Evidence for Cross Species Extrapolation of Mammalian-Based High-Throughput Screening Assay Results

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Feminization of male fish and the role of endocrine-active chemicals in this phenomenon has been an area of intense study for many years. Estrone (E1), a natural steroid, is found in aquatic environments sometimes at high concentrations relative to the estrogenic steroids 17β-estradiol (E2) and 17α-ethynylestradiol. However, E1 has been less thoroughly studied than E2 or 17α-ethynylestradiol due in part to a relatively lower potency in metabolically limited estrogen receptor (ER) binding/activation assays. Recent evidence suggests that in vivo biotransformation of E1 to E2 may occur in fathead minnows (Pimephales promelas) residing in environments with high concentrations of E1, such as near wastewater treatment plants. The enzymes likely responsible for this biotransformation, 17β-hydroxysteroid dehydrogenases (17βHSDs), have been well characterized in mammals but to a lesser extent in fish species. In the present study, a novel systematic analysis of amino acid sequence data from the National Center for Biotechnology Information database demonstrated that multiple 17βHSD isoforms are conserved across different fish species. Experimentally, we showed that metabolically active hepatic cytosolic preparations from 2 commercially important salmonid species, rainbow trout and lake trout, biotransformed E1 to E2 to a degree sufficient to alter results of competitive ER binding assays. These results from in silico and in vitro analyses indicate that E1 and biotransformation may play a significant role in adverse effects on development and reproduction of a variety of fish species in contaminated aquatic environments.

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Conversion of Estrone to 17β-Estradiol: A Potential Confounding Factor in Assessing Risks of Environmental Estrogens to Fish

Tapper

Kolanczyk

LaLone

et al. 2020

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“…Although ER and AR homology provides some information about pathway conservation, data are needed to compare responses in estrogen and androgen biosynthesis between mammals, fish, birds, and amphibians. Recent work with SeqAPASS and ToxCast/Tox21 mammalian‐based HTP assays showed a high degree of conservation between human and vertebrate ARs, steroidogenesis enzymes, and thyroid receptors and enzymes for most vertebrate groups (LaLone et al 2018). However, enzymes involved in glucocorticoid synthesis in some classes, such as Aves (birds) and Chondrichthyes (cartilaginous fishes), differed from human, and a 17β‐hydroxy‐steroid dehydrogenase differed between Lepidosauria (reptilian group) and Chondrichthyes compared with human (LaLone et al 2018).…”

Section: Biological Read‐across For Eatsmentioning

confidence: 99%

“…Recent work with SeqAPASS and ToxCast/Tox21 mammalian‐based HTP assays showed a high degree of conservation between human and vertebrate ARs, steroidogenesis enzymes, and thyroid receptors and enzymes for most vertebrate groups (LaLone et al 2018). However, enzymes involved in glucocorticoid synthesis in some classes, such as Aves (birds) and Chondrichthyes (cartilaginous fishes), differed from human, and a 17β‐hydroxy‐steroid dehydrogenase differed between Lepidosauria (reptilian group) and Chondrichthyes compared with human (LaLone et al 2018). These results for protein homology can be used as a line of evidence for pathway homology, but several factors (as discussed in the section Considerations and Limitations for Applying Biological Read‐Across Approaches ) can influence susceptibility to a chemical.…”

Section: Biological Read‐across For Eatsmentioning

confidence: 99%

Critical Review of Read-Across Potential in Testing for Endocrine-Related Effects in Vertebrate Ecological Receptors

McArdle

Freeman

Staveley

et al. 2020

Recent regulatory testing programs have been designed to evaluate whether a chemical has the potential to interact with the endocrine system and could cause adverse effects. Some endocrine pathways are highly conserved among vertebrates, providing a potential to extrapolate data generated for one vertebrate taxonomic group to others (i.e., biological read‐across). To assess the potential for biological read‐across, we reviewed tools and approaches that support species extrapolation for fish, amphibians, birds, and reptiles. For each of the estrogen, androgen, thyroid, and steroidogenesis (EATS) pathways, we considered the pathway conservation across species and the responses of endocrine‐sensitive endpoints. The available data show a high degree of confidence in the conservation of the hypothalamus–pituitary–gonadal axis between fish and mammals and the hypothalamus–pituitary–thyroid axis between amphibians and mammals. Comparatively, there is less empirical evidence for the conservation of other EATS pathways between other taxonomic groups, but this may be due to limited data. Although more information on sensitive pathways and endpoints would be useful, current developments in the use of molecular target sequencing similarity tools and thoughtful application of the adverse outcome pathway concept show promise for further advancement of read‐across approaches for testing EATS pathways in vertebrate ecological receptors. Environ Toxicol Chem 2020;39:739–753. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

High-throughput screening and environmental risk assessment: State of the science and emerging applications

Villeneuve

Coady

Escher

et al. 2019

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In 2007 the United States National Research Council (NRC) published a vision for toxicity testing in the 21st century that emphasized the use of in vitro high‐throughput screening (HTS) methods and predictive models as an alternative to in vivo animal testing. In the present study we examine the state of the science of HTS and the progress that has been made in implementing and expanding on the NRC vision, as well as challenges to implementation that remain. Overall, significant progress has been made with regard to the availability of HTS data, aggregation of chemical property and toxicity information into online databases, and the development of various models and frameworks to support extrapolation of HTS data. However, HTS data and associated predictive models have not yet been widely applied in risk assessment. Major barriers include the disconnect between the endpoints measured in HTS assays and the assessment endpoints considered in risk assessments as well as the rapid pace at which new tools and models are evolving in contrast with the slow pace at which regulatory structures change. Nonetheless, there are opportunities for environmental scientists and policymakers alike to take an impactful role in the ongoing development and implementation of the NRC vision. Six specific areas for scientific coordination and/or policy engagement are identified. Environ Toxicol Chem 2019;38:12–26. Published 2018 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.