Aryl hydrocarbon receptor activation leading to early life stage mortality via cardiovascular toxicity

The Aryl Hydrocarbon Receptor (Ahrs) are evolutionarily conserved ligand-dependent transcription factors that can be activated by structurally diverse compounds such as halogenated aromatic hydrocarbons, polycyclic aromatic hydrocarbons, and polychlorinated biphenyls. Ahr activation can cause developmental toxicity, including cardiovascular toxicity, that can lead to early-stage mortality. The current AOP describes a novel adverse outcome pathway (AOP) which describe how Ahr activation (molecular initiating event; MIE) can lead to early-stage mortality (adverse outcome; AO), via cardiovascular toxicity. The AOP includes two novel key events (KEs), increase in slincR expression, a newly characterized long non-coding RNA that has regulatory functions, and decrease in sox9 expression, a critical transcription factor implicated in several processes including cardiovascular development. Using a key event relationship (KER)-by-KER approach, we collected evidence using both relevant zebrafish literature as well as through broader key word searches in the AbstractSifter tool. Weight of evidence for each KER was assessed to inform overall assessment of the two AOPs which is presented here. Overall confidence levels ranged between medium and strong, with few inconsistencies as well several opportunities for future research identified. While the AOP has only been demonstrated in zebrafish with TCDD as an Ahr activator, we provide lines of evidence for the AOP to apply to majority of animals, as well as many Ahr activating chemicals. The addition of the AOP into the AOP-Wiki helps expand the growing Ahr-related AOP network.