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From Extrapolation to Precision Chemical Hazard Assessment: The Ecdysone Receptor Case Study.

ABSTRACT: Hazard assessment strategies are often supported by extrapolation of damage probabilities, regarding chemical action and species susceptibilities. Yet, growing evidence suggests that an adequate sampling of physiological responses across a representative taxonomic scope is of paramount importance. This is particularly relevant for Nuclear Receptors (NR), a family of transcription factors, often triggered by ligands and thus, commonly exploited by environmental chemicals. Within NRs, the ligand-induced Ecdysone Receptor (EcR) provides a remarkable example. Long regarded as arthropod specific, this receptor has been extensively targeted by pesticides, seemingly innocuous to non-target organisms. Yet, current evidence clearly suggests a wider presence of EcR orthologues across metazoan lineages, with unknown physiological consequences. Here, we address the state-of-the-art regarding the phylogenetic distribution and functional characterization of metazoan EcRs and provide a critical analysis of the potential disruption of such EcRs by environmental chemical exposure. Using EcR as a case study, hazard assessment strategies are also discussed in view of the development of a novel "precision hazard assessment paradigm.

SUBMITTER: Ruivo R

PROVIDER: S-EPMC8778615 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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From Extrapolation to Precision Chemical Hazard Assessment: The Ecdysone Receptor Case Study.

Ruivo Raquel R Sousa João J Neuparth Teresa T Geffard Olivier O Chaumot Arnaud A Castro L Filipe C LFC Degli-Esposti Davide D Santos Miguel M MM

Toxics 20211227 1

Hazard assessment strategies are often supported by extrapolation of damage probabilities, regarding chemical action and species susceptibilities. Yet, growing evidence suggests that an adequate sampling of physiological responses across a representative taxonomic scope is of paramount importance. This is particularly relevant for Nuclear Receptors (NR), a family of transcription factors, often triggered by ligands and thus, commonly exploited by environmental chemicals. Within NRs, the ligand-i ...[more]

PMID: 35051048

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Project description:Toxicology is traditionally divided between human and eco-toxicology. In the shared pursuit of environmental health, this separation does not account for discoveries made in the comparative studies of animal genomes. Here, we provide evidence on the feasibility of understanding the health impact of chemicals on all animals, including ecological keystone species and humans, based on a significant number of conserved genes and their functional associations to health-related outcomes across much of animal diversity. We test four conditions to understand the value of comparative genomics data to inform mechanism-based human and environmental hazard assessment: (1) genes that are most fundamental for health evolved early during animal evolution; (2) the molecular functions of pathways are better conserved among distantly related species than the individual genes that are members of these pathways; (3) the most conserved pathways among animals are those that cause adverse health outcomes when disrupted; (4) gene sets that serve as molecular signatures of biological processes or disease-states are largely enriched by evolutionarily conserved genes across the animal phylogeny. The concept of homology is applied in a comparative analysis of gene families and pathways among invertebrate and vertebrate species compared with humans. Results show that over 70% of gene families associated with disease are shared among the greatest variety of animal species through evolution. Pathway conservation between invertebrates and humans is based on the degree of conservation within vertebrates and the number of interacting genes within the human network. Human gene sets that already serve as biomarkers are enriched by evolutionarily conserved genes across the animal phylogeny. By implementing a comparative method for chemical hazard assessment, human and eco-toxicology converge towards a more holistic and mechanistic understanding of toxicity disrupting biological processes that are important for health and shared among animals (including humans).

Dataset Information

From Extrapolation to Precision Chemical Hazard Assessment: The Ecdysone Receptor Case Study.

Publications

From Extrapolation to Precision Chemical Hazard Assessment: The Ecdysone Receptor Case Study.

Similar Datasets

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