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

Abstract

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.

Summary of reference chemicals evaluated by the fish short‐term reproduction assay, OECD TG229, using Japanese Medaka,Oryzias latipes

“…The literature on adverse effects on reproduction of fish caused by several estrogenic substances, such as 17 β ‐estradiol (E2), 17 α ‐ethynylestradiol (EE2), and alkylphenols, has seen numerous papers published since the late 1990s when EDC issues became apparent (Hara, Hiramatsu, & Fujita, 2016 ; Matthiessen, Wheeler, & Weltje, 2018 ; OECD, 2009b ; Urushitani et al, 2007 ). Moreover, much research has been conducted to develop novel test methods, biomarkers and endpoints and select test species to assess various adverse effects that might be related to the endocrine system (Carnevali, Santangeli, Forner‐Piquer, & Basili, 2018 ; Manibusan & Touart, 2017 ; McArdle et al, 2020 ). On the other hand, there are studies in which multiple chemical substances in various modes of action (MOA) are comparably evaluated by a unified test species, conditions, and procedures, like a screening test in regulatory use.…”

Molecular Image-Based Prediction Models of Nuclear Receptor Agonists and Antagonists Using the DeepSnap-Deep Learning Approach with the Tox21 10K Library

“…Many chemical substances have potential harmful effects, causing the perturbation of endocrine homeostasis by interfering with various nuclear receptors (NRs) of hormones [ 1 , 2 , 3 , 4 , 5 ]. In the disruption of hormone pathways, structurally diverse groups of chemicals are known to interact primarily with ligand–NR bindings, which have the ability to substitute for natural ligands, ultimately resulting in proliferative, reproductive, and metabolic disorders [ 6 , 7 , 8 , 9 , 10 , 11 , 12 ].…”

Roles of Estrogens in the Healthy and Diseased Oviparous Vertebrate Liver

“…When male fishes are exposed to estrogenic compounds present in the water, their otherwise silent vitellogenin genes are activated and transcribed at elevated levels in the liver, which can be measured at the mRNA and protein levels [136]. Activation of these genes in several species has become and remains a gold standard robust biomarker for exposure to estrogenic compounds in the water [137][138][139][140][141][142][143][144][145]. Recently, an ultrasensitive label-free electrochemical immunosensors for detecting marine medaka (Oryzias melastigma) vitellogenin was developed, and its reliability for the detection of xenoestrogens in the marine environment was validated [146].…”