Ecdysone Receptor Agonism Leading to Lethal Molting Disruption in Arthropods: Review and Adverse Outcome Pathway Development

Abstract

Molting is critical for 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 chemicals (EDCs). Based on several known ED mechanisms, a wide range of pesticides has been developed to combat unwanted organisms in food production activities such as agriculture and aquaculture. Meanwhile, these chemicals may also pose hazards to nontarget species by causing molting defects, and thus potentially affecting the health of the ecosystems. The present review summarizes the available knowledge on molting-related endocrine regulation and chemically mediated disruption in arthropods (with special focus on insects and crustaceans), to identify research gaps and develop a mechanistic model for assessing environmental hazards of these compounds. Based on the review, multiple targets of EDCs in the molting processes were identified and the link between mode of action (MoA) and adverse effects 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 subjected to weight of evidence considerations by evolved Bradford Hill Criteria. This review proposes the first invertebrate ED AOP and may serve as a knowledge foundation for future environmental studies and AOP development.

In Silico Identification of Chemicals Capable of Binding to the Ecdysone Receptor

“…Importantly, this extended (with a minor reduction) to representative species sourced from alternative subphyla, such as crustaceans, myriapods, and arachnids. Such findings stand in support of evidence drawn from alternative studies, which suggest that EcR sequence homology conforms to a respectable degree across even substantially divergent species, albeit with minor amino acid variation at key positions holding association with variable sensitivity toward specific nonsteroidal pesticides (Nakagawa and Henrich 2009;Song et al 2017b;Evenseth et al 2019). Although experimental evidence from noninsect classes is scarce, a limited number of studies have reported the development of systems that may allow future widespread screening of EcR binding capacity in selected crustacean species, and hence providing routes through which these hypotheses might be tested (Yokota et al 2011;De Wilde et al 2013;Asada et al 2014;Chan et al 2019).…”

“…The AOPs associating perturbation of ecdysone signaling in arthropods with impaired molting culminating in death have been described (for a general outline, see Figure 2; Song et al 2017b;Song and Tollefsen 2018). A variety of endogenous and xenobiotic substances are known to act through the EcR, but definitions of the structural and physicochemical characteristics required for binding remain incomplete.…”

Establishment of a high‐sensitivity reporter system in mammalian cells for detecting juvenoids using juvenile hormone receptors of Daphnia pulex

“…However, most of the endangered species affected by EDCs in the natural environment are non‐model organisms and have not been subjected to such well‐established approaches. Therefore, we recently focused on understanding the molecular endocrine system of Daphnia , a keystone animal of limnetic ecosystems (Miyakawa, Sato, Song, Tollefsen, & Iguchi, ; Song, Villeneuve, Toyota, Iguchi, & Tollefsen, ). The new reporter assay system for JH detection established in the present study provides molecular evidence that some insecticides truly act as juvenoids.…”

Quantifying intra- and interspecific variability in trilobite moulting behaviour across the Palaeozoic

“…There has been a great deal of research on extant arthropod moulting behaviours, particularly in insects, and the biochemical pathways (involving ecdysones) that stimulate the moulting process (e.g., Nijhout, 1994;Ewer, 2005;Song et al, 2017). However, there has been very little work using the fossil record to explore the evolution of this key characteristic.…”