Science Inventory

Ecdysone receptor agonism leading to lethal molting disruption in arthropods: Review and adverse outcome pathway development


Song, Y., Dan Villeneuve, K. Toyota, T. Iguchi, AND K. Tollefsen. Ecdysone receptor agonism leading to lethal molting disruption in arthropods: Review and adverse outcome pathway development. ENVIRONMENTAL SCIENCE & TECHNOLOGY. American Chemical Society, Washington, DC, 51(8):4142-4157, (2017).


Development of high throughput toxicology (HTT) programs (e.g., ToxCast, Tox21) and potential application of those data has been heavily focused on human health. However, protecting ecosystems from harmful impacts of chemicals is another central aspect of EPA’s mission. At present, there a gaps in the HTT program with regard to biological pathways and molecular targets which are not relevant but are none the less critical to the survival, growth/development, and/or reproduction in other species. This paper reviews the critical role of ecdysteroid signaling in the endocrine control of molting behavior in arthropods, a phylum representing over a million described species. It details evidence that disruption of ecdysone receptor-mediated signaling can lead to fatal failures in molting across a broad range of arthropod species and that there are chemicals present in the environment that can cause these effects. Review of the basic biology underlying the molting process in arthropods provides a foundation for describing a series of adverse outcome pathways linking perturbation of various targets involved in arthropod endocrine signaling to adverse phenotypic outcomes of ecological significance. The AOPs, in turn, provide a scientific foundation for development of high throughput assays and/or in silico tools that can be used to screen chemicals for their ability to interact with and perturb key targets in these arthropod endocrine pathways. Thus, this work can help to address the gap in HTT programs relative to coverage of critical pathways involved in invertebrate endocrine function. The content of this review and the resulting AOPs and assay development will have direct relevance to the Endocrine Disruptor Screening Program, the Office of Pesticide Programs, as many pesticides are designed to target and impair arthropod molting, and the Office of Water relative to expedited criteria development.


Molting is a key biological process in growth, development, reproduction and survival in arthropods. Complex neuroendocrine pathways are involved in the regulation of molting and may potentially become targets of environmental endocrine disrupting compounds (EDCs). For example, several classes of pesticides used in agriculture and aquaculture specifically target key endocrine regulators of the molting process. These chemicals may also pose hazards to non-target species by causing molting defects, thus affecting the health of the ecosystems. The present review summarized the available knowledge on molting-related endocrine regulation and disruption in arthropods (with special focus on insects and crustaceans), in order to identify research gaps and develop a toxicity mechanism-based model for environmental hazard and risk assessment. Based on the review, multiple targets in the molting processes that EDCs can interact with were characterized to inform future studies. An adverse outcome pathway (AOP) describing ecdysone receptor agonism leading to incomplete ecdysis associated mortality was developed according to the OECD guideline and evaluated for weight of evidence using the Evolved Bradford Hill Criteria. This review proposed the first invertebrate endocrine disruption AOP and may serve as a knowledge foundation for future environmental studies and AOP development.

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Record Details:

Product Published Date: 04/01/2017
Record Last Revised: 04/11/2018
OMB Category: Other
Record ID: 336603