Aryl hydrocarbon receptor（AhR）activation

91-20-3

UFWIBTONFRDIAS-UHFFFAOYSA-N

Naphthalene

Albocarbon Dezodorator Moth flakes naftaleno, puro Naphtalene NAPHTHALENE SCALES Naphthalin Naphthene Napthalene NSC 37565 Tar camphor UN 2304 White tar

DTXSID8020913

83-32-9

CWRYPZZKDGJXCA-UHFFFAOYSA-N

Acenaphthene

Acenaphthylene, 1,2-dihydro- 1,2-Dihydroacenaphthylene 1,8-Ethylenenaphthalene acenafteno Acenaphtene Acenaphthen Naphthyleneethylene NSC 7657 peri-Ethylenenaphthalene

DTXSID3021774

208-96-8

HXGDTGSAIMULJN-UHFFFAOYSA-N

Acenaphthylene

acenaftileno acenaphthyene Acenaphthylen Acenaphtylene Cyclopenta[de]naphthalene NSC 59821

DTXSID3023845

86-73-7

NIHNNTQXNPWCJQ-UHFFFAOYSA-N

Fluorene

9H-Fluorene 2,2'-Methylenebiphenyl Diphenylenemethane Fluoren fluoreno Methane, diphenylene- NSC 6787 o-Biphenylenemethane

DTXSID8024105

85-01-8

YNPNZTXNASCQKK-UHFFFAOYSA-N

Phenanthrene

[3]Helicene fenantreno, puro NSC 26256 Phenanthren Ravatite

DTXSID6024254

120-12-7

MWPLVEDNUUSJAV-UHFFFAOYSA-N

Anthracene

Anthracen Anthracin antraceno, puro Green Oil NSC 7958 Paranaphthalene Tetra Olive N2G UN 1136

DTXSID0023878

206-44-0

GVEPBJHOBDJJJI-UHFFFAOYSA-N

Fluoranthene

ClusterCarbon 1,2-(1,8-Naphthylene)benzene Benzene, 1,2-(1,8-naphthalenediyl)- Benzo[jk]fluorene fluoranteno Fluoranthen NSC 6803

DTXSID3024104

129-00-0

BBEAQIROQSPTKN-UHFFFAOYSA-N

Pyrene

Benzo (d,e,f) phenanthrene Benzo[def]phenanthrene NSC 17534 NSC 66449 β-Pyrene

DTXSID3024289

218-01-9

WDECIBYCCFPHNR-UHFFFAOYSA-N

Chrysene

[4]Phenacene 1,2-Benzophenanthrene 1,2-Benzphenanthrene Benzo(a)phenanthrene Benzo[a]phenanthrene Chrysen criseno NSC 6175

DTXSID0022432

205-99-2

FTOVXSOBNPWTSH-UHFFFAOYSA-N

Benzo(b)fluoranthene

Benz[e]acephenanthrylene 2,3-Benzfluoranthene 2,3-Benzofluoranthrene 3,4-Benz(e)acephenanthrylene 3,4-Benz[e]acephenanthrylene 3,4-Benzfluoranthene 3,4-Benzofluoranthene Benz(e)acephenanthrylen benz(e)acephenanthrylene Benzo(b)flluoranthene benzo(e)acefenantrileno benzo(e)acephenanthrylene Benzo(e)fluoranthene Benzo[b]fluoranthene Benzo[e]fluoranthene NSC 89265

DTXSID0023907

207-08-9

HAXBIWFMXWRORI-UHFFFAOYSA-N

Benzo(k)fluoranthene

11,12-Benzofluoranthene 2,3,1',8'-Binaphthylene 8,9-Benzfluoranthene 8,9-Benzofluoranthene benzo(k)fluoranteno Benzo(k)fluoranthen Dibenzo[b,jk]fluorene

DTXSID0023909

50-32-8

FMMWHPNWAFZXNH-UHFFFAOYSA-N

Benzo(a)pyrene

BaP Benzo[a]pyrene 3,4-Benz[a]pyrene 3,4-Benzopyrene 3,4-Benzpyrene 6,7-Benzopyrene BENZ(A)PYREN Benz(a)pyrene Benz[a]pyrene Benzo[d,e,f]chrysene Benzo[def]chrysen Benzo[def]chrysene benzo[def]criseno NSC 21914 Benzo(d,e,f)chrysene 3,4-Benzo(a)pyrene 3,4-Benz(a)pyrene EINECS 200-028-5 RCRA waste number U022 3,4-Benzopirene 3,4-Benzpyren UNII-3417WMA06D

DTXSID2020139

56-55-3

DXBHBZVCASKNBY-UHFFFAOYSA-N

Benz(a)anthracene

Benz[a]anthracene 1,2-Benz[a]anthracene 1,2-Benzanthracene 1,2-Benzanthrene 1,2-Benzoanthracene 2,3-Benzophenanthrene 2,3-Benzphenanthrene BENZ(A)ANTHRACEN Benz[a]anthracen Benzanthracene Benzanthrene Benzo(a)anthracene Benzo[a]anthracene benzo[a]antraceno Benzo[b]phenanthrene Benzoanthracene Naphthanthracene NSC 30970 Tetraphene

DTXSID5023902

193-39-5

SXQBHARYMNFBPS-UHFFFAOYSA-N

Indeno(1,2,3-cd)pyrene

Indeno[1,2,3-cd]pyrene 1,10-(1,2-Phenylene)pyrene 1,10-(o-Phenylene)pyrene Indeno(1,2,3-c,d)pyrene indeno[1,2,3-cd]pireno Indeno[1,2,3-cd]pyren

DTXSID8024153

53-70-3

LHRCREOYAASXPZ-UHFFFAOYSA-N

Dibenz(a,h)anthracene

Dibenz[a,h]anthracene 1,2:5,6-Benzanthracene 1,2:5,6-Dibenz[a]anthracene 1,2:5,6-Dibenzanthracen 1,2:5,6-Dibenzanthracene 1,2:5,6-Dibenzoanthracene DIBENZ(A,H)ANTHRACEN Dibenz[a,h]anthracen Dibenzo(a,h)anthracene Dibenzo[a,h]anthracene dibenzo[a,h]antraceno NSC 22433

DTXSID9020409

191-24-2

GYFAGKUZYNFMBN-UHFFFAOYSA-N

Benzo(g,h,i)perylene

Benzo[ghi]perylene 1,12-Benzoperylene 1,12-Benzperylene BENZO(GHI)PERYLEN Benzo(ghi)perylene benzo[ghi]perileno Benzo[ghi]perylen NSC 89275

DTXSID5023908

60-35-5

DLFVBJFMPXGRIB-UHFFFAOYSA-N

Acetamide

Acetamid acetamida Acetic acid amide Acetimidic acid Ethanamide Ethanimidic acid Methanecarboxamide NSC 25945

DTXSID7020005

103-90-2

RZVAJINKPMORJF-UHFFFAOYSA-N

Acetaminophen

4-Acetamidophenol APAP Paracetamol 4-hydroxyacetanilide Acetamide, N-(4-hydroxyphenyl)- 4-(Acetylamino)phenol 4-(N-Acetylamino)phenol 4-Acetaminophenol 4'-Hydroxyacetanilide Abensanil Acetagesic Acetalgin ACETAMIDE, N-(4-HYDROXYPHENYL) Acetaminofen Acetanilide, 4'-hydroxy- ACETANILIDE, 4-HYDROXY- Algotropyl Alvedon Anaflon Apamide Banesin Ben-u-ron Bickie-mol Biocetamol Cetadol Citramon P Claratal Clixodyne Dafalgan Daphalgan Dial-a-gesic Disprol Doliprane Dolprone Dymadon Efferalgan Endophy Febrilex Febrilix Febro-Gesic Febrolin Fepanil Finimal Gattaphen T Gelocatil Gutte Enteric Homoolan Jin Gang Lestemp Liquagesic Lonarid Lyteca Syrup Minoset Momentum N-(4-Hydroxyphenyl)acetamide N-Acetyl-4-aminophenol N-Acetyl-4-hydroxyaniline N-Acetyl-p-aminophenol Napafen Naprinol Nobedon NSC 109028 NSC 3991 Ortensan p-(Acetylamino)phenol p-Aceaminophenol Pacemol p-Acetamidophenol p-Acetoaminophen P-ACETYLAMINOPHENOL Paldesic panadeine Panadol Panadol Actifast Panadol Extend Panaleve Panasorb Panodil Paracetamol DC Paracetamole Parageniol Paramol Paraspen Parelan Pasolind N Perfalgan Phenaphen Phendon p-Hydroxyacetanilide Prodafalgan Puerxitong Pyrinazine Resfenol Resprin Rhodapop NCR Salzone Tabalgin Tachipirina Tempanal Tralgon Tylenol TylolHot Valadol Valgesic Vermidon Vick Pyrena

DTXSID2020006

968-81-0

VGZSUPCWNCWDAN-UHFFFAOYSA-N

Acetohexamide

Benzenesulfonamide, 4-acetyl-N-[(cyclohexylamino)carbonyl]- 1-(p-Acetylbenzenesulfonyl)-3-cyclohexylurea 1-[(p-Acetylphenyl)sulfonyl]-3-cyclohexylurea Acetohexamid acetohexamida Dimelin Dimelor Dymelor Gamadiabet Hypoglicil Metaglucina Minoral N-(p-Acetylphenylsulfonyl)-N'-cyclohexylurea Ordimel Tsiklamid Urea, 1-[(p-acetylphenyl)sulfonyl]-3-cyclohexyl-

DTXSID7020007

67-66-3

HEDRZPFGACZZDS-UHFFFAOYSA-N

Chloroform

Trichloromethane Methane, trichloro- CARBON TRICHLORIDE Chloroforme cloroformo Formyl trichloride Methane trichloride Methane,trichloro- NSC 77361 Trichloroform UN 1888

DTXSID1020306

110-00-9

YLQBMQCUIZJEEH-UHFFFAOYSA-N

Furan

Divinylene oxide furanne Furfuran Oxacyclopentadiene Tetrole UN 2389

DTXSID6020646

7429-90-5

XAGFODPZIPBFFR-UHFFFAOYSA-N

AZDRQVAHHNSJOQ-UHFFFAOYSA-N

Aluminum

Aisin Metal Fiber Al 050P-H24 ALC Fine Alcan XI 1391 Almi-Paste SSP 303AR Aloxal 3010 Alpaste 00-0506 Alpaste 0100M Alpaste 0100MA Alpaste 0100M-C Alpaste 0200M Alpaste 0200T Alpaste 0230M Alpaste 0230T Alpaste 0241M Alpaste 0300M Alpaste 0500M Alpaste 0539X Alpaste 0620MS Alpaste 0625TS Alpaste 0638-70C Alpaste 0700M Alpaste 0780M Alpaste 0900M Alpaste 100M Alpaste 100MS Alpaste 100MSR Alpaste 1100M Alpaste 1100MA Alpaste 1100N Alpaste 1100NA Alpaste 1109MA Alpaste 1109MC Alpaste 1200M Alpaste 1200T Alpaste 1260MS Alpaste 1500MA Alpaste 1700NL Alpaste 1810YL Alpaste 1830YL Alpaste 1900M Alpaste 1900XS Alpaste 1950M Alpaste 1950N Alpaste 210N Alpaste 2172EA Alpaste 2173 Alpaste 240T Alpaste 241M Alpaste 417 Alpaste 46-046 Alpaste 4-621 Alpaste 4919 Alpaste 50-63 Alpaste 50-635 Alpaste 51-148B Alpaste 51-231 Alpaste 5205N Alpaste 5207N Alpaste 52-509 Alpaste 52-568 Alpaste 5301N Alpaste 5302N Alpaste 53-119 Alpaste 5422NS Alpaste 54-452 Alpaste 54-497 Alpaste 54-542 Alpaste 55-516 Alpaste 55-519 Alpaste 55-574 Alpaste 5620NS Alpaste 5630NS Alpaste 5640NS Alpaste 56-501 Alpaste 5650NS Alpaste 5653NS Alpaste 5654NS Alpaste 5680N Alpaste 5680NS Alpaste 60-600 Alpaste 60-760 Alpaste 60-768 Alpaste 62-356 Alpaste 6340NS Alpaste 6370NS Alpaste 6390NS Alpaste 640NS Alpaste 65-388 Alpaste 66NLB Alpaste 710N Alpaste 7130N Alpaste 7160N Alpaste 7160NS Alpaste 725N Alpaste 740NS Alpaste 7430NS Alpaste 7580NS Alpaste 7620NS Alpaste 7640NS Alpaste 7670M Alpaste 7670NS Alpaste 7675NS Alpaste 7679NS Alpaste 7680N Alpaste 7680NS Alpaste 76840NS Alpaste 7730N Alpaste 7770N Alpaste 7830N Alpaste 8004 Alpaste 8080N Alpaste 8260NAR Alpaste 891K Alpaste 91-0562 Alpaste 92-0592 Alpaste 93-0595 Alpaste 93-0647 Alpaste 94-2315 Alpaste 95-0570 Alpaste 96-0635 Alpaste 96-2104 Alpaste 97-0510 Alpaste 97-0534 Alpaste AW 520B Alpaste AW 612 Alpaste AW 9800 Alpaste F 795 Alpaste FM 7680K Alpaste FX 440 Alpaste FX 910 Alpaste FZ 0534 Alpaste FZU 40C Alpaste G Alpaste HR 8801 Alpaste HS 2 Alpaste J Alpaste K 9800 Alpaste MC 666 Alpaste MC 707 Alpaste MF 20 Alpaste MG 01 Alpaste MG 1000 Alpaste MG 1300 Alpaste MG 500 Alpaste MG 600 Alpaste MH 6601 Alpaste MH 8801 Alpaste MH 9901 Alpaste MR 7000 Alpaste MR 9000 Alpaste MS 630 Alpaste N 1700NL Alpaste NS 7670 Alpaste O 100N Alpaste O 2130 Alpaste O 300M Alpaste P 0100 Alpaste P 1950 Alpaste S Alpaste SAP 110 Alpaste SAP 414P Alpaste SAP 550N Alpaste SCR 5070 Alpaste TCR 2020 Alpaste TCR 2060 Alpaste TCR 2070 Alpaste TCR 3010 Alpaste TCR 3030 Alpaste TCR 3040 Alpaste TCR 3130 Alpaste TD 200T Alpaste UF 500 Alpaste WB 0230 Alpaste WD 500 Alpaste WJP-U 75C Alpaste WX 0630 Alpaste WX 7830 Alpaste WXA 7640 Alpaste WXM 0630 Alpaste WXM 0650 Alpaste WXM 0660 Alpaste WXM 1415 Alpaste WXM 1440 Alpaste WXM 5422 Alpaste WXM 760b Alpaste WXM 7640 Alpaste WXM 7675 Alpaste WXM-T 60B Alpaste WXM-U 75 Alpaste WXM-U 75C Altop X Aluchrome Ultrafin Super Alumat 1600 Alumet H 30 aluminio Aluminium Aluminium Flake Aluminum 27 Aluminum atom Aluminum element Aluminum Flake PCF 7620 Aluminum granules ALUMINUM METAL/GRANULE ALUMINUM PASTE ALUMINUM PIGMENT ALUMINUM TURNINGS Alumi-paste 640NS Alumipaste 91-0562 Alumipaste 98-1822T Alumipaste AW 620 Alumipaste CR 300 Alumipaste GX 180A Alumipaste GX 201A Alumipaste HR 7000 Alumipaste HR 850 Alumipaste MG 11 Alumipaste MH 8801 Aquamet NPW 2900 Aquapaste 205-5 Aquasilver LPW Astroflake 40 Astroflake Black N 020 Astroflake Black N 070 Astroflake LG 40 Astroflake LG 70 Astroflake Silver N 040 Astroshine NJ 1600 Astroshine T 8990 Atomizalumi VA 200 C.I. PIGMENT METAL 1 Chromal IV Chromal X Decomet 1001/10 Decomet 2018/10 Decomet High Gloss Al 1002/10 Ecka AS 081 Eckart 9155 Eterna Brite 301-1 Eterna Brite 601-1 Eterna Brite 651-1 Eterna Brite EBP 251PA Eterna Brite Primier 251PA Ferro FX 53-038 Friend Color F 500GR-W Friend Color F 500WT Friend Color F 700RE-W Friend Color F 701RE-W Hi Print 60T High Print 60T Hisparkle HS 2 Hydro Paste 8726 Hydrolac WHH 2153 Hydrolan 3560 Hydrolux Reflexal 100 Hydroshine WS 1001 JISA 51010P Kryal Z Lansford 243 LE Sheet 800 Leafing Alpaste LG-H Silver 25 Lunar Al-V 95 Metallux 161 Metallux 2154 Metallux 2192 Metalure Metalure 55350 Metalure L 55350 Metalure L 59510 Metalure W 2001 Metapor Metasheen 1800 Metasheen HR 0800 Metasheen KM 100 Metasheen KM 1000 Metasheen Slurry 1807 Metasheen Slurry 1811 Metasheen Slurry KM 100 Metax G Metax S Mirror Glow 1000 Mirror Glow 600 Mirrorsheen Noral Aluminium Noral Ink Grade Aluminium Obron 10890 Offset FM 4500 Puratronic Reflexal 145 Reynolds 400 Reynolds 4-301 Reynolds 4-591 Reynolds 667 SAP 260PW-HS SAP-FM 4010 SBC 516-20Z Scotchcal 7755SE Serumekku Setanium 50MIS-H8 Siberline ET 2025 Siberline ST 21030E1 Silvar A Silver VT 522 Silverline SSP 353 Silvex 793-20C Sparkle Silver 3141ST Sparkle Silver 3500 Sparkle Silver 3641 Sparkle Silver 5000AR Sparkle Silver 516AR Sparkle Silver 5242AR Sparkle Silver 5245AR Sparkle Silver 5271AR Sparkle Silver 5500 Sparkle Silver 5745 Sparkle Silver 7000AR Sparkle Silver 7005AR Sparkle Silver 7500 Sparkle Silver 960-25E1 Sparkle Silver E 1745AR Sparkle Silver L 1526AR Sparkle Silver Premier 751 Sparkle Silver SS 3130 Sparkle Silver SS 5242AR Sparkle Silver SS 5588 Sparkle Silver SSP 132AR Special PCR 507 Splendal 6001BG Spota Mobil 801 SSP 760-20C Stapa Aloxal PM 2010 Stapa Aloxal PM 3010 Stapa Aloxal PM 4010 Stapa Hydrolac BG 8n.1 Stapa Hydrolac BGH Chromal X Stapa Hydrolac PM Chromal VIII Stapa Hydrolac W 60NL Stapa Hydrolac WH 16 Stapa Hydrolac WH 66NL Stapa Hydrolux 2192 Stapa Hydrolux 8154 Stapa IL Hydrolan 2192-55900G Stapa Metallic R 607 Stapa Metallux 1050 Stapa Metallux 211 Stapa Metallux 212 Stapa Metallux 2196 Stapa Metallux 274 Stapa Mobilux 181 Stapa Offset 3000 Stapa PV 10 Stapa VP 46432G Starbrite 2100 Super Fine 18000 Super Fine 22000 Supramex 2022 Toyo Aluminum 02-0005 Toyo Aluminum 93-3040 Transmet K 102HE Tufflake 3645 Tufflake 5843 UN 1396 US Aluminum 809 Valimet H 2 Valimet H 3 White Silver 7080N White Silver 7130N

DTXSID3040273

7440-43-9

BDOSMKKIYDKNTQ-UHFFFAOYSA-N

Cadmium

Cadimium CADMIUM BLUE CADMIUM, IN PLATTEN, STANGEN, BROCKEN,KOERNER

DTXSID1023940

7439-97-6

QSHDDOUJBYECFT-UHFFFAOYSA-N

Mercury

Liquid silver Mercure MERCURIC METAL TRIPLE DISTILLED mercurio Mercury element Quecksilber Quicksilver UN 2024 UN 2809

DTXSID1024172

7440-61-1

JFALSRSLKYAFGM-UHFFFAOYSA-N

Uranium

Uranium, isotope of mass 238 238U Element UN 2979 (DOT) Uranium I

DTXSID1042522

7440-38-2

RQNWIZPPADIBDY-UHFFFAOYSA-N

Arsenic

As Arsenic black ARSENIC METAL arsenico Grey arsenic UN 1558

DTXSID4023886

7440-22-4

BQCADISMDOOEFD-UHFFFAOYSA-N

Silver

Ag Nanopaste NPS-J 90 Ag Sphere 2 Ag-C-GS Algaedyn Arctic Silver 3 Argentum Astroflake 5 Carey Lea silver Colloidal silver Dotite XA 208 Du Pont 4943 ECM 100AF4810 Enlight 600 Enlight silver plate 600 Epinall Finesphere SVND 102 Fordel DC FP 5369-502 Jelcon SH 1 Jungindai Takasago 300 KS (metal) LCP 1-19SFS Metz 3000-1 Nanomelt AGC-A Nanomelt Ag-XA 301 Nanomelt Ag-XF 301 Nanomelt Ag-XF 301H Nanopaste NPS-J 90 Perfect Silver Puff Silver X 1200 RT 1710S-C1 SD (metal) Shell Silver Silbest E 20 Silbest F 20 Silbest J 18 Silbest TC 12 Silbest TC 20E Silbest TC 25A Silbest TCG 1 Silbest TCG 7 Silcoat AgC 103 Silcoat AgC 2011 Silcoat AgC 209 Silcoat AgC 2190 Silcoat AgC 222 Silcoat AgC 2411 Silcoat AgC 74T Silcoat AgC-A Silcoat AgC-AO Silcoat AgC-B Silcoat AgC-BO Silcoat AgC-D Silcoat AgC-G Silcoat AgC-GS Silcoat AgC-L Silcoat AgC-O Silcoat GS Silcoat RF 200 Silflake 135 Silsphere 514 Silver atom Silver element Silver Flake 1 Silver Flake 25 Silver Flake 52 Silver Flake 7A SILVER FLAKES Silver metal Silvest TCG 11N Technic 299 Technic 450 Techno Alpha 175

DTXSID4024305

7439-96-5

PWHULOQIROXLJO-UHFFFAOYSA-N

Manganese

Colloidal manganese Cutaval Manganese element Manganese fulleride Manganese metal alloy Manganese-55 manganeso

DTXSID2024169

7440-02-0

PXHVJJICTQNCMI-UHFFFAOYSA-N

Nickel

Carbonyl 255 Carbonyl Ni 123 Carbonyl Ni 283 Carbonyl Nickel 123 Carbonyl Nickel 283 Carbonyl Nickel 287 Cerac N 2003 CNS 10 Micron Exmet 4 Ni X-4/0 Fibrex P Incofoam Nickel element NICKEL ROUND ANODES Nicrobraz LM:BNi 2 Ni-Flake 95 Novamet 123 Novamet 4SP Novamet 4SP10 Novamet 525 Novamet CNS 400 Novamet HCA 1 Novamet NI 255 Raney nickel Raney nickel 2800 UN 1325 UN 2881

DTXSID2020925

7440-66-6

HCHKCACWOHOZIP-UHFFFAOYSA-N

Zinc

Zn Asarco L 15 C.I. Pigment Black 16 Merrillite NC-Zinc Rheinzink Stapa TE Zinc AT UF (metal) UN 1436 Zinc dust Zinc Dust 3 Zinc Dust 500 mesh Zinc Dust LS 2 Zinc Dust MCS Zinc Flakes GTT ZINC METAL ZINC MOSSY ZINC STRIP ZINC, MOSSY Zincsalt GTT

DTXSID7035012

CHEBI:16991

CHEBI deoxyribonucleic acid

MP:0003674

MP oxidative stress

WIKI increased

WIKI functional change

Naphthalene

2026-07-03T11:28:12

Acenaphthene

2026-07-09T06:10:36

Acenaphthylene

2026-07-09T06:14:20

Fluorene

2026-07-09T06:14:57

Phenanthrene

2016-11-29T18:42:22

Anthracene

2026-07-03T11:29:36

Fluoranthene

2026-07-09T06:28:08

Pyrene

2026-07-03T11:30:22

Chrysene

2026-07-03T11:31:50

Benzo(b)fluoranthene

2026-07-03T11:22:50

Benzo(k)fluoranthene

2016-11-29T18:42:08

Benzo(a)pyrene

2020-03-20T20:17:42

Benz(a)anthracene

2026-07-03T11:31:06

Indeno(1,2,3-cd)pyrene

2026-07-09T07:32:19

Dibenz(a,h)anthracene

2026-07-09T07:32:49

Benzo(g,h,i)perylene

2026-07-09T07:33:24

Acetaminophen

2016-11-29T18:42:26

Chloroform

2016-11-29T18:42:27

furan

2020-05-01T14:35:22

Platinum

2022-02-04T14:36:54

Aluminum

2022-02-04T14:42:11

Cadmium

2017-10-25T08:33:12

Mercury

2016-11-29T18:42:19

Uranium

2021-08-05T14:28:50

Arsenic

2021-04-27T00:15:21

Silver

2022-02-03T11:20:11

Manganese

2022-02-04T14:47:23

Nickel

2022-02-04T14:47:59

Zinc

2022-02-04T15:05:00

nanoparticles

2016-12-21T09:40:06

Ionizing Radiation Ionizing radiation can vary in energy, dose, charge, and in the spatial distributions of energy transferred to other matter (linear energy transfer per unit length or LET) (ICRU 1970). At the same dose, low and high LET both generate energy deposition events, including many higher energy events (Goodhead and Nikjoo 1989). However, they differ in the spatial distribution and upper range of intensity of energy deposited. Lower LET such as gamma rays sparsely deposit many individual excitations or small clusters of excitations of low energy (Goodhead 1988). In contrast, high LET such as alpha particles have fewer tracks but readily transfer their energy to matter and therefore deposit their energy over a much smaller area (Goodhead 1994). Consequently, alpha and other high LET particles penetrate less deeply into tissue, interactions are densely focused on a narrow track, and individual energy depositions can be large (Goodhead 1988). These different energy deposition patterns can lead to differences in radiation effects including the pattern of DNA damage.

Exposure to ionizing radiation can come from natural and industrial sources. Space and terrestrial radiation includes a range of LET particles, while diagnostic radiation methods such as X-ray imaging, mammography and CT scans use low LET X-rays. Radiation therapy can use an external beam to direct radiation on a focused tissue area, or deposit solid or liquid radioactive materials in the body that release (mostly gamma) radiation internally. External radiotherapy typically uses X-rays but is moving towards higher LET charged particles such as protons and heavy ions (Durante, Orecchia et al. 2017).

2019-05-03T12:36:36

2019-05-07T12:12:13

Estrogen

2019-05-08T11:40:27

WikiUser_26

ApacheUser rodents

9606

NCBI Homo sapiens

WCS_9606

common toxicological species human

10116

NCBI rat

Aryl hydrocarbon receptor（AhR）activation

AhR activation

Molecular

AOPWiki 2026-07-09T03:41:46

2026-07-09T03:41:46

Increase, Oxidative Stress

Molecular

Oxidative stress is defined as an imbalance in the production of reactive oxygen species (ROS) and antioxidant defenses. High levels of oxidizing free radicals can be very damaging to cells and molecules within the cell.  As a result, the cell has important defense mechanisms to protect itself from ROS. For example, Nrf2 is a transcription factor and master regulator of the oxidative stress response. During periods of oxidative stress, Nrf2-dependent changes in gene expression are important in regaining cellular homeostasis (Nguyen, et al., 2009) and can be used as indicators of the presence of oxidative stress in the cell.  In addition to the directly damaging actions of ROS, cellular oxidative stress also changes cellular activities on a molecular level. Redox sensitive proteins have altered physiology in the presence and absence of ROS, which is caused by the oxidation of sulfhydryls to disulfides on neighboring amino acids (Antelmann & Helmann 2011). Importantly Keap1, the negative regulator of Nrf2, is regulated in this manner (Itoh, et al. 2010).  ROS also undermine the mitochondrial defense system from oxidative damage. The antioxidant systems consist of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, as well as antioxidants such as α-tocopherol and ubiquinol, or antioxidant vitamins and minerals including vitamin E, C, carotene, lutein, zeaxanthin, selenium, and zinc (Fletcher, 2010). The enzymes, vitamins and minerals catalyze the conversion of ROS to non-toxic molecules such as water and O2. However, these antioxidant systems are not perfect and endogenous metabolic processes and/or exogenous oxidative influences can trigger cumulative oxidative injuries to the mitochondria, causing a decline in their functionality and efficiency, which further promotes cellular oxidative stress (Balasubramanian, 2000; Ganea & Harding, 2006; Guo et al., 2013; Karimi et al., 2017).   However, an emerging viewpoint suggests that ROS-induced modifications may not be as detrimental as previously thought, but rather contribute to signaling processes (Foyer et al., 2017).    Sources of ROS Production  Direct Sources: Direct sources involve the deposition of energy onto water molecules, breaking them into active radical species. When ionizing radiation hits water, it breaks it into hydrogen (H*) and hydroxyl (OH*) radicals by destroying its bonds. The hydrogen will create hydroxyperoxyl free radicals (HO2*) if oxygen is available, which can then react with another of itself to form hydrogen peroxide (H2O2) and more O2 (Elgazzar and Kazem, 2015). Antioxidant mechanisms are also affected by radiation, with catalase (CAT) and peroxidase (POD) levels rising as a result of exposure (Seen et al. 2018; Ahmad et al. 2021).   Indirect Sources: An indirect source of ROS is the mitochondria, which is one of the primary producers in eukaryotic cells (Powers et al., 2008).  As much as 2% of the electrons that should be going through the electron transport chain in the mitochondria escape, allowing them an opportunity to interact with surrounding structures. Electron-oxygen reactions result in free radical production, including the formation of hydrogen peroxide (H2O2) (Zhao et al., 2019). The electron transport chain, which also creates ROS, is activated by free adenosine diphosphate (ADP), O2, and inorganic phosphate (Pi) (Hargreaves et al. 2020; Raimondi et al. 2020; Vargas-Mendoza et al. 2021). The first and third complexes of the transport chain are the most relevant to mammalian ROS production (Raimondi et al., 2020). The mitochondria has its own set of DNA and it is a prime target of oxidative damage (Guo et al., 2013). ROS is also produced through nicotinamide adenine dinucleotide phosphate oxidase (Nox) stimulation, an event commenced by angiotensin II, a product/effector of the renin-angiotensin system (Nguyen Dinh Cat et al. 2013; Forrester et al. 2018). Other ROS producers include xanthine oxidase, immune cells (macrophage, neutrophils, monocytes, and eosinophils), phospholipase A2 (PLA2), monoamine oxidase (MAO), and carbon-based nanomaterials (Powers et al. 2008; Jacobsen et al. 2008; Vargas-Mendoza et al. 2021).

Oxidative Stress: Direct measurement of ROS is difficult because ROS are unstable. The presence of ROS can be assayed indirectly by measurement of cellular antioxidants, or by ROS-dependent cellular damage. Listed below are common methods for detecting the KE, however there may be other comparable methods that are not listed  <ul> <li>Detection of ROS by chemiluminescence (https://www.sciencedirect.com/science/article/abs/pii/S0165993606001683) </li> <li>Detection of ROS by chemiluminescence is also described in OECD TG 495 to assess phototoxic potential. </li> <li>Glutathione (GSH) depletion. GSH can be measured by assaying the ratio of reduced to oxidized glutathione (GSH:GSSG) using a commercially available kit (e.g., http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green- ab138881.html). </li> <li>TBARS. Oxidative damage to lipids can be measured by assaying for lipid peroxidation using TBARS (thiobarbituric acid reactive substances) using a commercially available kit. </li> <li>8-oxo-dG. Oxidative damage to nucleic acids can be assayed by measuring 8-oxo-dG adducts (for which there are a number of ELISA based commercially available kits),or HPLC, described in Chepelev et al. (Chepelev, et al. 2015). </li> </ul>    Molecular Biology: Nrf2. Nrf2’s transcriptional activity is controlled post-translationally by oxidation of Keap1. Assay for Nrf2 activity include:  <ul> <li>Immunohistochemistry for increases in Nrf2 protein levels and translocation into the nucleus Western blot for increased Nrf2 protein levels </li> <li>Western blot of cytoplasmic and nuclear fractions to observe translocation of Nrf2 protein from the cytoplasm to the nucleus qPCR of Nrf2 target genes (e.g., Nqo1, Hmox-1, Gcl, Gst, Prx, TrxR, Srxn), or by commercially available pathway-based qPCR array (e.g., oxidative stress array from SABiosciences) </li> <li>Whole transcriptome profiling by microarray or RNA-seq followed by pathway analysis (in IPA, DAVID, metacore, etc.) for enrichment of the Nrf2 oxidative stress response pathway (e.g., Jackson et al. 2014) </li> <li>OECD TG422D describes an ARE-Nrf2 Luciferase test method </li> </ul> In general, there are a variety of commercially available colorimetric or fluorescent kits for detecting Nrf2 activation. <table border="1"> <tbody> <tr> <td> Assay Type & Measured Content  </td> <td> Description  </td> <td> Dose Range Studied  </td> <td> Assay Characteristics (Length/Ease of use/Accuracy)  </td> </tr> <tr> <td> ROS  Formation in the Mitochondria assay (Shaki et al., 2012)  </td> <td> “The mitochondrial ROS measurement was performed flow cytometry using DCFH-DA. Briefly, isolated kidney mitochondria were incubated with UA (0, 50, 100 and 200 µM) in respiration buffer containing (0.32 mM sucrose, 10mM Tris, 20 mM Mops, 50 µM EGTA, 0.5 mM MgCl2, 0.1 mM KH2PO4 and 5 mM sodium succinate) [32]. In the interval times of 5, 30 and 60 min following the UA addition, a sample was taken and DCFH-DA was added (final concentration, 10 µM) to mitochondria and was then incubated for 10 min.Uranyl acetate-induced ROS generation in isolated kidney mitochondria were determined through the flow cytometry (Partec, Deutschland) equipped with a 488-nm argon ion laser and supplied with the Flomax software and the signals were obtained using a 530-nm bandpass filter (FL-1 channel). Each determination is based on the mean fluorescence intensity of 15,000 counts.”    </td> <td> 0, 50,100 and 200 µM of Uranyl Acetate    </td> <td>  Long/ Easy High accuracy    </td> </tr> <tr> <td> Mitochondrial Antioxidant Content Assay Measuring GSH content (Shaki et al., 2012)    </td> <td> “GSH content was determined using DTNB as the indicator and spectrophotometer method for the isolated mitochondria. The mitochondrial fractions (0.5 mg protein/ml) were incubated with various concentrations of uranyl acetate for 1 h at 30 °C and then 0.1 ml of mitochondrial fractions was added into 0.1 mol/l of phosphate buffers and 0.04% DTNB in a total volume of 3.0 ml (pH 7.4). The developed yellow color was read at 412 nm on a spectrophotometer (UV-1601 PC, Shimadzu, Japan). GSH content was expressed as µg/mg protein.”  </td> <td> 0, 50,  100, or  200 µM  Uranyl Acetate  </td> <td>   </td> </tr> <tr> <td> H2O2 Production Assay Measuring H2O2 Production in isolated mitochondria (Heyno et al., 2008)    </td> <td> “Effect of CdCl2 and antimycin A (AA) on H2O2 production in isolated mitochondria from potato. H2O2 production was measured as scopoletin oxidation. Mitochondria were incubated for 30 min in the measuring buffer  (see the Materials and Methods) containing 0.5 mM succinate as an electron donor and 0.2 µM mesoxalonitrile 3‐chlorophenylhydrazone (CCCP) as an uncoupler, 10 U horseradish peroxidase and 5 µM scopoletin.”   </td> <td> 0, 10, 30  µM Cd2+     2 µM antimycin A  </td> <td>   </td> </tr> <tr> <td> Flow Cytometry ROS & Cell Viability (Kruiderig et al., 1997)    </td> <td> “For determination of ROS, samples taken at the indicated time points were directly transferred to FACScan tubes. Dih123 (10 mM, final concentration) was added and cells were incubated at 37°C in a humidified atmosphere (95% air/5% CO2) for 10 min. At t 5 9, propidium iodide (10 mM, final concentration) was added, and cells were analyzed by flow cytometry at 60 ml/min. Nonfluorescent Dih123 is cleaved by ROS to fluorescent R123 and detected by the FL1 detector as described above for Dc (Van de Water 1995)”“For determination of ROS, samples taken at the indicated time points were directly transferred to FACScan tubes. Dih123 (10 mM, final concentration) was added and cells were incubated at 37°C in a humidified atmosphere (95% air/5% CO2) for 10 min. At t 5 9, propidium iodide (10 mM, final concentration) was added, and cells were analyzed by flow cytometry at 60 ml/min. Nonfluorescent Dih123 is cleaved by ROS to fluorescent R123 and detected by the FL1 detector as described above for Dc (Van de Water 1995)”  </td> <td>   </td> <td>           Strong/easy medium  </td> </tr> <tr> <td> DCFH-DA  Assay Detection of hydrogen peroxide production (Yuan et al.,  2016)  </td> <td> Intracellular ROS production was measured using DCFH-DA as a probe. Hydrogen peroxide oxidizes DCFH to DCF. The probe is hydrolyzed intracellularly to DCFH carboxylate anion. No direct reaction with H2O2 to form fluorescent production.    </td> <td> 0-400  µM  </td> <td> Long/ Easy High accuracy  </td> </tr> <tr> <td> H2-DCF-DAAssay Detection of superoxide production (Thiebault etal., 2007)    </td> <td> This dye is a stable nonpolar compound which diffuses readily into the cells and yields H2-DCF. Intracellular OH or ONOO- react with H2-DCF when cells contain peroxides, to form the highly fluorescent compound DCF, which effluxes the cell. Fluorescence intensity of DCF is measured using a fluorescence spectrophotometer.  </td> <td> 0–600  µM  </td> <td> Long/ Easy High accuracy  </td> </tr> <tr> <td> CM-H2DCFDA  Assay (Eruslanov  & Kusmartsev, 2009)  </td> <td> The dye (CM-H2DCFDA) diffuses into the cell and is cleaved by esterases, the thiol reactive chlormethyl group reacts with intracellular glutathione which can be detected using flow cytometry.  </td> <td>   </td> <td> Long/Easy/ High Accuracy  </td> </tr> </tbody> </table>   <table border="1"> <tbody> <tr> <td> Method of Measurement   </td> <td> References   </td> <td> Description   </td> <td colspan="2"> OECD-Approved Assay  </td> </tr> <tr> <td> Chemiluminescence   </td> <td> (Lu, C. et al., 2006;   Griendling, K. K., et al., 2016)  </td> <td> ROS can induce electron transitions in molecules, leading to electronically excited products. When the electrons transition back to ground state, chemiluminescence is emitted and can be measured. Reagents such as luminol and lucigenin are commonly used to amplify the signal.   </td> <td colspan="2"> No    </td> </tr> <tr> <td> Spectrophotometry   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> NO has a short half-life. However, if it has been reduced to nitrite (NO2-), stable azocompounds can be formed via the Griess Reaction, and further measured by spectrophotometry.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> Direct or Spin Trapping-Based electron paramagnetic resonance (EPR) Spectroscopy   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> The unpaired electrons (free radicals) found in ROS can be detected with EPR and is known as electron paramagnetic resonance. A variety of spin traps can be used.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> Nitroblue Tetrazolium Assay   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> The Nitroblue Tetrazolium assay is used to measure O2.− levels. O2.− reduces nitroblue tetrazolium (a yellow dye) to formazan (a blue dye), and can be measured at 620 nm.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> Fluorescence analysis of dihydroethidium (DHE) or Hydrocyans   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> Fluorescence analysis of DHE is used to measure O2.− levels.  O2.− is reduced to O2 as DHE is oxidized to 2-hydroxyethidium, and this reaction can be measured by fluorescence. Similarly, hydrocyans can be oxidized by any ROS, and measured via fluorescence.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> Amplex Red Assay   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> Fluorescence analysis to measure extramitochondrial or extracellular H2O2 levels. In the presence of horseradish peroxidase and H2O2, Amplex Red is oxidized to resorufin, a fluorescent molecule measurable by plate reader.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> Dichlorodihydrofluorescein Diacetate (DCFH-DA)   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> An indirect fluorescence analysis to measure intracellular H2O2 levels.  H2O2 interacts with peroxidase or heme proteins, which further react with DCFH, oxidizing it to dichlorofluorescein (DCF), a fluorescent product.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> HyPer Probe   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> Fluorescent measurement of intracellular H2O2 levels. HyPer is a genetically encoded fluorescent sensor that can be used for in vivo and in situ imaging.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> Cytochrome c Reduction Assay   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> The cytochrome c reduction assay is used to measure O2.− levels. O O2.− is reduced to O2 as ferricytochrome c is oxidized to ferrocytochrome c, and this reaction can be measured by an absorbance increase at 550 nm.   </td> <td colspan="2"> No  </td> </tr> <tr> <td> Proton-electron double-resonance imaging (PEDRI)   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> The redox state of tissue is detected through nuclear magnetic resonance/magnetic resonance imaging, with the use of a nitroxide spin probe or biradical molecule.   </td> <td colspan="2"> No              </td> </tr> <tr> <td> Glutathione (GSH) depletion   </td> <td> (Biesemann, N. et al., 2018)   </td> <td> A downstream target of the Nrf2 pathway is involved in GSH synthesis. As an indication of oxidation status, GSH can be measured by assaying the ratio of reduced to oxidized glutathione (GSH:GSSG) using a commercially available kit (e.g., <a href="http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html" rel="noreferrer noopener" target="_blank">http://www.abcam.com/gshgssg-ratio-detection-assay-kit-fluorometric-green-ab138881.html</a>).    </td> <td colspan="2"> No  </td> </tr> <tr> <td> Thiobarbituric acid reactive substances (TBARS)   </td> <td> (Griendling, K. K., et al., 2016)  </td> <td> Oxidative damage to lipids can be measured by assaying for lipid peroxidation with TBARS using a commercially available kit.    </td> <td colspan="2"> No  </td> </tr> <tr> <td> Protein oxidation (carbonylation)  </td> <td> (Azimzadeh et al., 2017; Azimzadeh et al., 2015; Ping et al., 2020)  </td> <td> Can be determined with ELISA or a commercial assay kit. Protein oxidation can indicate the level of oxidative stress.  </td> <td colspan="2"> No  </td> </tr> <tr> <td> Seahorse XFp Analyzer  </td> <td> Leung et al. 2018  </td> <td> The Seahorse XFp Analyzer provides information on mitochondrial function, oxidative stress, and metabolic dysfunction of viable cells by measuring respiration (oxygen consumption rate; OCR) and extracellular pH (extracellular acidification rate; ECAR).  </td> <td> No  </td> </tr> </tbody> </table>   Molecular Biology: Nrf2. Nrf2’s transcriptional activity is controlled post-translationally by oxidation of Keap1. Assays for Nrf2 activity include:   <table border="1"> <tbody> <tr> <td> Method of Measurement   </td> <td> References   </td> <td> Description   </td> <td> OECD-Approved Assay  </td> </tr> <tr> <td> Immunohistochemistry   </td> <td> (Amsen, D., de Visser, K. E., and Town, T., 2009)  </td> <td> Immunohistochemistry for increases in Nrf2 protein levels and translocation into the nucleus    </td> <td> No  </td> </tr> <tr> <td> qPCR   </td> <td> (Forlenza et al., 2012)  </td> <td> qPCR of Nrf2 target genes (e.g., Nqo1, Hmox-1, Gcl, Gst, Prx, TrxR, Srxn), or by commercially available pathway-based qPCR array (e.g., oxidative stress array from SABiosciences)   </td> <td> No  </td> </tr> <tr> <td> Whole transcriptome profiling via microarray or via RNA-seq followed by a pathway analysis  </td> <td> (Jackson, A. F. et al., 2014)  </td> <td> Whole transcriptome profiling by microarray or RNA-seq followed by pathway analysis (in IPA, DAVID, metacore, etc.) for enrichment of the Nrf2 oxidative stress response pathway  </td> <td> No  </td> </tr> </tbody> </table>

Taxonomic applicability: Occurrence of oxidative stress is not species specific.   Life stage applicability: Occurrence of oxidative stress is not life stage specific.  Sex applicability: Occurrence of oxidative stress is not sex specific.  Evidence for perturbation by prototypic stressor: There is evidence of the increase of oxidative stress following perturbation from a variety of stressors including exposure to ionizing radiation and altered gravity (Bai et al., 2020; Ungvari et al., 2013; Zhang et al., 2009).

High Mixed

High

All life stages

High High

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(2013), “Angiotensin II, NADPH oxidase, and redox signaling in the vasculature”, Antioxidants & redox signaling, Vol. 19/10, Mary Ann Liebert, Larchmont, <a href="https://doi.org/10.1089/ars.2012.4641" rel="noreferrer noopener" target="_blank">https://doi.org/10.1089/ars.2012.4641</a>  Ping, Z. et al. (2020), “Oxidative Stress in Radiation-Induced Cardiotoxicity”, Oxidative Medicine and Cellular Longevity, Vol. 2020, Hindawi, <a href="https://doi.org/10.1155/2020/3579143" rel="noreferrer noopener" target="_blank">https://doi.org/10.1155/2020/3579143</a>  Powers, S.K. and M.J. Jackson. (2008), “Exercise-Induced Oxidative Stress: Cellular Mechanisms and Impact on Muscle Force Production”, Physiological Reviews, Vol. 88/4, American Physiological Society, Rockville, <a href="https://doi.org/10.1152/physrev.00031.2007" rel="noreferrer noopener" target="_blank">https://doi.org/10.1152/physrev.00031.2007</a>  Raimondi, V., F. Ciccarese and V. Ciminale. (2020), “Oncogenic pathways and the electron transport chain: a dangeROS liason”, British Journal of Cancer, Vol. 122/2, Nature Portfolio, London, <a href="https://doi.org/10.1038/s41416-019-0651-y" rel="noreferrer noopener" target="_blank">https://doi.org/10.1038/s41416-019-0651-y</a>  Seen, S. and L. Tong. (2018), “Dry eye disease and oxidative stress”, Acta Ophthalmologica, Vol. 96/4, John Wiley & Sons, Inc., Hoboken, <a href="https://doi.org/10.1111/aos.13526" rel="noreferrer noopener" target="_blank">https://doi.org/10.1111/aos.13526</a>  Ungvari, Z. et al. (2013), “Ionizing Radiation Promotes the Acquisition of a Senescence-Associated Secretory Phenotype and Impairs Angiogenic Capacity in Cerebromicrovascular Endothelial Cells: Role of Increased DNA Damage and Decreased DNA Repair Capacity in Microvascular Radiosensitivity”, The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, Vol. 68/12, Oxford University Press, Oxford, <a href="https://doi.org/10.1093/gerona/glt057." rel="noreferrer noopener" target="_blank">https://doi.org/10.1093/gerona/glt057.</a>     Vargas-Mendoza, N. et al. (2021), “Oxidative Stress, Mitochondrial Function and Adaptation to Exercise: New Perspectives in Nutrition”, Life, Vol. 11/11, Multidisciplinary Digital Publishing Institute, Basel, <a href="https://doi.org/10.3390/life11111269" rel="noreferrer noopener" target="_blank">https://doi.org/10.3390/life11111269</a>  Wang, H. et al. (2019), “Radiation-induced heart disease: a review of classification, mechanism and prevention”, International Journal of Biological Sciences, Vol. 15/10, Ivyspring International Publisher, Sydney, <a href="https://doi.org/10.7150/ijbs.35460" rel="noreferrer noopener" target="_blank">https://doi.org/10.7150/ijbs.35460</a>   Zhang, R. et al. (2009), “Blockade of AT1 receptor partially restores vasoreactivity, NOS expression, and superoxide levels in cerebral and carotid arteries of hindlimb unweighting rats”, Journal of applied physiology, Vol. 106/1, American Physiological Society, Rockville, <a href="https://doi.org/10.1152/japplphysiol.01278.2007" rel="noreferrer noopener" target="_blank">https://doi.org/10.1152/japplphysiol.01278.2007</a>.  Zhao, R. Z. et al. (2019), “Mitochondrial electron transport chain, ROS generation and uncoupling”, International journal of molecular medicine, Vol. 44/1, Spandidos Publishing Ltd., Athens, <a href="https://doi.org/10.3892/ijmm.2019.4188" rel="noreferrer noopener" target="_blank">https://doi.org/10.3892/ijmm.2019.4188</a>  AOPWiki 2017-05-30T13:58:17

2026-02-11T07:05:27

Increase, DNA damage

Increase, DNA Damage

Molecular

DNA nucleotide damage, single, and double strand breaks occur in the course of cellular operations such as DNA repair and replication and can be induced directly and in neighboring “bystander” cells by internal or external stressors like reactive oxygen species, chemicals, and radiation. Ionizing radiation and RONS such as hydroxyl radicals or peroxide can create a range of lesions (a change in molecular structure) in the base of the nucleotide, with guanine particularly vulnerable because of its low redox potential (David, O'Shea et al. 2007). The same stressors can also break the sugar (deoxyribose)-phosphate backbone creating a single strand break. Simultaneous proximal breaks in both strands of DNA form double strand breaks, which are considered to be more destructive and mutagenic than lesions or single strand breaks. Double strand breaks can generate chromosomal abnormalities including changes in chromosomal number, breaks and gaps, translocations, inversions, and deletions (Yang, Craise et al. 1992; Haag, Hsu et al. 1996; Ponnaiya, Cornforth et al. 1997; Yang, Georgy et al. 1997; Unger, Wienberg et al. 2010; Behjati, Gundem et al. 2016; Morishita, Muramatsu et al. 2016). However, DNA lesions and single strand breaks can also be destructive and mutagenic. Lesions can lead to point mutations (David, O'Shea et al. 2007) or single strand breaks (Regulus, Duroux et al. 2007). Lesions and single strand breaks can also promote the formation of double strand breaks: replication fork collapse and double strand breaks sometimes occur during mitosis when the replisome encounters an unrepaired single strand break (Kuzminov 2001), and clustered lesions and closely opposed single strand breaks can also form double strand breaks (Chaudhry and Weinfeld 1997; Vispe and Satoh 2000; Shiraishi, Shikazono et al. 2017). Complex damage consists of any combination of closely opposed DNA lesions, abasic sites, crosslinks, single, or double strand breaks in proximity. While classically induced by ionizing radiation, there is also evidence that it can be induced by oxidative activity (Sharma, Collins et al. 2016) or even by a single oxidizing particle (Ravanat, Breton et al. 2014). Complex damage is more difficult to repair (Kuhne, Rothkamm et al. 2000; Stenerlow, Hoglund et al. 2000; Pinto, Prise et al. 2005; Rydberg, Cooper et al. 2005). DNA damage and resulting repair activity can trigger a halt in the cell cycle, cell death (apoptosis), and cause permanent changes to DNA including deletions, translocations, and sequence changes. DNA damage is also associated with an increase in genomic instability - the new appearance of DNA damage including double strand breaks, mutations, and chromosomal damage following repair of initial damage in affected cells or in clonal descendants or neighbors of DNA damaged cells. The mechanism behind this long term DNA damage is not clear, but telomere erosion appears to play a major role (Murnane 2012; Sishc, Nelson et al. 2015). Genomic instability is more common and longer lasting following complex damage (Ponnaiya, Cornforth et al. 1997), and is influenced by multiple factors including variants in DNA repair genes (Ponnaiya, Cornforth et al. 1997; Yu, Okayasu et al. 2001; Yin, Menendez et al. 2012), RONS (Dayal, Martin et al. 2008), estrogen (Kutanzi and Kovalchuk 2013), caspases (Liu, He et al. 2015), and telomeres (Sishc, Nelson et al. 2015).

DNA damage can be studied in isolated DNA, fixed cells, or living cells. Types of damage that can be detected include single and double strand breaks, nucleotide damage, complex damage, and chromosomal or telomere damage. The OECD test guideline for DNA synthesis Test No. 486 (OECD 1997) detects nucleotide excision repair, so it will reflect the formation of bulky DNA adducts but not the majority of oxidative damage to nucleotides, which is typically repaired via the Base Excision Repair pathway. The OECD test guideline alkaline comet assay Test No. 489 (OECD 2016) detects single and double strand breaks, including those arising from repair as well as some (alkali sensitive) nucleotide lesions including some lesions from oxidative damage. OECD tests for chromosomal damage and micronuclei Test No. 473, 475, 483, and 487 measure longer term effects of DNA damage but these tests require the damaged cell to subsequently undergo replication (OECD 2016; OECD 2016; OECD 2016; OECD 2016).  They can therefore reflect a wider range of sources of DNA damage including changes in mitosis. Finally, tests for mutations reveal past DNA damage that resulted in a heritable change, and these are described in the key event ‘Increase in Mutation’. Many other (non-test guideline) techniques have been used to examine specific forms of DNA damage (Table 1). Double strand breaks are commonly reported because of the significant risk attributed to breaks and the relative ease of detecting and quantifying them. Historically, single and double strand breaks were measured using gel electrophoresis, but are now commonly visualized microscopically using fluorescent or other labeled probes for double and single strand break repair such as H2AX and XRCC2.  Base lesions can also be detected using labeled probes for base excision repair enzymes, or by chemical methods such as mass spectroscopy. Refinements on these methods can be used to characterize complex or clustered damage, in which various forms of damage occur in close proximity on a DNA molecule (Lorat, Timm et al. 2016; Nikitaki, Nikolov et al. 2016). Certain challenges are common to all methods of detecting DNA damage. In the time required to initiate the detection method, some DNA may already be repaired, leading to undercounting of damage. On the other hand, apoptotic DSBs may be incorrectly included in a measurement of direct (non-apoptotic) induction of DSB damage unless controlled. All methods have difficulty distinguishing individual components of clustered lesions, and microscopic methods may undercount disparate breaks that are processed together in repair centers (Barnard, Bouffler et al. 2013). Methods that use isolated DNA (gel electrophoresis, analytical chemistry) are vulnerable to artifacts and must ensure that the DNA sample is protected from oxidative damage during extraction (Pernot, Hall et al. 2012; Barnard, Bouffler et al. 2013; Ravanat, Breton et al. 2014). Table 1. Common methods of detecting DNA damage <table border="1" cellpadding="0" cellspacing="0"> <tbody> <tr> <td style="height:22px; width:127px"> Target </td> <td style="height:22px; width:167px"> Name </td> <td style="height:22px; width:133px"> Method </td> <td style="height:22px; width:211px"> Strengths/Weaknesses </td> </tr> <tr> <td style="height:22px; width:127px"> Nucleotide damage </td> <td style="height:22px; width:167px"> Single cell gel electrophoresis (comet assay) with restriction enzymes (Collins 2004) </td> <td style="height:22px; width:133px"> Gel electrophoresis   </td> <td style="height:22px; width:211px"> A variant of the comet assay in which restriction enzymes allow the identification of different types of nucleotide damage. The comet assay is more sensitive than PFGE, detecting damage from 0.1 Gy ionizing radiation (Pernot, Hall et al. 2012). A reproducible high-throughput application of the assay is available (Ge, Prasongtanakij et al. 2014; Sykora, Witt et al. 2018), and the test requires only a small (single cell) sample. Requires destruction of the cell. </td> </tr> <tr> <td style="height:22px; width:127px"> Nucleotide damage </td> <td style="height:22px; width:167px"> Labeled probes including Biotrin OxyDNA and anti- 8-oxoguanine-DNA glycosylase (OGG1) for oxidative damage and AP endonuclease (APE1) for Base Excision Repair of less bulky lesions such as oxidative damage. </td> <td style="height:22px; width:133px"> Microscopy, FACS </td> <td style="height:22px; width:211px"> Most useful with FACS or other measures of average or relative intensity, as locations and numbers of damaged nucleotides can be difficult to distinguish using fluorescence microscopy. (Ogawa, Kobayashi et al. 2003; Nikitaki, Nikolov et al. 2016). </td> </tr> <tr> <td style="height:22px; width:127px"> Nucleotide damage </td> <td style="height:22px; width:167px"> High performance liquid chromatography (HPLC), tandem mass spectrometry (MS/MS) </td> <td style="height:22px; width:133px"> Analytical chemistry </td> <td style="height:22px; width:211px"> Capable of quantifying low levels of specific nucleotide lesions (Madugundu, Cadet et al. 2014; Ravanat, Breton et al. 2014). Requires destruction of the cell. </td> </tr> <tr> <td style="height:22px; width:127px"> Nucleotide damage </td> <td style="height:22px; width:167px"> Unscheduled DNA synthesis test OECD Test Guideline 486 (OECD 1997) </td> <td style="height:22px; width:133px"> Autoradiography </td> <td style="height:22px; width:211px"> Measures DNA damage that is repaired using Nucleotide Excision Repair - mostly bulky adducts (OECD (Organisation for Economic Co-operation and Development) 2016). </td> </tr> <tr> <td style="height:22px; width:127px"> Non-specific DNA strand breaks </td> <td style="height:22px; width:167px"> Single cell gel electrophoresis (comet assay), alkali conditions OECD Test Guideline 489 (OECD 2016) </td> <td style="height:22px; width:133px"> Gel electrophoresis </td> <td style="height:22px; width:211px"> When used in alkali conditions, the comet assay reveals single and double strand breaks and alkali-sensitive nucleotide lesions. See single cell gel electrophoresis (comet assay) with restriction enzymes above for further comments.     </td> </tr> <tr> <td style="height:22px; width:127px"> Single strand breaks </td> <td style="height:22px; width:167px"> Labeled probe pXRCC1 (Lorat, Brunner et al. 2015) </td> <td style="height:22px; width:133px"> Microscopy </td> <td style="height:22px; width:211px"> Fluorescent probes can label single strand breaks in cells, while immunogold labeling is able to distinguish multiple single strand breaks in clusters (Lorat, Timm et al. 2016; Nikitaki, Nikolov et al. 2016). </td> </tr> <tr> <td style="height:22px; width:127px"> Double strand breaks </td> <td style="height:22px; width:167px"> Single cell gel electrophoresis (comet assay), neutral conditions </td> <td style="height:22px; width:133px"> Gel electrophoresis </td> <td style="height:22px; width:211px"> Neutral conditions help minimize the release of single strand breaks coiled DNA and alkali lesions, allowing the measurement of double strand breaks. Since single strand breaks can still appear, assay is not very sensitive or specific to double strand breaks (Pernot, Hall et al. 2012). See single cell gel electrophoresis (comet assay) with restriction enzymes above for further comments. </td> </tr> <tr> <td style="height:22px; width:127px"> Double strand breaks </td> <td style="height:22px; width:167px"> Pulsed field gel electrophoresis (PFGE) </td> <td style="height:22px; width:133px"> Gel electrophoresis </td> <td style="height:22px; width:211px"> Permits the quantitative measurement of double strand breaks, and can be combined with immunoblotting to detect DNA-associated proteins (Lobrich, Rydberg et al. 1995; Kawashima, Yamaguchi et al. 2017). Considered less sensitive than comet assay, but detected damage from 0.25 Gy ionizing radiation (Gradzka and Iwanenko 2005). Requires destruction of the cell. </td> </tr> <tr> <td style="height:22px; width:127px"> Double strand breaks </td> <td style="height:22px; width:167px"> Labeled probes including phosphorylated H2AX, 53BP1, Ku70, ATM (Lorat, Brunner et al. 2015) </td> <td style="height:22px; width:133px"> Microscopy </td> <td style="height:22px; width:211px"> Fluorescent probes can label individual double breaks in cells allowing for quantification, with immunogold labeling resolving breaks in clusters (Lorat, Timm et al. 2016; Nikitaki, Nikolov et al. 2016). Sensitive: detects damage from 0.001 Gy ionizing radiation (Rothkamm and Lobrich 2003; Ojima, Ban et al. 2008). </td> </tr> <tr> <td style="height:22px; width:127px"> Chromosomal damage </td> <td style="height:22px; width:167px"> Chromosomal aberrations and micronuclei OECD Test Guidelines 473, 475, 483, and 487 (OECD 2016; OECD 2016; OECD 2016; OECD 2016) </td> <td style="height:22px; width:133px"> Microscopy </td> <td style="height:22px; width:211px"> Detects major DNA damage resulting from large breaks and rearrangements, or mitotic failures. Damage does not appear until DNA undergoes mitosis, so slower and limited to damage in replicating cells. Insensitive tosmall deletions and substitutions. </td> </tr> </tbody> </table>

CL:0000255

CL eukaryotic cell

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"Novel gene rearrangements in transformed breast cells identified by high-resolution breakpoint analysis of chromosomal aberrations." Endocrine-related cancer 17(1): 87-98.</a> <a name="_ENREF_45">Vispe, S. and M. S. Satoh (2000). "DNA repair patch-mediated double strand DNA break formation in human cells." The Journal of biological chemistry 275(35): 27386-27392.</a> <a name="_ENREF_46">Yang, T.-H., L. M. Craise, et al. (1992). "Chromosomal changes in cultured human epithelial cells transformed by low- and high-LET radiation." Adv Space Res 12(2-3): 127-136.</a> <a name="_ENREF_47">Yang, T. C., K. A. Georgy, et al. (1997). "Initiation of oncogenic transformation in human mammary epithelial cells by charged particles." Radiat Oncol Investig 5(3): 134-138.</a> <a name="_ENREF_48">Yin, Z., D. Menendez, et al. (2012). "RAP80 is critical in maintaining genomic stability and suppressing tumor development." Cancer research 72(19): 5080-5090.</a> <a name="_ENREF_49">Yu, Y., R. Okayasu, et al. (2001). "Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene." Cancer Res 61(5): 1820-1824.</a> AOPWiki 2016-11-29T18:41:30

2019-05-08T12:28:46

Increase, Cell cycle arrest

Cell cycle arrest

Cellular

AOPWiki 2026-07-09T04:05:55

2026-07-09T04:05:55

Impact on sirtuins-related aging signaling pathway gene expression

Molecular

AOPWiki 2026-07-09T03:52:59

2026-07-09T03:52:59

Disruption, Mitochondrial dysfunction

Mitochondrial dysfunction

Cellular

AOPWiki 2026-07-09T04:54:21

2026-07-09T04:54:21

Increase, Myocardial and vascular structural remodeling

Myocardial and vascular structural remodeling

Tissue

AOPWiki 2026-07-09T05:00:47

2026-07-09T05:00:47

Increase, Systemic inflammation

Systemic inflammation

Cellular

AOPWiki 2026-07-09T05:02:47

2026-07-09T05:02:47

Increase, Blood pressure elevation

Blood pressure elevation

Tissue

AOPWiki 2026-07-09T05:06:35

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Increase, Cardiovascular aging

Cardiovascular aging

Individual

AOPWiki 2026-07-09T05:08:16

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Increase, Telomere attrition

Molecular

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AOPWiki 2026-07-09T08:19:33

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Binding and activation of AhR lead to cardiovascular aging

Shiheng Gui

Shiheng Gui Ruifang Fan

BY-SA

2.8

This AOP aims to elucidate the key biological pathways through which polycyclic aromatic hydrocarbons (PAHs) activate the aryl hydrocarbon receptor (AhR) and promote cardiovascular aging. AhR is a ligand-dependent transcription factor that plays a central role in regulating the expression of xenobiotic metabolism and detoxification-related enzymes (such as the CYP family); simultaneously, AhR is expressed in various tissue types including vascular endothelium, and its activation is closely associated with endothelial dysfunction, inflammatory responses, and vascular remodeling processes. As exogenous pollutants, PAHs may cause multi-system damage after entering the organism. In this AOP, the binding and activation of PAHs to AhR is defined as the Molecular Initiating Event (MIE). Subsequently, AhR signaling can directly or indirectly inhibit the expression or activity of SIRT1/SIRT6, serving as Key Event 1 (KE1), and induce DNA damage responses, further leading to upregulation of p16 and p21, accompanied by aging-related changes including enhanced systemic inflammation and oxidative stress, telomere attrition, and mitochondrial dysfunction. The persistent cellular damage described above ultimately drives structural and functional remodeling of the myocardium and vasculature, manifested as increased vascular calcium deposition, elevated blood pressure, and consequently the formation of cardiovascular aging as the Adverse Outcome (AO). We have identified multiple key events in this pathway and delineated the logical relationships between key events; based on this, we have constructed this AOP to describe the molecular mechanisms by which AhR binding and activation lead to cardiovascular aging. Polycyclic aromatic hydrocarbons (PAHs) refer to hydrocarbon compounds containing two or more benzene rings in their molecular structure, primarily originating from incomplete combustion of organic matter(Zhang, 2017) . PAHs are widely distributed in environmental water, air, soil, and food. Dietary intake, respiration, and dermal contact are the main routes of PAH exposure, characterized by persistence, passivity, and inevitability, increasing cancer risk and causing high incidence of cardiovascular diseases. Numerous population epidemiological studies have shown that PAHs exposure are closely associated with the development of cardiovascular diseases such as hypertension, atherosclerosis, and ischemic heart disease(Curfs et al., 2004; Xu et al., 2021) . Given their widespread environmental distribution and potential toxicity, the United States Environmental Protection Agency (EPA) has listed 16 of them as priority controlled toxic organic pollutants. Therefore, it is necessary to assess the health risks of PAHs based on the AOP (Adverse Outcome Pathway) framework.

adjacent

High

Moderate adjacent

High

High adjacent

High

High adjacent

High

High adjacent

High

High adjacent

High

High adjacent

High

Moderate adjacent

High

High adjacent

High

High adjacent

Moderate

High Male

High

During brain development, adulthood and aging

Low High

As the DNA damage effects of PAHs are widely recognized, previous research has primarily focused on the carcinogenic, teratogenic, and mutagenic effects induced by PAH-mediated DNA damage. However, DNA damage is also an important driving factor in accelerating cellular senescence, and cellular senescence is an important pathway for suppressing cellular malignant transformation; therefore, this Adverse Outcome Pathway (AOP) focuses on the association between PAH exposure and cardiovascular aging. However, current in vivo and in vitro evidence investigating PAH exposure-induced cardiovascular toxic effects remains relatively limited. Moreover, existing in vivo or in vitro studies typically focus on single or a few PAHs, and the exposure doses set are high, making it difficult to reflect the adverse effects of mixed PAHs at environmental doses on the cardiovascular system in the general population. Therefore, low-dose mixed animal exposure, cell experiments, and computer simulation studies are needed to investigate the adverse effects of mixed exposure to 16 priority-controlled PAHs on the cardiovascular system from the perspective of aging. This AOP takes AhR activation as the initiating event; PAHs can directly activate AhR(Das et al., 2016), then directly or indirectly inhibit the expression of SIRT1/SIRT6 in the cardiovascular system, and induce DNA damage responses, further leading to upregulation of p16 and p21, accompanied by aging-related changes including enhanced systemic inflammation and oxidative stress, telomere attrition, and mitochondrial dysfunction (Bin et al., 2010; Malik and Czajka, 2013) . Experimental results can be obtained from various models, including experimental animals, mice, and cell lines. Among these, in vivo animal experiments, in vitro experiments, and computer simulation evidence can confirm the associations between the Molecular Initiating Event (MIE) and Key Event Relationships (KERs). In HUVEC cells, studies have found that exposure to low doses (10-100 µM) of naphthalene, fluoranthene, and fluorene can cause Ca²⁺ ion influx, promote eNOS activation, and further lead to increased NO synthesis(Li et al., 2004) . This suggests that the negative regulatory effect between PAH exposure levels and blood pressure may be closely related to PAH-promoted NO synthesis in endothelial cells. Similarly, in HUVEC cells, exposure to environmental doses of mixed 16 priority-controlled PAHs caused inflammatory responses and oxidative stress, and significantly decreased migration and tube formation capabilities(He et al., 2022). In rat models, after B[a]P exposure, significant increases in systolic blood pressure, diastolic blood pressure, and mean arterial pressure were observed in rats, with significantly decreased maximal acetylcholine-stimulated aortic relaxation responses(Gan et al., 2012) . In mouse models, B[a]P exposure caused systemic inflammation in apolipoprotein-deficient (ApoE⁻/⁻) mice and led to atherosclerosis development; exposure to 16 priority-controlled PAHs promoted atherosclerotic plaque formation in ApoE⁻/⁻ mice by upregulating miR-155 and inhibiting SERPIND1 expression (He et al., 2021) . Additionally, in zebrafish models, exposure to Pyr, B[a]P, and B[k]P all caused cardiac developmental abnormalities (Zhang et al., 2021). Meanwhile, combining epidemiological surveys and experimental research results, PAH exposure has significant effects on cardiovascular aging, particularly on blood pressure, atherosclerosis formation, cardiac development, and heart rate. Existing studies have found that urinary 1-OHPhe levels in the hypertension group (0.152 µg/g) were significantly higher than those in the non-hypertension group (0.128 µg/g) (Lee et al., 2020) . Another study found that for every 1 µg/mmol increase in urinary 4-OHPhe or total -OHPAHs content, the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) increased by 12.63% or 11.91%, respectively (p < 0.05) (Yin et al., 2017) . Pregnancy and infancy are critical time windows for cardiac development, relatively sensitive to pollutant exposure. Maternal occupational PAH exposure during pregnancy increases the risk of congenital heart defects (CHD) in offspring, and among occupationally PAH-exposed populations, PAH metabolite levels are associated with decreased heart rate, with a dose-response relationship (Deng et al., 2022; Li et al., 2012).

MIE1: AhR activation PAHs (such as benzo[a]pyrene) enter cells as ligands and bind to AhR in the cytoplasm, triggering dissociation of AhR from the molecular chaperone complex (HSP90, XAP2, p23), nuclear translocation, and heterodimer formation with ARNT, thereby binding to XRE sequences to initiate target gene transcription. AhR activation not only initiates Phase I metabolic reactions but also lays the foundation for oxidative stress and inflammatory responses. KE1: Oxidative stress Oxidative stress refers to the disruption of redox balance in vivo or within cells, resulting in massive production of ROS (including superoxide anion, hydrogen peroxide, and hydroxyl radicals), while simultaneously consuming intracellular antioxidant substances (GSH, SOD, CAT), exceeding the scavenging capacity of the antioxidant defense system. KE2: Impact on sirtuins-related aging signaling pathway gene expression Among the sirtuins family, SIRT1 and SIRT6 are known as "longevity genes" and are NAD⁺-dependent deacetylases that play important roles in maintaining mitochondrial function and integrity, DNA damage repair, telomere maintenance, and cardiovascular homeostasis. KE3: DNA damage ROS and PAH active metabolites (such as BPDE) directly attack DNA, forming DNA adducts and leading to double-strand breaks or base mutations. KE4: Cell cycle arrest Both p16INK4a and p21Cip1 are cell cycle arrest proteins. When DNA damage occurs within cells, cell cycle checkpoints are activated, cell cycle arrest protein expression increases, causing cell cycle stagnation. KE5: Telomere attrition Telomeres serve as protective structures at chromosome ends; their attrition (length shortening or structural dysfunction) is caused by ROS-mediated oxidative damage and end replication problems during DNA replication. KE6: Mitochondrial dysfunction With increasing age, various adverse factors accumulate within mitochondria, such as mtDNA mutations and changes in mitochondrial dynamics, which can cause mitochondrial dysfunction, increased ROS generation, and further increase mitochondrial membrane permeability, thereby triggering inflammation and cell death. When mtDNAcn is abnormal, mitochondria are facing stress, which is one manifestation of mitochondrial dysfunction. KE7: Systemic inflammation An immune process occurring within cardiovascular tissues characterized by immune cell infiltration, inflammatory factor release, tissue damage, and repair responses. KE8: Myocardial and vascular structural remodeling Myocardial and vascular structural remodeling includes ventricular hypertrophy, thinning and loose structure of ventricular walls, focal vascular proliferation, and disordered arrangement of vascular smooth muscle, providing structural basis for subsequent blood pressure elevation and vascular calcification. KE9: Blood pressure elevation Vascular aging leads to increased vascular stiffness, disordered secretion of vasoactive substances, decreased vascular diastolic regulation capacity, and increased susceptibility to hypertension. Blood pressure elevation is manifested as sustained elevation of arterial systolic or diastolic pressure; hypertension accelerates vascular remodeling and calcification.

<table align="center" cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:151px"> Essentiality of KE </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:72px"> Definitional Question </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:118px"> High (Strong) </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:106px"> Moderate </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:106px"> Low (Weak) </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:151px">   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:72px"> If the upstream KE is blocked, will the downstream KE and/or AO be prevented? </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:118px"> Direct evidence from specifically designed experimental studies indicating that at least one important KE is essential </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:106px"> Indirect evidence suggesting that sufficient modification of the expected modulating factor would weaken or enhance the KE </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:106px"> No or contradictory experimental evidence proving the essentiality of any KE </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> KE1: Oxidative stress </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:72px"> Moderate </td> <td colspan="3" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:330px"> Extracellular signaling molecules bind and activate AhR, inducing CYP1A1/1B1 expression, metabolizing PAHs, and producing large amounts of ROS. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> KE2: Impact on sirtuins-related aging signaling pathway gene expression </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:72px"> High </td> <td colspan="3" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:330px"> The AhR/ARNT complex binds to XREs (xenobiotic response elements) in the SIRT1/SIRT6 promoter regions, inhibiting transcription. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> KE3: DNA damage </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:72px"> High </td> <td colspan="3" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:330px"> SIRT1/SIRT6 participate in DNA repair; reduced expression of both leads to decreased repair efficiency and accumulation of DNA damage. PAHs can directly and competitively bind to DNA strand binding sites in SIRT6, limiting its ability to bind damaged DNA strands, causing decreased DNA damage response capability of SIRT6, and exacerbating DNA damage in the cardiovascular system. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> KE4: Cell cycle arrest </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:72px"> High </td> <td colspan="3" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:330px"> DNA damage accumulation activates cell cycle checkpoints, cell cycle arrest proteins p16/p21 expression increases, causing stable cell cycle arrest. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> KE5: Telomere attrition </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:72px"> High </td> <td colspan="3" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:330px"> DNA damage can cause telomere dysfunction, telomere binding protein TRF2 expression is inhibited, and p53 expression is activated, thereby promoting cellular senescence or apoptosis. Telomerase activity is inhibited in senescent cells. The p53/p21 and p16/pRB pathways may synergistically limit telomerase expression. ROS continuously attacks telomere DNA. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> KE6: Mitochondrial dysfunction </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:72px"> High </td> <td colspan="3" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:330px"> DNA damage can cause mitochondrial dysfunction by inhibiting PGC-1α through p53, reducing mitochondrial biogenesis; increased ROS generation further increases mitochondrial membrane permeability, potentially causing abnormal mtDNAcn. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> KE7: Systemic inflammation </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:72px"> Moderate </td> <td colspan="3" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:330px"> Chronic inflammation caused by oxidative stress activates pathways such as NF-κB and releases pro-inflammatory cytokines such as TNF-α, causing cardiovascular system aging. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> KE8: Myocardial and vascular structural remodeling </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:72px"> High </td> <td colspan="3" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:330px"> Decreased SIRT1/SIRT6 expression causes cardiovascular aging and myocardial and vascular remodeling. Inflammatory factors promote myocardial and vascular structural remodeling. Environmental doses of PAHs cause ventricular hypertrophy in rats, while high concentrations of PAH exposure cause thinning of ventricular walls and structural dilation. High concentration PAH exposure causes focal arterial proliferation, disordered smooth muscle arrangement, and increased arterial calcium deposition, causing vascular structural changes. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> KE9: Blood pressure elevation </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:72px"> High </td> <td colspan="3" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:330px"> Decreased vascular compliance leads to increased peripheral resistance. Increased arterial stiffness leads to elevated systolic pressure and increased pulse pressure difference. </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:151px"> AO: Cardiovascular aging </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:72px"> High </td> <td colspan="3" style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:330px"> Cardiovascular aging caused by hypertension is usually associated with cardiovascular structural and functional abnormalities; sustained hypertension accelerates increased cardiac afterload, myocardial hypertrophy, and deterioration of vascular lesions. </td> </tr> </tbody> </table>

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

Not Specified

[1]   Bin, P., Leng, S., Cheng, J., Pan, Z.-f., Duan, H., Dai, Y., Li, H.-s., Niu, Y., Liu, Q.-j., Liu, Q.-j., Zheng, Y.-x., 2010. [Association between telomere length and occupational polycyclic aromatic hydrocarbons exposure]. Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine] 44 6, 535-538 [2]   Curfs, D.M., Lutgens, E., Gijbels, M.J., Kockx, M.M., Daemen, M.J., van Schooten, F.J., 2004. Chronic exposure to the carcinogenic compound benzo[a]pyrene induces larger and phenotypically different atherosclerotic plaques in ApoE-knockout mice. Am J Pathol 164, 101-108.10.1016/s0002-9440(10)63101-x [3]   Das, D., Panda, P., Naik, P.P., Mukhopadhyay, S., Sinha, N., Bhutia, S., 2016. Phytotherapeutic approach: a new hope for polycyclic aromatic hydrocarbons induced cellular disorders, autophagic and apoptotic cell death. Toxicology Mechanisms and Methods 27, 1-54.10.1080/15376516.2016.1268228 [4]   Deng, C., Pu, J., Deng, Y., Xie, L., Yu, L., Liu, L., Guo, X., Sandin, S., Liu, H., Dai, L., 2022. Association between maternal smoke exposure and congenital heart defects from a case-control study in China. Sci Rep 12, 14973.10.1038/s41598-022-18909-y [5]   Gan, T.E., Xiao, S.P., Jiang, Y., Hu, H., Wu, Y.H., Duerksen-Hughes, P.J., Sheng, J.Z., Yang, J., 2012. Effects of Benzo(a)pyrene on the Contractile Function of the Thoracic Aorta of Sprague-dawley Rats. Biomedical and Environmental Sciences 25, 549-556.<a href="https://doi.org/10.3967/0895-3988.2012.05.008" style="color:#467886; text-decoration:underline">https://doi.org/10.3967/0895-3988.2012.05.008</a> [6]   He, J., Pang, Q., Huang, C., Xie, J., Hu, J., Wang, L., Wang, C., Meng, L., Fan, R., 2022. Environmental dose of 16 priority-controlled PAHs mixture induce damages of vascular endothelial cells involved in oxidative stress and inflammation. Toxicology in Vitro 79, 105296.<a href="https://doi.org/10.1016/j.tiv.2021.105296" style="color:#467886; text-decoration:underline">https://doi.org/10.1016/j.tiv.2021.105296</a> [7]   He, X.N., Xin, J.Y., Zhan, J.L., Wu, F.K., Hou, J., Sun, Z., Wang, J., Zhang, X.L., Bai, Y.C., 2021. Polycyclic aromatic hydrocarbons induce endothelial injury through miR‐155 to promote atherosclerosis. Environmental and Molecular Mutagenesis 62, 409-421.10.1002/em.22454 [8]   Lee, T.W., Kim, D.H., Ryu, J.Y., 2020. Association between urinary polycyclic aromatic hydrocarbons and hypertension in the Korean population: data from the Second Korean National Environmental Health Survey (2012-2014). Sci Rep 10, 17142.10.1038/s41598-020-74353-w [9]   Li, C.-H., Lee, C.-C., Juang, H.-A., Kang, J.-J., 2004. Activation and up-regulation of nitric oxide synthase in human umbilical vein endothelial cells by polycyclic aromatic hydrocarbons. Toxicology letters 151, 367-374.10.1016/j.toxlet.2004.03.003 [10] Li, X., Feng, Y., Deng, H., Zhang, W., Kuang, D., Deng, Q., Dai, X., Lin, D., Huang, S., Xin, L., He, Y., Huang, K., He, M., Guo, H., Zhang, X., Wu, T., 2012. The dose-response decrease in heart rate variability: any association with the metabolites of polycyclic aromatic hydrocarbons in coke oven workers? PLoS One 7, e44562.10.1371/journal.pone.0044562 [11] Malik, A.N., Czajka, A., 2013. Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? Mitochondrion 13, 481-492 [12] Xu, C., Liu, Q., Liang, J., Weng, Z., Xu, J., Jiang, Z., Gu, A., 2021. Urinary biomarkers of polycyclic aromatic hydrocarbons and their associations with liver function in adolescents. Environmental Pollution 278, 116842.<a href="https://doi.org/10.1016/j.envpol.2021.116842" style="color:#467886; text-decoration:underline">https://doi.org/10.1016/j.envpol.2021.116842</a> [13] Yin, W., Hou, J., Xu, T., Cheng, J., Li, P., Wang, L., Zhang, Y., Wang, X., Hu, C., Huang, C., Yu, Z., Yuan, J., 2017. Obesity mediated the association of exposure to polycyclic aromatic hydrocarbon with risk of cardiovascular events. The Science of the total environment 616-617.10.1016/j.scitotenv.2017.10.238 [14] Zhang, S., Ou, K., Huang, J., Fang, L., Wang, C., 2021. In utero exposure to mixed PAHs causes heart mass reduction in adult male mice. Ecotoxicology and environmental safety 225, 112804.10.1016/j.ecoenv.2021.112804 [15] Zhang, Z., 2017. A review of polycyclic aromatic hydrocarbons (PAHs) research progress in China based on CNKI database. AIP Conference Proceedings 1820.10.1063/1.4977385   AOPWiki 2026-07-09T03:29:56

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