Effects of Naphtho[2,1- a ]pyrene Exposure on CYP1A1 Expression: An in Vivo and in Vitro Mechanistic Study Exploring the Role of ... Posttranscriptional Modification.

Publisher: National Institute of Environmental Health Sciences Country of Publication: United States NLM ID: 0330411 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-9924 (Electronic) Linking ISSN: 00916765 NLM ISO Abbreviation: Environ Health Perspect Subsets: MEDLINE

Original Publication: Research Triangle Park, N. C. National Institute of Environmental Health Sciences.

Cytochrome P-450 CYP1A1*/metabolism ; Cytochrome P-450 CYP1A1*/genetics ; Receptors, Aryl Hydrocarbon*/metabolism ; Receptors, Aryl Hydrocarbon*/genetics; Animals ; Mice ; Male ; Mice, Knockout ; Adenosine/analogs & derivatives ; Adenosine/metabolism ; Environmental Pollutants/toxicity ; RNA Processing, Post-Transcriptional/drug effects

Background: Currently, many emerging polycyclic aromatic hydrocarbons (PAHs) have been found to be widely present in the environment. However, little has been reported about their toxicity, particularly in relation to CYP1A1.
Objectives: This study aimed to explore the toxicity of naphtho[2,1- a ]pyrene (N21aP) and elucidate the mechanism underlying N21aP-induced expression of CYP1A1.
Methods: The concentration and sources of N21aP were detected and analyzed by gas chromatography-triple quadrupole mass spectrometry (GC-MS/MS) and diagnostic ratio analysis. Then the effects of CYP1A1 on the toxicity of N21aP were conducted in male wild-type (WT) and Cyp1a1 knockout mice exposed to N21aP (0.02, 0.2, and INLINEMATH ) through intratracheal instillation. Further, the aryl hydrocarbon receptor (AhR) pathway was examined through luciferase and chromatin immunoprecipitation (ChIP) assays. INLINEMATH -methyladenosine ( INLINEMATH ) modification levels were measured on global RNA and specifically on CYP1A1 mRNA using dot blotting and methylated RNA immunoprecipitation-quantitative real-time polymerase chain reaction (MeRIP qRT-PCR), with validation by INLINEMATH inhibitors, DAA and SAH. INLINEMATH sites on CYP1A1 were identified by bioinformatics and luciferase assays, and CYP1A1 mRNA's interaction with IGF2BP3 was confirmed by RNA pull-down, luciferase, and RNA binding protein immunoprecipitation (RIP) assays.
Results: N21aP was of the same environmental origin as benzo[ a ]pyrene (BaP) but was more stably present in the environment. N21aP could be metabolically activated by CYP1A1 to produce epoxides, causing DNA damage and further leading to lung inflammation. Importantly, in addition to the classical AhR pathway (i.e., BaP), N21aP also induced CYP1A1 expression with a posttranscriptional modification of INLINEMATH in CYP1A1 mRNA via the METTL14-IGF2BP3-CYP1A1 axis. Specifically, in the two recognition sites of METTL14 on the CYP1A1 mRNA transcript (position at 2700 and 5218), a methylation site (position at 5218) in the 3'-untranslated region (UTR) was recognized by IGF2BP3, enhanced the stability of CYP1A1 mRNA, and finally resulted in an increase in CYP1A1 expression.
Discussion: This study systematically demonstrated that in addition to AhR-mediated transcriptional regulation, N21aP, had a new additional mechanism of INLINEMATH -mediated posttranscriptional modification, jointly contributing to CYP1A1 expression. Given that PAHs are the metabolic substrates of CYP1A1, this study not only helps to understand the significance of environment-genetic interactions for the toxicity of PAHs but also helps to better understand the health risks of the emerging PAHs at environmental exposure levels. https://doi.org/10.1289/EHP14055.

Environ Pollut. 2021 Jan 15;269:116103. (PMID: 33261958)
Pharmacol Ther. 2013 Apr;138(1):103-41. (PMID: 23333322)
Environ Sci Technol. 2003 May 1;37(9):1873-81. (PMID: 12775060)
J Hazard Mater. 2022 Sep 5;437:129310. (PMID: 35749893)
J Hematol Oncol. 2022 Feb 3;15(1):13. (PMID: 35115038)
Cancers (Basel). 2023 Jan 18;15(3):. (PMID: 36765542)
EMBO J. 2021 Feb 1;40(3):e105977. (PMID: 33470439)
Sci Total Environ. 2022 Apr 20;818:151700. (PMID: 34798089)
BMC Bioinformatics. 2017 Nov 29;18(1):529. (PMID: 29187165)
Pharmacol Ther. 2018 Jul;187:71-87. (PMID: 29458109)
Sci Total Environ. 2024 Jan 10;907:167762. (PMID: 37852504)
Nat Neurosci. 2018 Feb;21(2):195-206. (PMID: 29335608)
Toxicol Appl Pharmacol. 2018 Nov 15;359:108-117. (PMID: 30253172)
Mol Cell. 2016 Jul 21;63(2):306-317. (PMID: 27373337)
Biochem Pharmacol. 2020 Jan;171:113697. (PMID: 31706844)
Chem Res Toxicol. 2016 Oct 17;29(10):1641-1650. (PMID: 27494294)
Environ Pollut. 2020 Apr;259:113908. (PMID: 31931413)
Nat Rev Mol Cell Biol. 2021 Mar;22(3):183-195. (PMID: 32632317)
Sci Total Environ. 2021 Sep 15;787:147596. (PMID: 33991922)
J Environ Sci (China). 2023 Feb;124:644-654. (PMID: 36182170)
Environ Int. 2022 Feb;160:107074. (PMID: 34995968)
Environ Sci Technol. 2022 Aug 2;56(15):10868-10878. (PMID: 35834827)
Sci Total Environ. 2021 May 10;768:145279. (PMID: 33736343)
Biofactors. 2015 Nov-Dec;41(6):431-42. (PMID: 26643788)
Chemosphere. 2019 Dec;237:124474. (PMID: 31377596)
Compr Rev Food Sci Food Saf. 2021 Mar;20(2):1422-1456. (PMID: 33506545)
Annu Rev Biochem. 2023 Jun 20;92:145-173. (PMID: 37068770)
Environ Sci Technol. 2011 Aug 15;45(16):6887-95. (PMID: 21766847)
Sci Total Environ. 2022 Oct 15;843:157052. (PMID: 35787903)
Sci Total Environ. 2021 Mar 1;758:143997. (PMID: 33333309)
Environ Pollut. 2018 Jun;237:767-774. (PMID: 29217392)
J Environ Manage. 2023 Mar 15;330:117214. (PMID: 36623386)
Mol Cancer. 2020 Apr 17;19(1):78. (PMID: 32303268)
Hepatology. 2021 Mar;73(3):1140-1157. (PMID: 32535965)
Int J Mol Sci. 2020 Dec 31;22(1):. (PMID: 33396476)
J Hazard Mater. 2022 Mar 5;425:128041. (PMID: 34906874)
Chem Res Toxicol. 2021 Sep 20;34(9):2145-2156. (PMID: 34472326)
Semin Cancer Biol. 2021 Nov;76:3-16. (PMID: 34242741)
Sci Total Environ. 2017 Dec 15;605-606:172-179. (PMID: 28666172)
Environ Sci Technol. 2001 May 15;35(10):1943-52. (PMID: 11393972)
Bio Protoc. 2020 Sep 05;10(17):e3741. (PMID: 33659401)
Chemosphere. 2023 Nov;340:139800. (PMID: 37572709)
Nucleic Acids Res. 2016 Jun 2;44(10):e91. (PMID: 26896799)
Nat Chem Biol. 2014 Feb;10(2):93-5. (PMID: 24316715)
Biochem Pharmacol. 2022 Nov;205:115247. (PMID: 36113565)
Environ Health Perspect. 2022 Feb;130(2):25004. (PMID: 35225689)
Toxicol Lett. 2018 Jun 1;289:54-62. (PMID: 29545172)
Drug Metab Rev. 2002 Nov;34(4):791-820. (PMID: 12487150)
Environ Int. 2023 Sep;179:108159. (PMID: 37607426)
Curr Opin Cell Biol. 2018 Jun;52:96-104. (PMID: 29518673)
Environ Sci Technol. 2012 Sep 4;46(17):9745-52. (PMID: 22913732)
J Hazard Mater. 2022 Mar 5;425:127766. (PMID: 34916105)
Chem Biol Interact. 2023 Mar 1;373:110376. (PMID: 36736874)
Nature. 2012 Apr 29;485(7397):201-6. (PMID: 22575960)
Environ Health Perspect. 2023 Mar;131(3):37014. (PMID: 36975775)
Annu Rev Pharmacol Toxicol. 2003;43:149-73. (PMID: 12171978)
J Environ Monit. 2011 Sep;13(9):2568-74. (PMID: 21789327)
Mol Cell. 2017 Dec 7;68(5):993-1005.e9. (PMID: 29107537)
Mol Cancer. 2023 Mar 1;22(1):42. (PMID: 36859310)
Nat Cell Biol. 2018 Mar;20(3):285-295. (PMID: 29476152)
Environ Health Perspect. 2020 Nov;128(11):117009. (PMID: 33253011)
Elife. 2016 Sep 14;5:. (PMID: 27627798)
Aging Cell. 2019 Dec;18(6):e13035. (PMID: 31532069)
Sci Total Environ. 2016 Dec 15;573:115-122. (PMID: 27552735)
Cell Stem Cell. 2018 Feb 1;22(2):191-205.e9. (PMID: 29290617)
Trends Cell Biol. 2019 Jun;29(6):487-499. (PMID: 30940398)
Environ Pollut. 2015 Oct;205:70-7. (PMID: 26017113)
Environ Int. 2013 Oct;60:71-80. (PMID: 24013021)
Mol Ther. 2023 Aug 2;31(8):2524-2542. (PMID: 37340635)
Cell. 2017 Jun 15;169(7):1187-1200. (PMID: 28622506)
Sci Adv. 2020 Feb 19;6(8):eaaw9960. (PMID: 32128390)
Toxicol Appl Pharmacol. 2014 Feb 1;274(3):408-16. (PMID: 24355420)
Int J Environ Health Res. 2021 Nov;31(7):823-834. (PMID: 31722538)
Biochem Pharmacol. 2020 Dec;182:114264. (PMID: 33035507)
Environ Sci Technol Lett. 2016;3(6):234-242. (PMID: 30079367)
Environ Int. 2023 May;175:107941. (PMID: 37146469)
Environ Health Perspect. 2012 Jan;120(1):85-91. (PMID: 21979745)
Sci Total Environ. 2019 Jul 15;674:179-188. (PMID: 31004894)
Environ Health Perspect. 2016 Feb;124(2):184-92. (PMID: 26220256)
Redox Biol. 2020 Jul;34:101530. (PMID: 32354640)
Sci Total Environ. 2017 May 15;586:284-295. (PMID: 28174048)
Nat Commun. 2021 Dec 10;12(1):7213. (PMID: 34893641)
J Toxicol Environ Health B Crit Rev. 2023 Jan 2;26(1):28-65. (PMID: 36617662)

EC 1.14.14.1 (Cytochrome P-450 CYP1A1)
0 (Receptors, Aryl Hydrocarbon)
K72T3FS567 (Adenosine)
CLE6G00625 (N-methyladenosine)
0 (Environmental Pollutants)
EC 1.14.14.1 (Cyp1a1 protein, mouse)

Date Created: 20240812 Date Completed: 20240812 Latest Revision: 20240814

20250114

PMC11318572

10.1289/EHP14055

39133094