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.

Fig. 1. Putative model illustrating the neuroendocrine regulation of molting in arthropods. A: Regulation of ecdysteroid titer; B: Regulation of new cuticle secretion; C: Regulation of old cuticle degradation; D: Regulation of ecdysis behavior; E: Regulation of cuticle tanning.

Ptth: prothoracicotropic hormone; Mih: Molt-inhibiting hormone; Chh: crustacean hyperglycemic hormone; cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; Torso: Ptth receptor; Ras: Ras signaling; ERK: extracellular signal-regulated kinase; 7-dc: 7-dehydrocholesterol; E: ecdysone; 2-dE: 2-deoxyecdysone; 20E: 20-hydroxyecdysone; 20, 26E: 20, 26-dihydroxyecdysone; 20Eoic: 20-hydroxyecdysonoic acid; Nvd: Neverland (7, 8-dehydrogenase); Spo: spook/Cyp307a1; Spok: spookier/Cyp307a2; Sro: shroud; Cyp6t3: cytochrome p450 6t3; Phm: phantom/Cyp306a1 (25-hydroxylase); Dib: disembodied/Cyp302a1 (22-hydroxylase); Sad: shadow/Cyp315a1 (2-hydroxylase); Shd: shade/Cyp314a1 (20-hydroxylase); EcR: ecdysone receptor; Usp: ultraspiracle protein; Cyp18a1: cytochrome p450 18a1; KnK: Knickkopf; Chs: chitin synthase; Cht: chitinase; Ctbs: chitobiase; Mfp: molting fluid protease; Hr38: hormone receptor 38; Br-c: broad-complex; Ftz-f1: Fushi tarazu factor-1; NO: nitric oxide; Hr4: hormone receptor 4; Hr3: hormone receptor 3; E75b: nuclear receptor E75B; E74: nuclear receptor E74; E78: nuclear receptor E78; Crz: corazonin; CrzR: corazonin receptor; Eth: ecdysis triggering hormone; EthR: ecdysis triggering hormone receptor; Eh: eclosion hormone; Ccap: crustacean cardioactive peptide; Ddc: dopa decarboxylase; Burs: bursicon; Pka: protein kinase A; Th: tyrosine hydroxylase.

Fig. 2

Incomplete ecdysis in adult female Daphnia magna after 96h exposure to 750 nmol/L of the endogenous ecdysone receptor agonist 20-hydroxyecdysone (20E).

Fig. 3. Adverse outcome pathway of ecdysone receptor agonism leading to incomplete ecdysis associated mortality.

MIE: Molecular initiating event; KE: Key event; AO: Adverse outcome; EcR: ecdysone receptor; E75b: nuclear receptor E75B; Ftz-f1: Fushi tarazu factor-1; Eth: ecdysis triggering hormone; Ccap: crustacean cardioactive peptide; Solid line with arrow: directly triggers; Dashed line with arrow: Indirectly triggers.