Transcriptomic and Network Analyses Reveal Mechanistic-Based Biomarkers of Endocrine Disruption in the Marine Mussel, <i>Mytilus edulis</i>

Blalock, Bonnie J.; Robinson, William E.; Loguinov, Alex; Vulpe, Chris D.; Krick, Keegan S.; Poynton, Helen C.

doi:10.1021/acs.est.8b01604

Cited by 49 publications

(26 citation statements)

References 95 publications

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“…A review of research on the identification and functioning of invertebrate receptors and pathways, in comparison to those in their vertebrate counterparts can be found in Lafont & Mathieu (2007). More recently Blalock et al (2018) have reported evidence of a cholesterol side chain cleavage enzyme consistent with endogenous production of steroids and oestrogen signalling pathway, as a likely mechanism of action in mussels M. edulis exposed to 17-α-ethinylestradiol and 4-nonylphenol. A ligand-activated ER-like receptor has also been found in reproductive tissue of marine rotifers Brachionus manjavacas (Fontaneto, Giordani, Melone & Serra, 2007) which appears to bind human oestradiol and regulates reproductive output in females.…”

Section: Invertebratesmentioning

confidence: 99%

Endocrine disruption and altered sexual development in aquatic organisms: an invertebrate perspective

Langston

2020

J. Mar. Biol. Ass.

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Contaminants causing sex-altering, endocrine disrupting-like (ED) effects, or otherwise influencing reproduction, have been of growing concern to humans for more than 50 years. They have also been a perturbing, though less well-studied, phenomenon in marine organisms, following the recognition of tributyltin (TBT)-induced imposex and population extinctions in (neo)gastropods in the 1970s. Whilst ED impacts in mammals and fish are characterized by mimicry or antagonism of endogenous hormones by environmental contaminants (acting through Nuclear Receptors which are present in all metazoans) much less is known regarding pathways to effects in invertebrates. Despite the absence of a defined steroidal/mechanistic component, the extent, severity and widespread nature of ED-like manifestations and altered sexual characteristics observed in marine invertebrates gives rise to comparable concerns, and have been a long-term component of the MBA's research remit. The manifestations seen in sensitive taxa such as molluscs and crustaceans confirm they are valuable indicators of environmental quality, and should be exploited in this capacity whilst we seek to understand the pervasiveness and underlying mechanisms. In so doing, invertebrate indicators address aims of organizations, such as the EEA, OECD, UNEP and WHO, charged with management and monitoring of chemicals and ensuring that adverse effects on humans and the environment are minimized (Bergman et al., 2013). In view of the recent general declines in marine biodiversity, and the potential contribution of ED-like phenomena, safeguarding against deleterious effects through increased research which links pollutant exposure with reproductive dysfunction among invertebrates, is seen as a high priority.

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Section: Invertebratesmentioning

confidence: 99%

Endocrine disruption and altered sexual development in aquatic organisms: an invertebrate perspective

Langston

2020

J. Mar. Biol. Ass.

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“…Presence of numerous contaminants from various (e.g., wastewater effluent, industrial wastewater discharge, oil and chemical spills, urban runoff, agricultural runoff) sources make the risk assessment and monitoring challenging. 17 High-throughput in vitro assays and AOP-based approach is promising for the assessment of health and ecotoxicological risks from exposure to pollutants and their mixtures. [17][18][19][20][21] Establishment of a quantitative AOP framework through integration of computational modeling with in-vitro assays would require identification and selection of relevant biomarkers from appropriate bioassays that link to risk assessment pathways and phenotypic impacts.…”

Section: Environmental Implicationsmentioning

confidence: 99%

“…17 High-throughput in vitro assays and AOP-based approach is promising for the assessment of health and ecotoxicological risks from exposure to pollutants and their mixtures. [17][18][19][20][21] Establishment of a quantitative AOP framework through integration of computational modeling with in-vitro assays would require identification and selection of relevant biomarkers from appropriate bioassays that link to risk assessment pathways and phenotypic impacts. 18,21,66 Current toxicomics approach still mostly rely on large number of redundant markers without pre-selection or ranking; 3,51,67 therefore, selection of relevant biomarkers with minimal redundancy would reduce the number of markers to be monitored and reduce the cost, time, and complexity of the toxicity risk monitoring.…”

Section: Environmental Implicationsmentioning

confidence: 99%

“…[9][10][11][12][13][14][15][16] Adverse-outcome pathway (AOP) framework is the state-of-the-art approach to link mechanistic toxicity mechanisms with the phenotypic adverse outcome that would enable the assessment of health risk as well as ecotoxicological risks from exposure to pollutants and their mixtures. [17][18][19][20][21] Coalesce of effective biomarkers and proper predicting framework would enable more cost-effective and wider implementation of toxicomics in monitoring of genotoxicity and predict adverse toxic responses. 22-our ability to link molecular-level effects recorded in in-vitro assays to the in-vivo regulatory relevant phenotypic endpoints, or system-level impacts in many fields such as, environmental toxicity, disease prediction and health risk identification.…”

Section: Introductionmentioning

confidence: 99%

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Machine Learning-based Biomarkers Identification and Validation from Toxicogenomics - Bridging to Regulatory Relevant Phenotypic Endpoints

Rahman

Lan

Kaeli

et al. 2020

Preprint

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High-throughput in vitro assays and AOP-based approach is promising for the assessment of health and ecotoxicological risks from exposure to pollutants and their mixtures. However, one of the major challenges in realization and implementations of the Tox21 vision is the urgent need to establish quantitative link between in-vitro assay molecular endpoint and in-vivo phenotypic toxicity endpoint. Here, we demonstrated that, using time series toxicomics in-vitro assay along with machine learning-based feature selection (MRMR) and classification method (SVM), an “optimal” number of biomarkers with minimum redundancy can be identified for prediction of phenotypic endpoints with good accuracy. We included two case studies for in-vivo carcinogenicity and Ames genotoxicity prediction with 20 selected chemicals including model genotoxic chemicals and negative controls, respectively, using an in-vitro toxicogenomic assay that captures real-time proteomic response data of 38 GFP-fused proteins of S. cerevisiae strains covering biomarkers indicative of all known DNA damage and repair pathways in yeast. The results suggested that, employing the adverse outcome pathway (AOP) concept, molecular endpoints based on a relatively small number of properly selected biomarker-ensemble involved in the conserved DNA-damage and repair pathways among eukaryotes, were able to predict both in-vivo carcinogenicity in rats and Ames genotoxicity endpoints. The specific biomarkers identified are different for the two different phenotypic genotoxicity assays. The top-ranked five biomarkers for the in-vivo carcinogenicity prediction mainly focused on double strand break repair and DNA recombination, whereas the selected top-ranked biomarkers for Ames genotoxicity prediction are associated with base- and nucleotide-excision repair. Current toxicomics approach still mostly rely on large number of redundant markers without pre-selection or ranking, therefore, selection of relevant biomarkers with minimal redundancy would reduce the number of markers to be monitored and reduce the cost, time, and complexity of the toxicity screening and risk monitoring. The method developed in this study will help to fill in the knowledge gap in phenotypic anchoring and predictive toxicology, and contribute to the progress in the implementation of tox 21 vision for environmental and health applications.TOC Art

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“…More recently, toxicogenomics data mining and in silico techniques have been gradually developing as efficient approaches to speed up AOP development. − Premier public resources (such as the Comparative Toxicogenomics Database (CTD), ToxCast, AOP Wiki database, etc.) can provide a chance to generate analytical toxic pathways. ,− Oki and Edwards generated multiple AOP predictions by evaluating the associations of chemical–gene–disease data in the CTD . Jeong et al developed AOPs using mammalian toxicity data obtained from ToxCast .…”

Section: Introductionmentioning

confidence: 99%

Integration of Computational Toxicology, Toxicogenomics Data Mining, and Omics Techniques to Unveil Toxicity Pathways

Wang

Chen

et al. 2021

ACS Sustainable Chem. Eng.

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Growing numbers of synthetic chemicals have potential endocrine-disrupting effects and cause potential ecological and health risks. However, the primary toxicity pathways and mechanisms of endocrine disruption are poorly understood and the existing risk assessment relies heavily on animal testing. Database mining, omics technology, and computer simulation can serve as an alternative approach to explore the mechanisms by building adverse outcome pathways (AOPs). The present study took a case of thyroid interference with triphenyl phosphate (TPP) to explain the potential toxic effects at levels from submolecules to cells utilizing the AOP framework developed by multiple techniques. This study retrieved the data from a comparative toxicogenomics database (CTD) and screened out the core gene. Molecular dynamics (MD) analysis was used to explore configuration changes and confirm the molecular initiating event (MIE). The transcriptomic analysis was further utilized to supplement the relationships between MIEs and key events (KEs) of the AOP. The thyroid hormone receptor beta (THRB) was identified as the core gene at submolecular levels. MD analysis found that the configuration changes of C-terminal helix 12 (H12) of thyroid hormone receptor β (TRβ) were discovered as the MIE. The transcriptomic analysis extended the related KE1 at the subcellular level, such as changes in gene expression levels for coding cycle regulation (CCND1), inflammatory response (IL1A and IL6), and cell proliferation and apoptosis (BAD, TP53, and CASP9). Then, the KE2 at cellular levels such as apoptosis, cell cycle control, and cell proliferation were influenced accordingly. As a result, these alterations led to thyroid disorder as adverse outcomes. This study provided an efficient way to facilitate the complement of possible AOPs and brought new insights into understanding the toxic mechanisms of emerging synthetic chemicals.

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Transcriptomic and Network Analyses Reveal Mechanistic-Based Biomarkers of Endocrine Disruption in the Marine Mussel, Mytilus edulis

Cited by 49 publications

References 95 publications

Endocrine disruption and altered sexual development in aquatic organisms: an invertebrate perspective

Endocrine disruption and altered sexual development in aquatic organisms: an invertebrate perspective

Machine Learning-based Biomarkers Identification and Validation from Toxicogenomics - Bridging to Regulatory Relevant Phenotypic Endpoints

Integration of Computational Toxicology, Toxicogenomics Data Mining, and Omics Techniques to Unveil Toxicity Pathways

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