AOP Report: Aryl Hydrocarbon Receptor Activation Leads to Early-Life Stage Mortality via Sox9 Repression-Induced Craniofacial and Cardiac Malformations.

Publisher: SETAC Press Country of Publication: United States NLM ID: 8308958 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-8618 (Electronic) Linking ISSN: 07307268 NLM ISO Abbreviation: Environ Toxicol Chem Subsets: MEDLINE

Publication: Pensacola, FL : SETAC Press
Original Publication: New York : Pergamon Press, c1982-

Polychlorinated Dibenzodioxins*/metabolism ; Polycyclic Aromatic Hydrocarbons*/toxicity ; Hydrocarbons, Aromatic*; Animals ; Humans ; Zebrafish/genetics ; Zebrafish/metabolism ; Receptors, Aryl Hydrocarbon/genetics ; Receptors, Aryl Hydrocarbon/metabolism

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. Environ Toxicol Chem 2023;42:2063-2077. © 2023 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
(© 2023 SETAC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Nat Rev Mol Cell Biol. 2023 Jun;24(6):430-447. (PMID: 36596869)
Reprod Toxicol. 2021 Apr;101:33-49. (PMID: 33607186)
Toxicol Appl Pharmacol. 1997 Jan;142(1):56-68. (PMID: 9007034)
Hum Mutat. 2014 Aug;35(8):1011-20. (PMID: 24934569)
Mol Pharmacol. 1993 Dec;44(6):1142-51. (PMID: 8264550)
Lancet. 2018 Nov 10;392(10159):1736-1788. (PMID: 30496103)
Mar Environ Res. 2012 Jun;77:30-4. (PMID: 22336231)
Toxicol Sci. 2007 Sep;99(1):101-17. (PMID: 17556759)
Toxicol Sci. 1999 Jan;47(1):40-51. (PMID: 10048152)
Mol Pharmacol. 2017 Jun;91(6):609-619. (PMID: 28385905)
Chem Res Toxicol. 2008 Jan;21(1):102-16. (PMID: 18076143)
Toxicol Sci. 2008 Sep;105(1):5-23. (PMID: 18156145)
Dev Biol. 1997 Nov 15;191(2):297-305. (PMID: 9398442)
J Dent Res. 2021 Apr;100(4):406-414. (PMID: 33155500)
Arch Toxicol. 2018 Dec;92(12):3549-3564. (PMID: 30288550)
Teratog Carcinog Mutagen. 1984;4(5):427-36. (PMID: 6150558)
Mol Biol Rep. 2014 Dec;41(12):7973-83. (PMID: 25163633)
Environ Toxicol Chem. 2018 Jun;37(6):1723-1733. (PMID: 29488651)
Arch Toxicol Suppl. 1995;17:80-95. (PMID: 7786195)
Toxicol Appl Pharmacol. 2016 Oct 15;309:63-76. (PMID: 27576004)
J Vet Diagn Invest. 2000 Sep;12(5):477-9. (PMID: 11021441)
Mol Pharmacol. 2013 Sep;84(3):353-60. (PMID: 23775563)
Environ Sci Pollut Res Int. 2013 Mar;20(3):1219-24. (PMID: 23054770)
Biol Reprod. 2014 Jan 16;90(1):8. (PMID: 24174576)
Dev Dyn. 2003 Nov;228(3):480-9. (PMID: 14579386)
Nature. 1997 Mar 27;386(6623):403-7. (PMID: 9121557)
Environ Health Perspect. 1998 Dec;106(12):775-92. (PMID: 9831538)
Toxicol Sci. 2013 Sep;135(1):1-16. (PMID: 23771949)
Biochim Biophys Acta Rev Cancer. 2021 Apr;1875(2):188517. (PMID: 33524528)
Annu Rev Pharmacol Toxicol. 2003;43:309-34. (PMID: 12540743)
Aquat Toxicol. 2011 Jan 17;101(1):165-74. (PMID: 21040984)
Fish Physiol Biochem. 2012 Feb;38(1):61-83. (PMID: 21918861)
Mol Cell Endocrinol. 2012 May 6;354(1-2):121-38. (PMID: 21958697)
Environ Toxicol Chem. 2010 Mar;29(3):730-41. (PMID: 20821501)
Immunology. 2009 Jul;127(3):299-311. (PMID: 19538249)
Sci Adv. 2017 Sep 27;3(9):eaao2110. (PMID: 28959731)
Zoolog Sci. 2005 Jan;22(1):1-19. (PMID: 15684579)
Biomed Pharmacother. 2019 Mar;111:395-401. (PMID: 30594777)
Curr Opin Toxicol. 2017 Feb;2:87-92. (PMID: 32296737)
Toxicol Sci. 2004 Nov;82(1):250-8. (PMID: 15282404)
Animals (Basel). 2020 Apr 13;10(4):. (PMID: 32294879)
J Appl Toxicol. 2016 Jun;36(6):802-14. (PMID: 26278112)
Environ Sci Pollut Res Int. 2018 Jan;25(3):2436-2449. (PMID: 29127629)
Mol Genet Genomic Med. 2022 May;10(5):e1909. (PMID: 35218327)
Environ Sci Technol. 2018 Jul 3;52(13):7524-7533. (PMID: 29863850)
Dev Genes Evol. 2002 May;212(4):203-6. (PMID: 12012235)
Toxicol Sci. 2017 Jan;155(1):3-21. (PMID: 27864543)
Environ Sci Technol. 2009 Jan 1;43(1):201-7. (PMID: 19209607)
EFSA J. 2018 Nov 20;16(11):e05333. (PMID: 32625737)
Environ Sci Technol. 2020 Jun 2;54(11):6456-6467. (PMID: 32267150)
Proc Natl Acad Sci U S A. 2006 Apr 18;103(16):6252-7. (PMID: 16606854)
Sci Rep. 2018 Sep 17;8(1):13906. (PMID: 30224706)
Toxicol Sci. 2014 Dec;142(2):312-20. (PMID: 25466378)
Development. 2002 Jan;129(2):421-32. (PMID: 11807034)
Birth Defects Res A Clin Mol Teratol. 2006 Jan;76(1):7-18. (PMID: 16333842)
Environ Sci Pollut Res Int. 2016 Feb;23(3):2160-72. (PMID: 25877901)
PLoS One. 2018 Mar 1;13(3):e0193484. (PMID: 29494622)
Development. 2005 Mar;132(5):851-61. (PMID: 15705856)
Evol Dev. 2014 Jul-Aug;16(4):197-206. (PMID: 24934187)
Arch Environ Contam Toxicol. 2017 Jul;73(1):63-75. (PMID: 28695255)
Mol Pharmacol. 2006 Mar;69(3):776-87. (PMID: 16306231)
Toxicol Sci. 2021 Nov 24;184(2):183-190. (PMID: 34534351)
Aquat Toxicol. 2011 Oct;105(3-4):669-80. (PMID: 21979385)
J Cardiovasc Dis Res. 2011 Apr;2(2):91-5. (PMID: 21814412)
J Cell Biochem Suppl. 2001;Suppl 36:71-8. (PMID: 11455572)
Mol Pharmacol. 2008 Dec;74(6):1544-53. (PMID: 18784347)
Toxicol Sci. 2006 Nov;94(1):175-82. (PMID: 16936225)
Environ Sci Pollut Res Int. 2014 Dec;21(24):13732-43. (PMID: 24595754)
Toxicol Sci. 2020 Dec 1;178(2):215-238. (PMID: 32976604)
Proc Natl Acad Sci U S A. 2014 Apr 15;111(15):E1510-8. (PMID: 24706825)
Reprod Toxicol. 2021 Oct;105:25-43. (PMID: 34363983)
J Toxicol Environ Health. 1991 Aug;33(4):455-520. (PMID: 1875430)
Genesis. 2011 Apr;49(4):200-8. (PMID: 21309066)
Toxicol Appl Pharmacol. 1996 Sep;140(1):173-9. (PMID: 8806883)
Mar Environ Res. 2011 May;71(4):257-65. (PMID: 21349578)
Toxicol Sci. 2005 Apr;84(2):368-77. (PMID: 15635151)
Biochem Pharmacol. 2009 Feb 15;77(4):547-59. (PMID: 18977336)
Nat Genet. 1995 Jan;9(1):15-20. (PMID: 7704017)
Toxicol Sci. 2001 May;61(1):187-96. (PMID: 11294989)
Environ Toxicol Chem. 2011 Jan;30(1):64-76. (PMID: 20963853)
RSC Adv. 2018 Nov 14;8(67):38315-38323. (PMID: 35559110)
Connect Tissue Res. 2017 Jan;58(1):2-14. (PMID: 27128146)
Environ Health Perspect. 2018 Nov;126(11):117002. (PMID: 30398377)
Regul Toxicol Pharmacol. 2015 Aug;72(3):514-37. (PMID: 25863193)
Toxicol Sci. 2015 Oct;147(2):397-411. (PMID: 26141390)
F1000Res. 2017 Dec 21;6:. (PMID: 29479422)
Environ Sci Technol. 2016 May 3;50(9):4826-35. (PMID: 27070345)
Genome Biol. 2017 Oct 31;18(1):206. (PMID: 29084573)
Toxicol Sci. 2009 May;109(1):75-87. (PMID: 19279074)
Arch Toxicol. 1990;64(3):188-92. (PMID: 2372232)
Curr Opin Toxicol. 2017 Feb;2:58-71. (PMID: 28286876)
Biochem Pharmacol. 2023 Feb;208:115371. (PMID: 36528068)
Nat Rev Mol Cell Biol. 2021 Feb;22(2):96-118. (PMID: 33353982)
Toxicol Sci. 2012 Dec;130(2):349-61. (PMID: 22903824)
Environ Toxicol Chem. 2011 Jul;30(7):1659-68. (PMID: 21509806)
Int J Mol Sci. 2019 Jan 31;20(3):. (PMID: 30708991)
Development. 2015 Dec 15;142(24):4340-50. (PMID: 26525672)
Toxicol Sci. 2023 Jul 28;194(2):153-166. (PMID: 37220911)
Hum Mutat. 2013 Dec;34(12):1628-31. (PMID: 24115316)

EPA999999 United States ImEPA Intramural EPA

Keywords: Adverse outcome pathway; Polychlorinated biphenyls (PCBs); Polycyclic aromatic hydrocarbons (PAHs)

0 (Receptors, Aryl Hydrocarbon)
0 (Polychlorinated Dibenzodioxins)
0 (Polycyclic Aromatic Hydrocarbons)
0 (Hydrocarbons, Aromatic)

Date Created: 20230621 Date Completed: 20231023 Latest Revision: 20241003

20250114

PMC10772968

10.1002/etc.5699

37341548