Citation:

Shankar, P. AND D. Villeneuve. AOP Report: Aryl Hydrocarbon Receptor Activation Leads to Early–Life Stage Mortality via Sox9 Repression-Induced Craniofacial and Cardiac Malformations. ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY. Society of Environmental Toxicology and Chemistry, Pensacola, FL, 42(10):2063-2077, (2023). https://doi.org/10.1002/etc.5699

Impact/Purpose:

The refine and reduce the use of animal toxicity testing in chemical safety assessment, EPA and other stakeholders aim to make more effective use of mechanistic information emanating from high throughput cellular and molecular screening assays and chemical-biological interactions predicted using computational models. To effectively utilize such data for decision-making, there is a need to assemble scientifically credible support for a causal, and predictive relationship between the kinds of effects measured at the molecular/biochemical/cellular level of biological organization and the effects considered significant for risk assessment and regulatory decision-making (e.g., effects on individual health, survival, growth, reproduction, etc.). The present manuscript, and associated AOP-Wiki entry, organize and present scientific evidence supporting a linkage between chemical activation of the aryl hydrocarbon receptor and effects on craniofacial development and/or cardiac development that can impact survival and ecological fitness. This product helps aid the use of molecular screening data, including data associated with specific ToxCast and Tox21 assays in the context of ecological hazard assessment. Such connections are expected to aid EPA's program offices, regions, and stakeholders in interpreting and applying data from new approach methodologies in chemical safety-related decision-making.

Description:

The aryl hydrocarbon receptors (Ahrs) are evolutionarily conserved ligand-dependent transcription factors that are activated by structurally diverse endogenous compounds as well as environmental chemicals such as polycyclic aromatic hydrocarbons and halogenated aromatic hydrocarbons. Activation of the Ahr leads to several transcriptional changes that can cause developmental toxicity resulting in mortality. Evidence was assembled and evaluated for two novel adverse outcome pathways (AOPs) which describe how Ahr activation (molecular initiating event) can lead to early–life stage mortality (adverse outcome), via either SOX9-mediated craniofacial malformations (AOP 455) or cardiovascular toxicity (AOP 456). Using a key event relationship (KER)-by-KER approach, we collected evidence using both a narrative search and a systematic review based on detailed search terms. Weight of evidence for each KER was assessed to inform overall confidence of the AOPs. The AOPs link to previous descriptions of Ahr activation and connect them to two novel key events (KEs), increase in slincR expression, a newly characterized long noncoding RNA with regulatory functions, and suppression of SOX9, a critical transcription factor implicated in chondrogenesis and cardiac development. In general, confidence levels for KERs ranged between medium and strong, with few inconsistencies, as well as several opportunities for future research identified. While the majority of KEs have only been demonstrated in zebrafish with 2,3,7,8-tetrachlorodibenzo-p-dioxin as an Ahr activator, evidence suggests that the two AOPs likely apply to most vertebrates and many Ahr-activating chemicals. Addition of the AOPs into the AOP-Wiki (https://aopwiki.org/) helps expand the growing Ahr-related AOP network to 19 individual AOPs, of which six are endorsed or in progress and the remaining 13 relatively underdeveloped.

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