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Transcriptional Responses as Biomarkers of General Toxicity: A Systematic Review and Meta-Analysis on Metal-Exposed Bivalves
University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Department of Biology, Lund University, Sweden. (Ekologisk modellering, Ecological modelling)ORCID iD: 0000-0002-2418-1163
Centre for Environmental and Climate Science, Lund University, Sweden.
University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. (Ekologisk modellering, Ecological modelling)ORCID iD: 0000-0002-3965-7371
Department of Biology, Lund University, Sweden.
2023 (English)In: Environmental Toxicology and Chemistry, ISSN 0730-7268, E-ISSN 1552-8618, Vol. 42, no 3, p. 628-641Article, review/survey (Refereed) Published
Abstract [en]

Through a systematic review and a series of meta-analyses, we evaluated the general responsiveness of putative transcriptional biomarkers of general toxicity and chemical stress. We targeted metal exposures performed on bivalves under controlled laboratory conditions, and selected six transcripts associated with general toxicity for evaluation: catalase (cat), glutathione-S-transferase (gst), heat shock proteins 70 and 90 (hsp70, hsp90), metallothionein (mt) and superoxide dismutase (sod). Transcriptional responses (n = 396) were extracted from published scientific articles (k = 22) and converted to log response ratios (lnRRs). By estimating toxic units (TUs), we normalized different metal exposures to a common scale, as a proxy of concentration. Using Bayesian hierarchical random effect models, we then tested the effects of metal exposure on lnRR, both for metal exposure in general and in meta-regressions using TU and exposure time as independent variables. Corresponding analyses were also repeated with transcript and tissue as additional moderators. Observed patterns were similar for general as for transcript- and tissue-specific responses. The expected overall response to arbitrary metal exposure was a lnRR of 0.50, corresponding to a 65 % increase relative a non-exposed control. However, when accounting for publication bias, the estimated ‘true’ response showed no such effect. Furthermore, expected response magnitude increased slightly with exposure time, but there was little support for general monotonic concentration-dependence with regards to TU. Altogether, this work reveals potential limitations that need consideration prior to applying the selected transcripts as biomarkers in environmental risk assessment. This article is protected by copyright. All rights reserved. Environ Toxicol Chem 2022;00:0–0. 

Place, publisher, year, edition, pages
John Wiley & Sons, 2023. Vol. 42, no 3, p. 628-641
Keywords [en]
Chemical analysis, Metals, Molluscs, Random processes, Risk assessment, Superoxide dismutase, Tissue, Toxicity, Aquatic toxicology, Bayesian statistics, Eco-toxicology, Meta-regression, Metal exposures, Mollusk toxicology, Publication bias, Risks assessments, Toxic unit, Transcriptional response, Biomarkers, ecotoxicology
National Category
Environmental Sciences Pharmacology and Toxicology Biochemistry and Molecular Biology Other Biological Topics
Research subject
Ecological Modelling Group
Identifiers
URN: urn:nbn:se:his:diva-22097DOI: 10.1002/etc.5494ISI: 000928969800001PubMedID: 36200657Scopus ID: 2-s2.0-85142195831OAI: oai:DiVA.org:his-22097DiVA, id: diva2:1715121
Note

CC BY 4.0

© 2022 SETAC. This article is protected by copyright. All rights reserved.

First published: 06 October 2022

Correspondence gustaf.ekelund_ugge@biol.lu.se

Available from: 2022-12-01 Created: 2022-12-01 Last updated: 2023-03-09Bibliographically approved
In thesis
1. Transcriptional biomarkers of toxicity – powerful tools or random noise?: An applied perspective from studies on bivalves
Open this publication in new window or tab >>Transcriptional biomarkers of toxicity – powerful tools or random noise?: An applied perspective from studies on bivalves
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Aquatic organisms are constantly at risk of being exposed to potentially harmful chemical compounds of natural or anthropogenic origin. Biological life can for instance respond to chemical stressors by changes in gene expression, and thus, certain gene transcripts can potentially function as biomarkers, i.e. early warnings, of toxicity and chemical stress. A major challenge for biomarker application is the extrapolation of transcriptional data to potential effects at the organism level or above. Importantly, successful biomarker use also requires basal understanding of how to distinguish actual responses from background noise. The aim of this thesis is, based on response magnitude and variation, to evaluate the biomarker potential in a set of putative transcriptional biomarkers of general toxicity and chemical stress.

Specifically, I addressed a selection of six transcripts involved in cytoprotection and oxidative stress: catalase (cat), glutathione-S-transferase (gst), heat shock proteins 70 and 90 (hsp70, hsp90), metallothionein (mt) and superoxide dismutase (sod). Moreover, I used metal exposures to serve as a proxy for general chemical stress, and due to their ecological relevance and nature as sedentary filter-feeders, I used bivalves as study organisms.

In a series of experiments, I tested transcriptional responses in the freshwater duck mussel, Anodonta anatina, exposed to copper or an industrial wastewater effluent, to address response robustness and sensitivity, and potential controlled (e.g. exposure concentration) and random (e.g. gravidness) sources of variation. In addition, I performed a systematic review and meta-analysis on transcriptional responses in metal exposed bivalves to (1) evaluate what responses to expect from arbitrary metal exposures, (2) assess the influence from metal concentration (expressed as toxic unit), exposure time and analyzed tissue, and (3) address potential impacts from publication bias in the scientific literature.

Response magnitudes were generally small in relationship to the observed variation, both for A. anatina and bivalves in general. The expected response to an arbitrary metal exposure would generally be close to zero, based on both experimental observations and on the estimated impact from publication bias. Although many of the transcripts demonstrated concentration-response relationships, large background noise might in practice obscure the small responses even at relatively high exposures. As demonstrated in A. anatina under copper exposure, this can be the case already for single species under high resolution exposures to single pollutants. As demonstrated by the meta-regression, this problem can only be expected to increase further upon extrapolation between different species and exposure scenarios, due to increasing heterogeneity and random variation. Similar patterns can also be expected for time-dependent response variation, although the meta-regression revealed a general trend of slightly increasing response magnitude with increasing exposure times.

In A. anatina, gravidness was identified as a source of random variability that can potentially affect the baseline of most assessed biomarkers, particularly when quantified in gills. Response magnitudes and variability in this species were generally similar for selected transcripts as for two biochemical biomarkers included for comparison (AChE, GST), suggesting that the transcripts might not capture early warnings more efficiently than other molecular endpoints that are more toxicologically relevant. Overall, high concentrations and long exposure durations presumably increase the likelihood of a detectable transcriptional response, but not to an extent that justifies universal application as biomarkers of general toxicity and chemical stress. Consequently, without a strictly defined and validated application, this approach on its own appears unlikely to be successful for future environmental risk assessment and monitoring. Ultimately, efficient use of transcriptional biomarkers might require additional implementation of complementary approaches offered by current molecular techniques.

Place, publisher, year, edition, pages
Lund: Lund University (Media-Tryck), 2023. p. 199
Keywords
Biomarkers, Bivalves, Bivalvia, Ecotoxicology, Environmental toxicology, Environmental risk assessment, RT-qPCR, qPCR, Quantitative PCR, Systematic review, Meta-analysis, Dose-response relationships, Concentration-response relationships, Heavy metals, Metals, General toxicity, Copper, Duck mussel, Anodonta anatina, Freshwater, Gene transcription, Biomarkörer, Musslor, Bivalvia, Ekotoxikologi, Miljötoxikologi, Miljöriskbedömning, RT-qPCR, qPCR, Kvantitativ PCR, Systematic review, Metaanalys, Dos-responssamband, Koncentration-responssamband, Tungmetaller, Metaller, Allmän toxicitet, Koppar, Allmän dammussla, Anodonta anatina, Sötvatten, Gentranskription
National Category
Biochemistry and Molecular Biology Pharmacology and Toxicology Environmental Sciences Genetics Ecology
Research subject
Ecological Modelling Group
Identifiers
urn:nbn:se:his:diva-22180 (URN)978-91-8039-496-3 (ISBN)978-91-8039-495-6 (ISBN)
Public defence
2023-02-10, Blå hallen, Sölvegatan 37, Lund, 09:00 (English)
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Supervisors
Available from: 2023-01-12 Created: 2023-01-12 Last updated: 2023-01-25Bibliographically approved

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Ekelund Ugge, Gustaf Magnus OskarJonsson, Annie

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