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

208-96-8

HXGDTGSAIMULJN-UHFFFAOYSA-N

Acenaphthylene

acenaftileno acenaphthyene Acenaphthylen Acenaphtylene Cyclopenta[de]naphthalene NSC 59821

DTXSID3023845

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

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

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

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

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

79-94-7

VEORPZCZECFIRK-UHFFFAOYSA-N

3,3',5,5'-Tetrabromobisphenol A

3,3’,5,5’-Tetrabromobisphenol A (Tetrabromobisphenol A) (Phenol, 4,4'-(1-methylethylidene)bis[2,6-dibromo-) (TBBPA) Phenol, 4,4'-(1-methylethylidene)bis[2,6-dibromo- 2, 2-Bis (4'-hydroxy-3',-5'-dibromophenyl) propane 2,2',6,6'-Tetrabrom-4,4'-isopropylidendiphenol 2,2',6,6'-tetrabromo-4,4'-isopropilidendifenol 2,2',6,6'-tetrabromo-4,4'-isopropylidenediphenol 2,2',6,6'-Tetrabromobisphenol A 2,2-Bis(3,5-dibromo-4-hydroxyphenyl)propane 2,2-Bis(4-hydroxy-3,5-dibromophenyl)propane 3,5,3',5'-Tetrabromobisphenol A 4,4'-(1-Methylethylidene)bis[2,6-dibromophenol] 4,4'-Isopropylidenebis[2,6-dibromophenol] BIS(PHENOL, 2,6-DIBROMO), 4,4'-(1-METHYLETHYLIDENE) BISPHENOL A, TETRABROMO- BISPHENOL, 4,4'-(1-METHYLETHYLIDENE)TETRABROMO- Bromdian Fire Guard 2000 Firemaster BP 4A NSC 59775 Phenol, 4,4'-isopropylidenebis[2,6-dibromo- Saytex CP 2000 Saytex RB 100 Saytex RB 100PC Tetrabromobisphenol A TETRABROMOBISPHENOL-A Tetrabromodian Tetrabromodiphenylolpropane

DTXSID1026081

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

PR:000006101

PR cytochrome P450 1A1

GO:0010467

GO gene expression

MP:0003674

MP oxidative stress

WIKI increased

Naphthalene

2026-07-03T11:28:12

Acenaphthylene

2026-07-09T06:14:20

Acenaphthene

2026-07-09T06:10:36

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

Benz(a)anthracene

2026-07-03T11:31:06

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

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

Tetrabromobisphenol A

2017-03-10T00:10:21

2018-07-20T05:36:51

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

7904

NCBI Acipenser transmontanus

WCS_8022

common ecological species Oncorhynchus mykiss

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

Activation of PPARγ

Molecular

AOPWiki 2018-03-18T09:40:59

2018-03-18T09:40:59

Up Regulation, CYP1A1

Molecular

CL:0000182

CL hepatocyte

High High

AOPWiki 2016-11-29T18:41:22

2017-09-16T10:15:14

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, Hepatic inflammation

Hepatic inflammation

Tissue

AOPWiki 2026-07-09T09:01:01

2026-07-09T09:01:01

Increased , Fatty acid synthesis and transport

Increased fatty acid synthesis and transport

Tissue

AOPWiki 2026-07-09T09:03:33

2026-07-09T09:03:33

Decrease, Fatty acid β-oxidation

Decrease, FAO

Cellular

AOPWiki 2020-11-25T10:26:08

2020-11-25T10:26:08

Increase, Abnormal lipid accumulation

Abnormal lipid accumulation

Organ

AOPWiki 2026-07-09T09:06:32

2026-07-09T09:06:32

Increase, Hepatocyte injury

Hepatocyte injury

Tissue

AOPWiki 2026-07-09T09:07:58

2026-07-09T09:08:59

Abnormal lipid metabolism

Cellular

AOPWiki 2022-04-07T09:21:33

2022-04-07T09:21:33

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AOPWiki 2026-07-09T09:10:56

2026-07-09T09:10:56

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AOPWiki 2026-07-09T09:11:41

2026-07-09T09:11:41

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AOPWiki 2026-07-09T09:12:38

2026-07-09T09:12:38

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AOPWiki 2026-07-09T09:14:38

2026-07-09T09:14:38

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AOPWiki 2026-07-09T09:11:24

2026-07-09T09:11:24

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AOPWiki 2026-07-09T09:12:22

2026-07-09T09:12:22

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AOPWiki 2026-07-09T09:13:39

2026-07-09T09:13:39

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AOPWiki 2026-07-09T09:26:43

2026-07-09T09:26:43

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AOPWiki 2026-07-09T09:27:56

2026-07-09T09:27:56

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AOPWiki 2026-07-09T09:28:17

2026-07-09T09:28:17

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AOPWiki 2026-07-09T09:29:01

2026-07-09T09:29:01

Binding and activation of AhR/PPARγ lead to lipid metabolism disorders

Shiheng Gui

Ruifang Fan、Shiheng Gui

BY-SA

2.8

Polycyclic aromatic hydrocarbons (PAHs) are a class of persistent organic pollutants derived from incomplete combustion processes, widely present in tobacco smoke, vehicle exhaust, industrial emissions, and high-temperature cooking fumes. Humans can be exposed through multiple routes including the respiratory tract, digestive tract, and skin, posing clear risks of teratogenicity, carcinogenicity, and mutagenicity. This Adverse Outcome Pathway (AOP) systematically describes how PAHs, upon exposure, bind to and activate the Aryl Hydrocarbon Receptor (AhR), inducing high mRNA expression of the phase I metabolic enzyme CYP1A1, while simultaneously triggering oxidative stress and elevated levels of pro-inflammatory factors. Through the interactive regulation between AhR and the Peroxisome Proliferator-Activated Receptor gamma (PPARγ) signaling pathways, this leads to an imbalance in the expression profile of lipid metabolism-related genes. Specifically, genes related to lipid synthesis and fatty acid transport (SREBP-1, DGAT1, FAS, CD36) are significantly upregulated, whereas genes related to fatty acid β-oxidation (PPARα, CPT1A) are significantly downregulated. The cascading effects of these molecular events ultimately drive abnormal elevations in hepatic triglyceride (TG) and total cholesterol (TC) levels, leading to lipid metabolism disorders. This AOP constructs a complete causal chain from the molecular initiating event to the adverse outcome, providing a mechanistic foundation and theoretical basis for the quantitative health risk assessment of PAHs and the targeted prevention and control of metabolic diseases. Polycyclic aromatic hydrocarbons (PAHs) are a class of persistent organic compounds composed of two or more fused benzene rings, ubiquitous in the environment(Biache et al., 2014). They are primarily generated through incomplete combustion processes, such as vehicle exhaust, industrial emissions, tobacco smoke, and cooking fumes (Zhang and Tao, 2009), and are intrinsic to the optical properties and toxicity of combustion particles. Humans are mainly exposed to PAHs through inhalation, dietary intake, and dermal contact (Kim et al., 2013). The health effects of PAHs depend on both the exposure concentration, duration, and route, as well as the relative toxicity of individual PAHs (Mallah et al., 2022). The United States Environmental Protection Agency (USEPA) has listed 16 PAHs as priority control pollutants based on their environmental concentrations and biological toxicity (Mallah et al., 2022). Generally, PAHs are metabolized and detoxified by the liver; therefore, prolonged exposure to PAHs can exacerbate hepatic detoxification overload. As the core organ for lipid metabolism, the liver maintains lipid homeostasis through pathways including fatty acid uptake and export, de novo fatty acid synthesis, and fatty acid β-oxidation (Badmus et al., 2022). Imbalance in this regulatory network leads to intrahepatocellular lipid accumulation, accompanied by abnormal elevations in serum triglycerides (TG) and total cholesterol (TC), and may even induce cardiovascular diseases (Zhao et al., 2023). Therefore, it is necessary to assess the health risks of PAHs to the liver based on the Adverse Outcome Pathway (AOP) framework.

adjacent

High

High adjacent

High

High adjacent

High

High adjacent

High

High adjacent

High

High adjacent

High

High adjacent

High

High adjacent

High

High adjacent

Moderate

Moderate adjacent

Moderate

Moderate adjacent

High

High Male

High

During development and at adulthood

Low High

Since PAHs are volatile hydrocarbons produced by incomplete combustion of organic matter, previous research has focused on the damage caused by PAHs to the respiratory system, particularly the lungs. Epidemiological studies have also found that PAH exposure may increase the risk of fatty liver disease by affecting hepatic lipid metabolism (Zhou et al., 2024). Therefore, this Adverse Outcome Pathway (AOP) focuses on the association between PAH exposure and abnormal hepatic lipid metabolism. However, current in vivo and in vitro evidence exploring PAH exposure-induced abnormal hepatic lipid metabolism remains relatively scarce, and the specific mechanisms are still unclear. Moreover, existing studies have mostly focused on the exposure toxicity of individual PAH congeners, which cannot reflect real-world environmental PAH exposure scenarios. Therefore, this AOP uses the concentrations of 16 priority-controlled PAHs detected in the serum of the general population as a reference, setting three exposure concentration gradients to investigate the hepatotoxicity of PAH exposure and the molecular mechanisms by which it affects hepatic lipid metabolism. This AOP takes AhR activation as the initiating event. PAHs can directly activate AhR, accompanied by enhanced systemic inflammation and oxidative stress, leading to significantly increased expression of PPARγ and genes related to lipid synthesis and fatty acid transport, significantly decreased expression of genes related to fatty acid β-oxidation, abnormal lipid accumulation, elevated hepatic TG and TC, and ultimately inducing abnormal lipid metabolism. Experimental results can be obtained from various models, including experimental animals and mice. Evidence from in vivo animal experiments, in vitro experiments, and computational simulations can confirm the associations between the Molecular Initiating Event (MIE) and Key Event Relationships (KERs). In Hepa 1c1c7 cells, studies have found that benzo[a]pyrene exposure can cause AhR activation and lead to oxidative stress and lipid peroxidation (Elbekai et al., 2004). This indicates that AhR activation is the core initiating event for PAH-induced disruption of lipid metabolism. Similarly, in HepG2 cells, B[a]P exposure activates the Aryl Hydrocarbon Receptor (AHR), inducing cytochrome P450 enzyme expression, and further CYP1B1-induced mTOR activation and decreased lipophagy, ultimately leading to lipid accumulation (Bu et al., 2024). Animal experiments demonstrate that AhR activation significantly promotes the development of abnormal lipid metabolism. In mouse models, low-dose B[a]P exposure can induce hepatic lipid deposition (Li et al., 2023) . Similarly, in mouse models, BbF exposure activates the AhR receptor, elevates CYP enzyme levels, upregulates SREBP-1c and SCD1, accompanied by inflammatory responses and hepatic oxidative stress, ultimately leading to lipid metabolism disorders (Liu et al., 2025) . Among CYP enzymes, CYP1A1 is a key enzyme in oxidative stress; its overexpression can trigger oxidative stress by affecting reactive oxygen species (ROS) and superoxide dismutase (SOD) levels. After African catfish were exposed to benzo[b]fluoranthene, hepatic antioxidant markers (glutathione-S-transferase, SOD, catalase) were significantly reduced, and oxidative stress was exacerbated (Obanya et al., 2019). Meanwhile, epidemiological studies in human populations have found that PAH exposure is associated with disease risk. PAH exposure has significant effects on lipid metabolism, particularly on the development of dyslipidemia and fatty liver disease. One study found that elevated levels of urinary PAH metabolites were associated with increased concentrations of total cholesterol (TC) and LDL-C (Ma et al., 2019). Similarly, a study of 827 adolescents found that 22.13% of the adolescents had metabolic syndrome, and their urinary levels of PAH metabolites such as 2-hydroxynaphthalene (2-NAP) and 2-hydroxyfluorene (2-FLU) were significantly higher than those in the non-metabolic syndrome group (Wu et al., 2025). Occupational exposure is an important pathway for elevated internal PAH burdens in young and middle-aged populations (Jiang and Zhao, 2024). Typical high-risk occupations include coke oven workers and firefighters, whose work environments have significantly higher PAH concentrations than the general population (Pále&scaron;ová et al., 2023). In addition, tobacco use rates are higher in this age group, and smoking behavior can further increase PAH exposure. Studies have shown that urinary PAH biomarker levels in smokers are significantly higher than in non-smokers (Wang et al., 2019).

MIE: AhR activation After entering target cells as exogenous ligands, polycyclic aromatic hydrocarbons (PAHs) bind with high affinity to the Aryl Hydrocarbon Receptor (AhR), which is maintained in the cytoplasm by a chaperone complex including HSP90, XAP2, and p23. This binding induces conformational changes in AhR and releases the chaperones, exposing its nuclear localization signal. AhR then rapidly translocates to the nucleus, forms a heterodimer with the AhR Nuclear Translocator (ARNT), recognizes and binds to xenobiotic response elements (XREs) in the promoter regions of target genes, and initiates the transcription of phase I metabolic enzymes such as CYP1A1 and downstream inflammatory genes, thereby triggering the molecular initiating event of the entire toxicity cascade. MIE: PPARγ activation Under PAH exposure conditions, the Peroxisome Proliferator-Activated Receptor gamma (PPARγ), a core nuclear receptor regulating adipogenesis and lipid storage, undergoes abnormal changes in its activity state (activation or functional remodeling). It forms a heterodimer with the Retinoid X Receptor (RXR) and binds to PPRE response elements, directly regulating the transcription of downstream lipid metabolism target genes. This event, together with AhR activation, constitutes the MIE, laying the molecular foundation for subsequent lipid synthesis and oxidation imbalance through the interaction of two nuclear receptor signaling pathways. KE1: Upregulated CYP1A1 mRNA leves Driven by the binding of the AhR-ARNT dimer to XREs, the transcriptional level of the CYP1A1 gene is significantly upregulated, followed by increased protein expression and enzymatic activity. This accelerates the metabolic activation of PAHs, generating highly reactive electrophilic intermediate metabolites (such as benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide, BPDE), while simultaneously producing large amounts of reactive oxygen species (ROS). KE2: Oxidative stress CYP1A1-mediated metabolic activation of PAHs and mitochondrial electron transport chain dysfunction lead to excessive accumulation of ROS within hepatocytes, exceeding the scavenging capacity of endogenous antioxidant systems such as superoxide dismutase (SOD). KE3: Hepatic inflammation Under the dual activation of oxidative stress and AhR signaling, transcription factors such as Nuclear Factor-kappa B (NF-κB) are activated and translocate into the nucleus, driving the massive synthesis and secretion of pro-inflammatory cytokines and chemokines such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), and IL-1β. This forms a chronic low-grade inflammatory microenvironment, further disrupting lipid metabolic homeostasis. KE4: Increased fatty acid synthesis and transport Under the interactive regulation of inflammatory signals and dysregulated nuclear receptors (AhR/PPARγ), the expression of sterol regulatory element-binding protein-1 (SREBP-1), fatty acid synthase (FAS)—a key enzyme for de novo fatty acid synthesis, diacylglycerol acyltransferase 1 (DGAT1)—a key enzyme for triglyceride synthesis, and CD36—a fatty acid uptake transporter, are significantly upregulated in the liver and adipose tissue. Together, these promote the uptake of exogenous fatty acids and the synthesis of endogenous lipids, leading to overactivation of the lipid input pathway. KE5: Decreased fatty acid β-oxidation Accompanying the activation of synthetic pathways, hepatic fatty acid β-oxidation capacity is significantly inhibited. The expression of key oxidative enzymes and transporters such as Peroxisome Proliferator-Activated Receptor alpha (PPARα) and Carnitine Palmitoyltransferase 1A (CPT1A) is markedly downregulated, forming a metabolic imbalance pattern characterized by "increased synthesis and decreased decomposition." KE6: Abnormal lipid accumulation Due to increased fatty acid synthesis and uptake coupled with decreased β-oxidation, triglycerides and cholesterol are massively deposited within hepatocytes and adipocytes, resulting in significantly elevated levels of triglycerides (TG) and total cholesterol (TC) in hepatic tissue, and forming lipid droplet accumulation. KE7: Hepatocyte injury Under normal conditions, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are primarily located within hepatocytes, with very low levels in serum. When hepatocyte membrane integrity is compromised or cells undergo necrosis, these enzymes are released into the bloodstream, leading to elevated serum levels.

<table 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:147px"> 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:85px"> 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:107px"> 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:107px"> 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:107px"> 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:147px">   </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:85px"> 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:107px"> 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:107px"> 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:107px"> 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:147px"> KE1: Upregulated CYP1A1 mRNA leves </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:85px"> 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:321px"> Various PAHs such as BaP and TCDD can dose-dependently induce CYP1A1 mRNA and protein expression </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:147px"> KE2: 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:85px"> 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:321px"> CYP1A1 catalyzes the metabolic activation of PAHs to produce highly reactive epoxide and quinone intermediates, which can generate large amounts of ROS through redox cycling. Meanwhile, the catalytic cycle of CYP1A1 itself can also leak electrons to generate superoxide anions. </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:147px"> KE3: Hepatic inflammation </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:85px"> 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:321px"> ROS can activate redox-sensitive signaling pathways such as NF-κB and release pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6, leading to hepatocyte injury and inflammation. </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:147px"> KE4: Increased fatty acid synthesis and transport </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:85px"> 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:321px"> Elevated PPARγ expression can upregulate lipogenic transcription factors such as SREBP-1c. Inflammatory factors (TNF-α, IL-1, and IL-6) can activate the SREBP-1c pathway, promoting fatty acid synthesis. Meanwhile, inflammation can induce the expression of uptake proteins such as CD36. </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:147px"> KE5: Decreased fatty acid β-oxidation </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:85px"> 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:321px"> Elevated PPARγ expression may inhibit PPARα expression. Inflammatory factors can inhibit PPARα and reduce CPT1A expression. Meanwhile, inflammation may induce malonyl-CoA accumulation, inhibiting CPT1A activity. </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:147px"> KE6: Abnormal lipid accumulation </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:85px"> 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:321px"> Increased fatty acid synthesis coupled with decreased oxidation creates a metabolic imbalance characterized by "more in, less out," leading to massive accumulation of fatty acids within hepatocytes and resulting in elevated TG and TC levels in hepatic tissue. </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:147px"> KE7: Hepatocyte injury </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:85px"> 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:321px"> Excessive lipid accumulation in hepatic tissue may induce lipotoxicity, oxidative stress, and inflammatory responses, ultimately leading to hepatocyte apoptosis and necrosis, with elevated serum levels of AST and ALT. </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:147px"> AO: Abnormal hepatic lipid metabolism </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:85px"> 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:321px"> Hepatocyte injury leads to impaired liver function, including dysfunction in lipid synthesis, oxidation, transport, and secretion, ultimately manifesting as comprehensive abnormal hepatic lipid metabolism. </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

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