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

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.