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Activation, AhR leads to Altered, Cardiovascular development/function
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Aryl hydrocarbon receptor activation leading to early life stage mortality via cardiovascular toxicity||non-adjacent||High||Prarthana Shankar (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
- The Ahr signaling pathway has been shown to have critical functions in the heart, including development of the heart and angiogenesis in a variety of organisms (See “Activation, AhR” Key event 18 page for references).
- Further, disruption of the Ahr signaling pathway has been associated with cardiovascular toxicity in animals including birds and fish (Heid et al. 2001; Incardona et al. 2009).
- This KER page provides some highlights of the evidence relating Ahr activation and cardiovascular development and function.
Evidence Collection Strategy
Evidence Supporting this KER
KER 2765 concordance table: https://aopwiki.org/system/dragonfly/production/2022/10/21/7su9acuq5b_Concordance_Table_AHR_to_cardiovascular_clean.pdf
- Ahr mRNA and protein expression (along with Ahr signaling pathways genes, such as cyp1a) have been detected in the developing heart of a number of organisms including mice (Abbott et al. 1995) and zebrafish (Andreasen et al. 2002). Ahr activating chemicals (such as, TCDD) increase expression of these genes in the heart (Andreasen et al. 2002) providing biological plausibility evidence for the role of Ahr in cardiotoxicity.
Uncertainties and Inconsistencies
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Abbott BD, Birnbaum LS, Perdew GH. 1995. Developmental expression of two members of a new class of transcription factors: I. Expression of aryl hydrocarbon receptor in the c57bl/6n mouse embryo. Dev Dyn. 204(2):133-143.
Andreasen EA, Spitsbergen JM, Tanguay RL, Stegeman JJ, Heideman W, Peterson RE. 2002. Tissue-specific expression of ahr2, arnt2, and cyp1a in zebrafish embryos and larvae: Effects of developmental stage and 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure. Toxicol Sci. 68(2):403-419.
Bugiak BJ, Weber LP. 2010. Phenotypic anchoring of gene expression after developmental exposure to aryl hydrocarbon receptor ligands in zebrafish. Aquat Toxicol. 99(3):423-437.
Fu H, Wang L, Wang J, Bennett BD, Li JL, Zhao B, Hu G. 2019. Dioxin and ahr impairs mesoderm gene expression and cardiac differentiation in human embryonic stem cells. Sci Total Environ. 651(Pt 1):1038-1046.
Heid SE, Walker MK, Swanson HI. 2001. Correlation of cardiotoxicity mediated by halogenated aromatic hydrocarbons to aryl hydrocarbon receptor activation. Toxicol Sci. 61(1):187-196.
Incardona JP, Carls MG, Day HL, Sloan CA, Bolton JL, Collier TK, Scholz NL. 2009. Cardiac arrhythmia is the primary response of embryonic pacific herring (clupea pallasi) exposed to crude oil during weathering. Environ Sci Technol. 43(1):201-207.
Jayasundara N, Van Tiem Garner L, Meyer JN, Erwin KN, Di Giulio RT. 2015. Ahr2-mediated transcriptomic responses underlying the synergistic cardiac developmental toxicity of pahs. Toxicol Sci. 143(2):469-481.
Jonsson ME, Jenny MJ, Woodin BR, Hahn ME, Stegeman JJ. 2007. Role of ahr2 in the expression of novel cytochrome p450 1 family genes, cell cycle genes, and morphological defects in developing zebra fish exposed to 3,3',4,4',5-pentachlorobiphenyl or 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicol Sci. 100(1):180-193.
Knecht AL, Truong L, Marvel SW, Reif DM, Garcia A, Lu C, Simonich MT, Teeguarden JG, Tanguay RL. 2017. Transgenerational inheritance of neurobehavioral and physiological deficits from developmental exposure to benzo[a]pyrene in zebrafish. Toxicol Appl Pharmacol. 329:148-157.
Li M, Wang X, Zhu J, Zhu S, Hu X, Zhu C, Guo X, Yu Z, Han S. 2014. Toxic effects of polychlorinated biphenyls on cardiac development in zebrafish. Mol Biol Rep. 41(12):7973-7983.
Liu H, Nie FH, Lin HY, Ma Y, Ju XH, Chen JJ, Gooneratne R. 2016. Developmental toxicity, erod, and cyp1a mrna expression in zebrafish embryos exposed to dioxin-like pcb126. Environmental toxicology. 31(2):201-210.
McGee SP, Konstantinov A, Stapleton HM, Volz DC. 2013. Aryl phosphate esters within a major pentabde replacement product induce cardiotoxicity in developing zebrafish embryos: Potential role of the aryl hydrocarbon receptor. Toxicol Sci. 133(1):144-156.
Tang C, Shen C, Zhu K, Zhou Y, Chuang YJ, He C, Zuo Z. 2020. Exposure to the ahr agonist cyprodinil impacts the cardiac development and function of zebrafish larvae. Ecotoxicol Environ Saf. 201:110808.