Following exposure to mixtures of LCM collected from 6 LCD devices, significant modulation of 5 genes, , , , , and , was observed in vitro. Modulation of expressions of mRNAs coding for these genes has frequently been reported for toxic (T) persistent organic pollutants (POPs). In LCM mixtures, 33 individual LCMs were identified by use of mass spectrometry and screened for in 53 samples of dust from indoor environments. LCMs were detectable in 47% of analyzed samples, and 17 of the 33 LCMs were detectable in at least 1 sample of dust. Based on chemical properties, including P&B&T of LCMs and their ubiquitous detection in dust samples, the initial screening information suggests a need for studies to determine status and trends in concentrations of LCMs in various environmental matrices as well as tissues of humans and wildlife. There is also a need for more comprehensive in vivo studies to determine toxic effects and potencies of LCMs during chronic, sublethal exposures.
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http://dx.doi.org/10.1073/pnas.1915322116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936347PMC
December 2019

T1000: a reduced gene set prioritized for toxicogenomic studies.

PeerJ 2019 29;7:e7975. Epub 2019 Oct 29.

Institute of Parasitology, McGill University, Montreal, Canada.

There is growing interest within regulatory agencies and toxicological research communities to develop, test, and apply new approaches, such as toxicogenomics, to more efficiently evaluate chemical hazards. Given the complexity of analyzing thousands of genes simultaneously, there is a need to identify reduced gene sets. Though several gene sets have been defined for toxicological applications, few of these were purposefully derived using toxicogenomics data. Here, we developed and applied a systematic approach to identify 1,000 genes (called Toxicogenomics-1000 or T1000) highly responsive to chemical exposures. First, a co-expression network of 11,210 genes was built by leveraging microarray data from the Open TG-GATEs program. This network was then re-weighted based on prior knowledge of their biological (KEGG, MSigDB) and toxicological (CTD) relevance. Finally, weighted correlation network analysis was applied to identify 258 gene clusters. T1000 was defined by selecting genes from each cluster that were most associated with outcome measures. For model evaluation, we compared the performance of T1000 to that of other gene sets (L1000, S1500, Genes selected by Limma, and random set) using two external datasets based on the rat model. Additionally, a smaller (T384) and a larger version (T1500) of T1000 were used for dose-response modeling to test the effect of gene set size. Our findings demonstrated that the T1000 gene set is predictive of apical outcomes across a range of conditions (e.g., and , dose-response, multiple species, tissues, and chemicals), and generally performs as well, or better than other gene sets available.
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http://dx.doi.org/10.7717/peerj.7975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824333PMC
October 2019

An Early-Life Stage Alternative Testing Strategy for Assessing the Impacts of Environmental Chemicals in Birds.

Environ Toxicol Chem 2020 01;39(1):141-154

Department of Natural Resource Sciences, McGill University, Montreal, Quebec, Canada.

Early-life stage (ELS) toxicity tests are recognized as an advancement over current testing methodologies in terms of cost, animal use, and biological relevance. However, standardized ELS tests are not presently available for some vertebrate taxa, including birds. The present study describes a Japanese quail (Coturnix japonica) ELS test that is a promising candidate for standardization and applies it to test 8 environmental chemicals (ethinylestradiol, benzo[a]pyrene, chlorpyrifos, fluoxetine, lead(II)nitrate, trenbolone, seleno-L-methionine, hexabromocyclododecane). Individual chemicals were injected into the air cell of unincubated Japanese quail eggs at 3 concentrations, all predicted to cause ≤20% mortality. Survival to embryonic day 16 was consistently high (>90%) among the vehicle-injected controls. All chemicals, except ethinylestradiol, were detected in liver tissue, most at concentrations suggestive of embryonic clearance. Adverse effects were observed for 5 of the 8 chemicals; chlorpyrifos (41.1 µg/g) significantly increased developmental abnormalities and decreased embryo and gallbladder mass. Ethinylestradiol (54.2 µg/g) and hexabromocyclododecane (0.02 µg/g) decreased embryo mass and tarsus length, respectively. Benzo[a]pyrene (0.83 µg/g) and fluoxetine hydrochloride (32.7 µg/g) exceeded the 20% mortality cutoff. No effects were observed following lead(II)nitrate, seleno-L-methionine, or trenbolone exposure up to 10.7, 0.07, and 4.4 µg/g, respectively. Overall, our ELS approach was time- and cost-effective, caused minimal mortality in controls, effectively delivered diverse chemicals to the embryo, and permitted identification of apical outcomes, all of which provide support toward standardization. Environ Toxicol Chem 2019;39:141-154. © 2019 SETAC.
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http://dx.doi.org/10.1002/etc.4582DOI Listing
January 2020

A comparative study of 3 alternative avian toxicity testing methods: Effects on hepatic gene expression in the chicken embryo.

Environ Toxicol Chem 2019 11 4;38(11):2546-2555. Epub 2019 Oct 4.

Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada.

There is growing interest in developing alternative methods to screen and prioritize chemical hazards, although few studies have compared responses across different methods. The objective of the present study was to compare 3 alternative liver methods derived from white Leghorn chicken (Gallus gallus domesticus): primary hepatocyte culture, liver slices, and liver from in ovo injected embryos. We examined hepatic gene expression changes after exposure to 3 chemicals (17β-trenbolone [17βT], 17β-estradiol [E2], and 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]) using a custom quantitative polymerase chain reaction (qPCR) array with 7 genes (vitellogenin [VTG], apolipoprotein [Apo], cytochrome P450 1A4 [CYP1A4], liver basic fatty acid binding protein [LBFABP], 3β hydroxysteroid dehydrogenase [HSD3β1], stearoyl coenzyme A desaturase [SCD], and estrogen sulfotransferase [SULT1E1]). Gene expression across the 3 methods was examined using hierarchical clustering. Up-regulation of CYP1A4 in response to TCDD was consistent across all methods, and the magnitude was higher in hepatocytes (>150-fold) compared with slices (>31-fold) and in ovo liver (>27-fold). In hepatocytes, SCD and VTG up-regulation in response to 17βT and E2 was >4-fold and 16-fold, respectively. The rank order of cases with significant changes in gene expression among the 3 methods was: hepatocytes (22) > in ovo liver (11) > liver slices (6). Hierarchical clustering grouped liver slices and in ovo liver as more similar, whereas hepatocytes were grouped separately from in ovo liver. More introspective comparisons are needed to understand how and why alternative methods differ and to aid in their integration into toxicity testing. Environ Toxicol Chem 2019;38:2546-2555. © 2019 SETAC.
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http://dx.doi.org/10.1002/etc.4555DOI Listing
November 2019

Extracts of Passive Samplers Deployed in Variably Contaminated Wetlands in the Athabasca Oil Sands Region Elicit Biochemical and Transcriptomic Effects in Avian Hepatocytes.

Environ Sci Technol 2019 Aug 19;53(15):9192-9202. Epub 2019 Jul 19.

Ecotoxicology and Wildlife Health Division , Environment and Climate Change Canada, National Wildlife Research Centre, Carleton University , Ottawa , Ontario K1A 0H3 , Canada.

Recent contaminant monitoring in boreal wetlands situated in Alberta's Athabasca oil sands region revealed increased concentrations of polycyclic aromatic compounds (PACs) in passive sampling devices deployed in wetlands close to bitumen surface mining operations. In this study, graded concentrations of semipermeable membrane device (SPMD) extracts, collected from 4 wetlands with variable burdens of PACs, were administered to chicken and double-crested cormorant (DCCO) embryonic hepatocytes to determine effects on 7-ethoxyresorufin--deethylase (EROD) activity and mRNA expression. Concentrations and composition of PACs detected in SPMDs varied among sites, and the proportion of alkyl PACs was greater than parent compounds at all sites. ΣPACs was the highest in SPMDs deployed within 10 km of mining activity (near-site wetland [5930 ng SPMD]) compared to those ∼50 km south (far-site wetland [689 ng SPMD]). Measures of EROD activity and mRNA expression allowed the ranking of wetland sites based on aryl hydrocarbon receptor-mediated end points; EROD activity and mRNA induction were the highest at the near-site wetland. ToxChip PCR arrays (one chicken and one DCCO) provided a more exhaustive transcriptomic evaluation across multiple toxicological pathways following exposure to the SPMD extracts. Study sites with the greatest PAC concentrations had the most genes altered on the chicken ToxChip (12-15/43 genes). Exposure of avian hepatocytes to SPMD extracts from variably contaminated wetlands highlighted traditional PAC-related toxicity pathways as well as other novel mechanisms of action. A novel combination of passive sampling techniques and high-throughput toxicity evaluation techniques shows promise in terms of identifying hotspots of chemical concern in the natural environment.
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http://dx.doi.org/10.1021/acs.est.9b02066DOI Listing
August 2019

Transcriptomic points-of-departure from short-term exposure studies are protective of chronic effects for fish exposed to estrogenic chemicals.

Toxicol Appl Pharmacol 2019 09 19;378:114634. Epub 2019 Jun 19.

National Wildlife Research Center, Environment and Climate Change Canada, Ontario, Canada. Electronic address:

Resource limitations often require risk assessors to extrapolate chronic toxicity from acute tests using assessment factors. Transcriptomic dose-response analysis following short-term exposures may provide a more reliable and biologically-based alternative for estimating chronic toxicity. Here, we demonstrate that transcriptomic dose-response analysis in fish following short-term exposure to endocrine disrupting chemicals (EDCs) provides estimates of chronic toxicity that may be used as protective points-of-departure (POD) for risk assessment. The benchmark dose (BMD) method was used on publicly available datasets (n = 5) to determine transcriptomic PODs in fish exposed to three EDCs (bisphenol A, ethinylestradiol, and diethylstilbestrol). To test for potential bias related to data processing, our analysis compared the effect of different normalization, filtering, and BMD-grouping methods on the transcriptomic PODs. The resulting PODs were then compared to the empirically-derived chronic LOEC of each substance. Normalization and filtering methods had limited impact on the final PODs. However, we found that PODs derived from ontology- or pathway-based gene grouping methods were highly variable, whereas PODs from grouping methods that focused on the most responsive genes were more stable and provided POD estimates that were most similar to the chronic LOEC. Overall, 72% of transcriptomic PODs were within 1 order of magnitude of the chronic LOEC, regardless of data analysis method. When our recommended analysis approach was applied, the concordance improved to 100%. These results suggest that toxicogenomic dose-response analysis has the potential to be a protective decision-support tool for compounds with chronic toxicity, such as EDCs.
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http://dx.doi.org/10.1016/j.taap.2019.114634DOI Listing
September 2019

EcoToxChip: A next-generation toxicogenomics tool for chemical prioritization and environmental management.

Environ Toxicol Chem 2019 02;38(2):279-288

Toxicology Center, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

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http://dx.doi.org/10.1002/etc.4309DOI Listing
February 2019
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