PUBLICATION
AOP Report: Aryl Hydrocarbon Receptor (Ahr) Activation Leads to Early Life Stage Mortality via Sox9 Repression Induced Craniofacial and Cardiac Malformations
- Authors
- Shankar, P., Villeneuve, D.L.
- ID
- ZDB-PUB-230622-35
- Date
- 2023
- Source
- Environmental toxicology and chemistry 42(10): 2063-2077 (Review)
- Registered Authors
- Shankar, Prarthana
- Keywords
- adverse outcome pathway, polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs)
- MeSH Terms
-
- Animals
- Humans
- Hydrocarbons, Aromatic*
- Polychlorinated Dibenzodioxins*/metabolism
- Polycyclic Aromatic Hydrocarbons*/toxicity
- Receptors, Aryl Hydrocarbon/genetics
- Receptors, Aryl Hydrocarbon/metabolism
- Zebrafish/genetics
- Zebrafish/metabolism
- PubMed
- 37341548 Full text @ Environ. Toxicol. Chem.
Citation
Shankar, P., Villeneuve, D.L. (2023) AOP Report: Aryl Hydrocarbon Receptor (Ahr) Activation Leads to Early Life Stage Mortality via Sox9 Repression Induced Craniofacial and Cardiac Malformations. Environmental toxicology and chemistry. 42(10):2063-2077.
Abstract
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. Ahr activation 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; MIE) can lead to early life stage mortality (adverse outcome; AO), 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 through 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 non-coding 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 majority of the KEs have only been demonstrated in zebrafish with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) 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 nineteen individual AOPs, of which six are endorsed or in progress, and the remaining 13 relatively underdeveloped.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping