94-26-8QFOHBWFCKVYLES-UHFFFAOYSA-NQFOHBWFCKVYLES-UHFFFAOYSA-N
ButylparabenButyl 4-hydroxybenzoate
Benzoic acid, 4-hydroxy-, butyl ester
4-(Butoxycarbonyl)phenol
4-hidroxibenzoato de butilo
4-Hydroxybenzoate de butyle
4-HYDROXYBENZOESAEURE-BUTYLESTER
4-Hydroxybenzoic acid butyl ester
Aseptoform Butyl
BENZOATE, 4-HYDROXY-, BUTYL
Benzoic acid, p-hydroxy-, butyl ester
Butoben
Butyl Butex
Butyl chemosept
BUTYL PARABEN
Butyl parabens
Butyl parasept
Butyl Tegosept
Butyl-4-hydroxybenzoat
Mekkings B
n-Butyl 4-hydroxybenzoate
n-Butyl p-hydroxybenzoate
n-Butylparaben
Nipabutyl
NSC 13164
NSC 8475
p-Hydroxybenzoic acid butyl ester
P-OXYBUTYLBENZOATE
Preserval B
Solbrol B
Tegosept B
Tegosept Butyl
Butyl p-hydroxybenzoate
n-Butyl-p-hydroxybenzoate
DTXSID302020972-55-9UCNVFOCBFJOQAL-UHFFFAOYSA-NUCNVFOCBFJOQAL-UHFFFAOYSA-N
p,p'-DDE1,1-Dichloro-2,2-bis(4-chlorophenyl)ethene
p,p'-Dichlorodiphenyl dichloroethylene
Benzene, 1,1'-(dichloroethenylidene)bis[4-chloro-
1,1'-(Dichloroethenylidene)bis(4-chlorobenzene)
1,1-Bis(4-chlorophenyl)-2,2-dichloroethene
1,1-BIS-(4-CHLORPHENYL)-2,2-DICHLOR-AETHEN
1,1-Bis(p-chlorophenyl)-2,2-dichloroethylene
1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene
1,1-Dichloro-2,2-di(p-chlorophenyl)ethylene
2,2-bis(4-Chlorophenyl)-1,1-dichloroethylene
2,2-bis(p-chlorophenyl)-1,1-dichloroethylene
2,2-Bis(p-chlorphenyl)-1,1-dichlorethylen
2,2-bis(p-clorofenil)-1,1-dicloroetileno
2,2-Dichloro-1,1-bis(4-chlorophenyl)ethylene
4,4'-Dichlorodiphenyldichloroethylene
Benzene, 1,1'-(2,2-dichloroethenylidene)bis[4-chloro-
Benzene, 1,1'-(dichloroethenylidene)bis(4-chloro-
Dichloro diphenyl dichloroethane
DICHLORODIPHENYLDICHLOROETHYLENE
Ethylene, 1,1-dichloro-2,2-bis(p-chlorophenyl)-
Ethylene, 1,1-dichloro-2,2-bis(p-chlorophenyl)-,
NSC 1153
p,p'-Dichlorodiphenyldichloroethylene
DTXSID9020374117-81-7BJQHLKABXJIVAM-UHFFFAOYNA-NBJQHLKABXJIVAM-UHFFFAOYSA-N
Di(2-ethylhexyl) phthalate1,2-Benzenedicarboxylic acid, bis(2-ethylhexyl) ester
DEHP
1,2-Benzedicarboxylic acid, bis(2-ethyl-hexyl) ester
1,2-Benzenedicarboxylic acid bis(2-ethylhexyl) ester
1,2-Benzenedicarboxylic acid, 1,2-bis(2-ethylhexyl) ester
1,2-Benzenedicarboxylic acid,bis(2-ethylhexylester)
Bis(2-ethylhexyl) 1,2-benzenedicarboxylate
Bis(2-ethylhexyl) o-phthalate
bis(2-ethylhexyl) phthalate
Bis(2-ethylhexyl)phthalat
Bis(2-ethylhexyl)phthalate
Bisoflex 81
Bisoflex DOP
Corflex 400
Di(2-ethylhexyl)phthalate
Di(isooctyl) phthalate
Di-2-ethylhexlphthalate
Di-2-ethylhexyl phthalate
DI-2-ETHYLHEXYL-PHTHALATE
Diacizer DOP
Diethylhexyl phthalate
Dioctylphthalate
DOF
Ergoplast FDO
Ergoplast FDO-S
ETHYLHEXYL PHTHALATE
Eviplast 80
Eviplast 81
Fleximel
Flexol DOD
Flexol DOP
ftlalato de bis(2-etilhexilo)
Garbeflex DOP-D 40
Good-rite GP 264
Hatco DOP
Jayflex DOP
Kodaflex DEHP
Kodaflex DOP
Monocizer DOP
NSC 17069
Palatinol AH
Palatinol AH-L
Phtalate de Bis (Ethyle-2-Hexyle)
Phtalate de bis(2-ethylhexyle)
PHTHALATE, BIS(2-ETHYLHEXYL)
Phthalic acid di(2-ethylhexyl) ester
Phthalic acid, bis(2-ethylhexyl) ester
PHTHALIC ACID, BIS(2-ETHYLHEXYL)ESTER
PHTHALSAEURE-BIS-(2-AETHYLHEXYL)-ESTER
Pittsburgh PX 138
Plasthall DOP
Reomol D 79P
Sansocizer DOP
Sansocizer R 8000
Sconamoll DOP
Staflex DOP
Truflex DOP
Vestinol AH
Vinycizer 80
Vinycizer 80K
Witcizer 312
DTXSID502060750-02-2UREBDLICKHMUKA-CXSFZGCWSA-NUREBDLICKHMUKA-CXSFZGCWSA-N
DexamethasonePregna-1,4-diene-3,20-dione, 9-fluoro-11,17,21-trihydroxy-16-methyl-, (11beta,16alpha)-
(11beta,16alpha)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione
16alpha-Methyl-9alpha-fluoro-1,4-pregnadiene-11beta,17alpha,21-triol-3,20-dione
16alpha-Methyl-9alpha-fluoro-11beta,17alpha,21-trihydroxypregna-1,4-diene-3,20-dione
16alpha-Methyl-9alpha-fluoroprednisolone
16alpha-Methyl-9alpha-fluoro-delta1-hydrocortisone
1-Dehydro-16alpha-methyl-9alpha-fluorohydrocortisone
9-Fluoro-11beta,17,21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione
9alpha-Fluoro-11beta,17alpha,21-trihydroxy-16alpha-methyl-1,4-pregnadiene-3,20-dione
9alpha-Fluoro-16alpha-methyl-1,4-pregnadiene-11beta,17alpha,21-triol-3,20-dione
9alpha-Fluoro-16alpha-methyl-11beta,17,21-trihydroxypregna-1,4-diene-3,20-dione
9alpha-Fluoro-16alpha-methylprednisolone
Adexone
Aeroseb-Dex
Aphtasolon
Aphthasolone
Calonat
Corsone
Cortisumman
Decacort
Decaderm
Decadron A
Decalix
Decasone
Dekacort
Delipos
Deltafluorene
Dergramin
Deronil
Desadrene
Desameton
Deseronil
Dexacort
Dexacortal
Dexa-Cortidelt
Dexacortin
Dexadeltone
Dexafarma
Dexalona
Dexaltin
Dexa-Mamallet
dexametasona
Dexameth
Dexamethason
Dexamethasone alcohol
Dexamonozon
Dexapolcort
Dexapos
Dexaprol
Dexa-Scheroson
Dexa-sine
Dexason
Dexasone
Dexinoral
Dexonium
Dextelan
Dinormon
Etacortilen
Fluormone
Fluorocort
Gammacorten
Gentalipos
Hexadecadrol
Hexadrol
Isopto-Dex
Lokalison F
Loverine
Luxazone
Maxidex
Millicorten
NSC 34521
Oradexon
Pet-Derm III
Prednisolon F
Prednisolone F
Pregna-1,4-diene-3,20-dione, 9-fluoro-11beta,17,21-trihydroxy-16alpha-methyl-
Superprednol
Surodex
Visumetazone
Aeroseb-D
Anaflogistico
Auxiron
Bisu DS
Decacortin
Decadron
Decaspray
Dectancyl
Desametasone
Desamethasone
Dexa Mamallet
Dexa-Cortisyl
Dex-ide
Dexinolon
EINECS 200-003-9
Fluormethylprednisolone
delta1-9alpha-Fluoro-16alpha-methylcortisol
4-alpha-Fluoro-16-alpha-methyl-11-beta,17,21-trihydroxypregna-1,4-diene-3,20-dione
Mediamethasone
16alpha-Methyl-9alpha-fluoro-1-dehydrocortisol
16-alpha-Methyl-9-alpha-fluoro-1-dehydrocortisol
16-alpha-Methyl-9-alpha-fluoroprednisolone
16alpha-Methyl-9alpha-fluoro-delta(sup 1)-hydrocortisone
16-alpha-Methyl-9-alpha-fluoro-delta(sup 1)-hydrocortisone
16-alpha-Methyl-9-alpha-fluoro-11-beta,17-alpha,21-trihydroxypregna-1,4-diene-3,20-dione
Mexidex
Ocu-trol
Pet Derm III
Policort
Prednisolone, 9alpha-fluoro-16alpha-methyl-
SK-Dexamethasone
Spoloven
Sunia Sol D
delta(sup 1)-9-alpha-Fluoro-16-alpha-methylcortisol
Dexamethasone Intensol
Dexone 0.75
Mymethasone
Decaject
Decaject-L.A.
Decameth
Methylfluorprednisolone
Dexamethasonum
UNII-7S5I7G3JQL
Ozurdex
DTXSID3020384122-14-5ZNOLGFHPUIJIMJ-UHFFFAOYSA-NZNOLGFHPUIJIMJ-UHFFFAOYSA-N
FenitrothionPhosphorothioic acid, O,O-dimethylO-(3-methyl-4-nitrophenyl) ester
Accothion
Agriya 1050
Agrothion
Arbogal
Bayer 41831
Bayer S 5660
Dimethyl 4-nitro-m-tolyl phosphorothionate
Fenition
fenitrotion
Fenutrithion
Folithion
Folithion EC 50
Insectigas F
Metathion
Metathion E 50
Metathione
Metathionine E 50
Metation
Metation E 50
Methadion
Methylnitrophos
Mglawik F
Monsanto CP 47114
Nitrophos
Nuvanol
O, O-Dimethyl-O-(3-methyl-4-nitrophenyl) phosphorothioate
O,O-DiMe O-(3-methyl-4-nitrophenyl) thiophosphate
O,O-Dimethyl O-(3-methyl-4-nitrophenyl) phosphorothioate
O,O-Dimethyl O-(3-methyl-4-nitrophenyl) thiophosphate
O,O-Dimethyl O-(4-nitro-3-methylphenyl)thiophosphate
O,O-Dimethyl O-4-nitro-m-tolyl phosphorothioate
O,O-Dimethyl O-4-nitro-m-tolyl thiophosphate
Oleometathion
Oleosumifene
Ovadofos
Owadofos
Owadophos
Phenitrothion
PHOSPHOROTHIOATE, O,O-DIMETHYL O-(3-METHYL- 4-NITROPHENYL)
Phosphorothioic acid O,O-dimethyl O-(3-methyl-4-nitrophenyl) ester
Phosphorothioic acid, O,O-dimethyl O-(3-methyl-4-nitrophenyl) ester
Phosphorothioic acid, O,O-dimethyl O-(4-nitro-m-tolyl) ester
Sumi oil
Sumifene
Sumigran
Sumithion
Sumithion 20F
Sumithion 20MC
Sumithion 50EC
Super Sumithion
Tionfos 50 LE
Verthion
DTXSID403261313311-84-7MKXKFYHWDHIYRV-UHFFFAOYSA-NMKXKFYHWDHIYRV-UHFFFAOYSA-N
FlutamidePropanamide, 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-
4-Nitro-3-(trifluoromethyl)isobutyranilide
4'-Nitro-3'-trifluoromethylisobutyranilide
Eulexin
Flucinom
Flutamid
flutamida
m-Propionotoluidide, α,α,α-trifluoro-2-methyl-4'-nitro-
N-(Isopropylcarbonyl)-4-nitro-3-trifluoromethylaniline
Niftholide
Niftolide
NSC 147834
NSC 215876
DTXSID703200465277-42-1XMAYWYJOQHXEEK-OZXSUGGESA-NXMAYWYJOQHXEEK-OZXSUGGESA-N
Ketoconazole, 2R,4S-
Piperazine, 1-acetyl-4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-, rel-
(.+-.)-Ketoconazole
Brizoral
cis-1-Acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazole-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazine
Ethanone, 1-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]-, rel-
Fungarest
Fungoral
Ketoconazol
Ketoderm
Ketoisdin
Ketozoral
Nizoral
Onofin K
Orifungal M
Panfungol
Piperazine, 1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-, cis-
Piperazine,1-acetyl-4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-, rel-
DTXSID7029879330-55-2XKJMBINCVNINCA-UHFFFAOYSA-NXKJMBINCVNINCA-UHFFFAOYSA-N
LinuronUrea, N'-(3,4-dichlorophenyl)-N-methoxy-N-methyl-
1-(3,4-Dichlorophenyl)-3-methoxy-3-methylurea
1-Methoxy-1-methyl-3-(3,4-dichlorophenyl)urea
3-(3',4'-Dichlorophenyl)-1-methoxy-1-methylurea
3-(3,4-Dichlorophenyl)-1-methoxy-1-methylurea
3-(3,4-Dichlorophenyl)-1-methyl-1-methoxyurea
Afalon inuron
Alfalon
Alfalone
Aphalon
Cephalon
Du Pont 326
Du Pont Herbicide 326
Herbicide 326
Linurex
Methoxydiuron
N'-(3,4-Dichlorophenyl)-N-methoxy-N-methylurea
N-(3,4-Dichlorophenyl)-N'-methoxy-N'-methylurea
N-(3,4-Dichlorophenyl)-N'-methyl-N'-methoxyurea
Sarclex
Sinuron
Urea, 3-(3,4-dichlorophenyl)-1-methoxy-1-methyl-
DTXSID202416367747-09-5TVLSRXXIMLFWEO-UHFFFAOYSA-NTVLSRXXIMLFWEO-UHFFFAOYSA-N
Prochloraz1H-Imidazole-1-carboxamide, N-propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl]-
BTS 40542-7877
N-propil-N-[2-(2,4,6-triclorofenoxi)etil]-1H-imidazol-1-carboxamida
N-propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl]-1H-imidazole-1-carboxamide
N-Propyl-N-[2-(2,4,6-trichlorophenoxy)ethyl-1H-imidazole-1-carboxamide
N-Propyl-N-[2-(2,4,6-trichlorphenoxy)ethyl]-1H-imidazol-1-carboxamid
Plocloraz
Prelude
Sportak
Sportake
DTXSID402427032809-16-8QXJKBPAVAHBARF-UHFFFAOYNA-NQXJKBPAVAHBARF-UHFFFAOYSA-N
Procymidone3-(3,5-Dichlorophenyl)-1,5-dimethyl-3-azabicyclo(3.1.0)hexane-2,4-dione
3-Azabicyclo[3.1.0]hexane-2,4-dione, 3-(3,5-dichlorophenyl)-1,5-dimethyl-
1,2-Cyclopropanedicarboximide, N-(3,5-dichlorophenyl)-1,2-dimethyl-
1,2-Dimethyl-N-(3,5-dichlorophenyl)cyclopropanedicarboximide
3-(3,5-dichlorophenyl)-1,5-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione
3-(3,5-Dichlorphenyl)-1,5-dimethyl-3-azabicyclo[3.1.0]hexan-2,4-dion
3-(3,5-diclorofenil)-1,5-dimetil-3-azabiciclo[3.1.0]hexano-2,4-diona
Dicyclidine
Kenolex
N-(3,5-Dichlorophenyl)-1,2-dimethyl-1,2-cyclopropanedicarboximide
N-(3,5-Dichlorophenyl)-1,2-dimethylcyclopropane-1,2-dicarboximide
PROCYMIDON
Procymidor
Procymidox
Salithiex
Sumilex
Sumilex 50WP
Sumisclex
DTXSID9033923131983-72-7PPDBOQMNKNNODG-UHFFFAOYNA-NPPDBOQMNKNNODG-UHFFFAOYSA-N
Triticonazole5-[(4-Chlorophenyl)methylene]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)cyclopentanol
DTXSID003265550471-44-8FSCWZHGZWWDELK-UHFFFAOYNA-NFSCWZHGZWWDELK-UHFFFAOYSA-N
Vinclozolin2,4-Oxazolidinedione, 3-(3,5-dichlorophenyl)-5-ethenyl-5-methyl-
(.+-.)-Vinclozolin
BAS 352-04F
N-3,5-Dichlorophenyl-5-methyl-5-vinyl-1,3-oxazolidine-2,4-dione
N-3,5-Dichlorophenyl-5-methyl-5-vinyloxazolidine-2,4-dione
N-3,5-Dichlorphenyl-5-methyl-5-vinyl-1,3-oxazolidin-2,4-dion
N-3,5-diclorofenil-5-metil-5-vinil-1,3-oxazolidina-2,4-diona
Ornalin
Ranilan
Ronilan
Ronilan 50WP
DTXSID402236184-61-7VOWAEIGWURALJQ-UHFFFAOYSA-NVOWAEIGWURALJQ-UHFFFAOYSA-N
Dicyclohexyl phthalate1,2-Benzenedicarboxylic acid, dicyclohexyl ester
DTXSID5025021CHEBI:26523reactive oxygen speciesCHEBI:16991deoxyribonucleic acidGO:0005739mitochondrionPR:000027727estrogen receptor alpha complexCHEBI:17347testosteroneCL:0000019spermD005298fertilityFMA:264621Musculature of male perineumGO:1903409reactive oxygen species biosynthetic processMP:0003674oxidative stressGO:0061726mitochondrion disassemblyGO:0030520intracellular estrogen receptor signaling pathwayGO:0006915apoptotic processVT:0002673sperm quantityGO:0030521androgen receptor signaling pathway1increased7functional change2decreased8morphological change9disruptedIonizing Radiation<p>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.</p>
<p>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).</p>
2019-05-03T12:36:362019-05-07T12:12:13Estrogen2019-05-08T11:40:272019-05-08T11:40:27Butylparaben2020-05-18T12:14:362020-05-18T12:14:36p,p'-DDE2020-05-18T12:15:232020-05-18T12:15:23Bis(2-ethylhexyl) phthalate2016-11-29T18:42:082016-11-29T18:42:08Dexamethasone2019-06-01T00:56:522019-06-01T00:56:52Fenitrothion2020-05-18T12:51:252020-05-18T12:51:25Finasteride2016-11-29T18:42:272016-11-29T18:42:27Flutamide2016-11-29T18:42:272016-11-29T18:42:27Ketoconazole2017-05-02T11:08:422017-05-02T11:08:42Linuron2020-05-18T12:53:542020-05-18T12:53:54Prochloraz2016-11-29T18:42:222016-11-29T18:42:22Procymidone2020-05-18T12:55:122020-05-18T12:55:12Triticonazole2020-05-16T11:02:072020-05-16T11:09:42Vinclozolin2020-05-14T11:28:312020-05-14T11:28:31di-n-hexyl phthalate<p>CAS Number: 84-75-3;</p>
<p>Synonym: 1,2-Benzenedicarboxylic acid 1,2-dihexyl ester</p>
2020-05-18T14:34:222020-05-18T14:36:56Dicyclohexyl phthalate2020-05-18T14:41:462020-05-18T14:41:46butyl benzyl phthalate2020-05-18T14:46:292020-05-18T14:46:29monobenzyl phthalate2020-05-18T14:49:442020-05-18T14:49:44di-n-heptyl phthalate2020-05-18T15:01:032020-05-18T15:01:03WikiUser_28Vertebrates9606Homo sapiens10090Mus musculus10116Rattus norvegicus6239Caenorhabditis elegansWCS_9606human10116rat10090mouseIncreased, Reactive oxygen speciesIncreased, Reactive oxygen speciesCellular<p>Biological State: increased reactive oxygen species (ROS)</p>
<p>Biological compartment: an entire cell -- may be cytosolic, may also enter organelles.</p>
<p>Reactive oxygen species (ROS) are O2- derived molecules that can be both free radicals (e.g. superoxide, hydroxyl, peroxyl, alcoxyl) and non-radicals (hypochlorous acid, ozone and singlet oxygen) (Bedard and Krause 2007; Ozcan and Ogun 2015). ROS production occurs naturally in all kinds of tissues inside various cellular compartments, such as mitochondria and peroxisomes (Drew and Leeuwenburgh 2002; Ozcan and Ogun 2015). Furthermore, these molecules have an important function in the regulation of several biological processes – they might act as antimicrobial agents or triggers of animal gamete activation and capacitation (Goud et al. 2008; Parrish 2010; Bisht et al. 2017). <br />
However, in environmental stress situations (exposure to radiation, chemicals, high temperatures) these molecules have its levels drastically increased, and overly interact with macromolecules, namely nucleic acids, proteins, carbohydrates and lipids, causing cell and tissue damage (Brieger et al. 2012; Ozcan and Ogun 2015). </p>
<p>Photocolorimetric assays (Sharma et al. 2017; Griendling et al. 2016) or through commercial kits purchased from specialized companies.</p>
<p>ROS is a normal constituent found in all organisms.</p>
HighUnspecificHighAll life stagesHigh<p>Bedard, Karen, and Karl-Heinz Krause. 2007. “The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology.” Physiological Reviews 87 (1): 245–313.</p>
<p>Ozcan, Ayla, and Metin Ogun. 2015. “Biochemistry of Reactive Oxygen and Nitrogen Species.” In Basic Principles and Clinical Significance of Oxidative Stress, edited by Sivakumar Joghi Thatha Gowder. Rijeka: IntechOpen.</p>
<p>Drew, Barry, and Christiaan Leeuwenburgh. 2002. “Aging and the Role of Reactive Nitrogen Species.” Annals of the New York Academy of Sciences 959 (April): 66–81.</p>
<p>Goud, Anuradha P., Pravin T. Goud, Michael P. Diamond, Bernard Gonik, and Husam M. Abu-Soud. 2008. “Reactive Oxygen Species and Oocyte Aging: Role of Superoxide, Hydrogen Peroxide, and Hypochlorous Acid.” Free Radical Biology & Medicine 44 (7): 1295–1304.</p>
<p>Parrish, A. R. 2010. “2.27 - Hypoxia/Ischemia Signaling.” In Comprehensive Toxicology (Second Edition), edited by Charlene A. McQueen, 529–42. Oxford: Elsevier.</p>
<p>Bisht, Shilpa, Muneeb Faiq, Madhuri Tolahunase, and Rima Dada. 2017. “Oxidative Stress and Male Infertility.” Nature Reviews. Urology 14 (8): 470–85.</p>
<p>Brieger, K., S. Schiavone, F. J. Miller Jr, and K-H Krause. 2012. “Reactive Oxygen Species: From Health to Disease.” Swiss Medical Weekly 142 (August): w13659.</p>
<p>Sharma, Gunjan, Nishant Kumar Rana, Priya Singh, Pradeep Dubey, Daya Shankar Pandey, and Biplob Koch. 2017. “p53 Dependent Apoptosis and Cell Cycle Delay Induced by Heteroleptic Complexes in Human Cervical Cancer Cells.” Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie 88 (April): 218–31.</p>
<p>Griendling, Kathy K., Rhian M. Touyz, Jay L. Zweier, Sergey Dikalov, William Chilian, Yeong-Renn Chen, David G. Harrison, Aruni Bhatnagar, and American Heart Association Council on Basic Cardiovascular Sciences. 2016. “Measurement of Reactive Oxygen Species, Reactive Nitrogen Species, and Redox-Dependent Signaling in the Cardiovascular System: A Scientific Statement From the American Heart Association.” Circulation Research 119 (5): e39–75.</p>
2016-11-29T18:41:292023-04-10T14:01:30Increased, Oxidative StressIncreased, Oxidative StressMolecularCL:0000255eukaryotic cell2016-11-29T18:41:292022-02-03T14:20:13Increase, DNA damageIncrease, DNA DamageMolecular<p>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).</p>
<p>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).</p>
<p>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).</p>
<p>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’.</p>
<p>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).</p>
<p>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).</p>
<p>Table 1. Common methods of detecting DNA damage</p>
<table border="1" cellpadding="0" cellspacing="0">
<tbody>
<tr>
<td style="height:22px; width:127px">
<p><strong>Target</strong></p>
</td>
<td style="height:22px; width:167px">
<p><strong>Name</strong></p>
</td>
<td style="height:22px; width:133px">
<p><strong>Method</strong></p>
</td>
<td style="height:22px; width:211px">
<p><strong>Strengths/Weaknesses</strong></p>
</td>
</tr>
<tr>
<td style="height:22px; width:127px">
<p><strong>Nucleotide damage</strong></p>
</td>
<td style="height:22px; width:167px">
<p>Single cell gel electrophoresis (comet assay) with restriction enzymes (Collins 2004)</p>
</td>
<td style="height:22px; width:133px">
<p>Gel electrophoresis</p>
<p> </p>
</td>
<td style="height:22px; width:211px">
<p>A variant of the comet assay in which restriction enzymes allow the identification of different types of nucleotide damage.</p>
<p>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.</p>
</td>
</tr>
<tr>
<td style="height:22px; width:127px">
<p><strong>Nucleotide damage</strong></p>
</td>
<td style="height:22px; width:167px">
<p>Labeled probes including Biotrin OxyDNA and anti- 8-oxoguanine-DNA glycosylase (OGG1) for oxidative damage and AP</p>
<p>endonuclease (APE1) for Base Excision Repair of less bulky lesions such as oxidative damage.</p>
</td>
<td style="height:22px; width:133px">
<p>Microscopy, FACS</p>
</td>
<td style="height:22px; width:211px">
<p>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).</p>
</td>
</tr>
<tr>
<td style="height:22px; width:127px">
<p><strong>Nucleotide damage</strong></p>
</td>
<td style="height:22px; width:167px">
<p>High performance liquid chromatography (HPLC), tandem mass spectrometry (MS/MS)</p>
</td>
<td style="height:22px; width:133px">
<p>Analytical chemistry</p>
</td>
<td style="height:22px; width:211px">
<p>Capable of quantifying low levels of specific nucleotide lesions (Madugundu, Cadet et al. 2014; Ravanat, Breton et al. 2014). Requires destruction of the cell.</p>
</td>
</tr>
<tr>
<td style="height:22px; width:127px">
<p><strong>Nucleotide damage</strong></p>
</td>
<td style="height:22px; width:167px">
<p>Unscheduled DNA synthesis test OECD Test Guideline 486 (OECD 1997)</p>
</td>
<td style="height:22px; width:133px">
<p>Autoradiography</p>
</td>
<td style="height:22px; width:211px">
<p>Measures DNA damage that is repaired using Nucleotide Excision Repair - mostly bulky adducts (OECD (Organisation for Economic Co-operation and Development) 2016).</p>
</td>
</tr>
<tr>
<td style="height:22px; width:127px">
<p><strong>Non-specific DNA strand breaks</strong></p>
</td>
<td style="height:22px; width:167px">
<p>Single cell gel electrophoresis (comet assay), alkali conditions</p>
<p>OECD Test Guideline 489 (OECD 2016)</p>
</td>
<td style="height:22px; width:133px">
<p>Gel electrophoresis</p>
</td>
<td style="height:22px; width:211px">
<p>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. </p>
<p> </p>
</td>
</tr>
<tr>
<td style="height:22px; width:127px">
<p><strong>Single strand breaks</strong></p>
</td>
<td style="height:22px; width:167px">
<p>Labeled probe pXRCC1 (Lorat, Brunner et al. 2015)</p>
</td>
<td style="height:22px; width:133px">
<p>Microscopy</p>
</td>
<td style="height:22px; width:211px">
<p>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).</p>
</td>
</tr>
<tr>
<td style="height:22px; width:127px">
<p><strong>Double strand breaks</strong></p>
</td>
<td style="height:22px; width:167px">
<p>Single cell gel electrophoresis (comet assay), neutral conditions</p>
</td>
<td style="height:22px; width:133px">
<p>Gel electrophoresis</p>
</td>
<td style="height:22px; width:211px">
<p>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.</p>
</td>
</tr>
<tr>
<td style="height:22px; width:127px">
<p><strong>Double strand breaks</strong></p>
</td>
<td style="height:22px; width:167px">
<p>Pulsed field gel electrophoresis (PFGE)</p>
</td>
<td style="height:22px; width:133px">
<p>Gel electrophoresis</p>
</td>
<td style="height:22px; width:211px">
<p>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.</p>
</td>
</tr>
<tr>
<td style="height:22px; width:127px">
<p><strong>Double strand breaks</strong></p>
</td>
<td style="height:22px; width:167px">
<p>Labeled probes including phosphorylated H2AX, 53BP1, Ku70, ATM (Lorat, Brunner et al. 2015)</p>
</td>
<td style="height:22px; width:133px">
<p>Microscopy</p>
</td>
<td style="height:22px; width:211px">
<p>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).</p>
</td>
</tr>
<tr>
<td style="height:22px; width:127px">
<p><strong>Chromosomal damage</strong></p>
</td>
<td style="height:22px; width:167px">
<p>Chromosomal aberrations and micronuclei</p>
<p>OECD Test Guidelines 473, 475, 483, and 487 (OECD 2016; OECD 2016; OECD 2016; OECD 2016)</p>
</td>
<td style="height:22px; width:133px">
<p>Microscopy</p>
</td>
<td style="height:22px; width:211px">
<p>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.</p>
</td>
</tr>
</tbody>
</table>
CL:0000255eukaryotic cell<p><a name="_ENREF_1">Barnard, S., S. Bouffler, et al. (2013). "The shape of the radiation dose response for DNA double-strand break induction and repair." Genome integrity 4(1): 1.</a></p>
<p><a name="_ENREF_2">Behjati, S., G. Gundem, et al. (2016). "Mutational signatures of ionizing radiation in second malignancies." Nat Commun 7: 12605.</a></p>
<p><a name="_ENREF_3">Chaudhry, M. A. and M. Weinfeld (1997). "Reactivity of human apurinic/apyrimidinic endonuclease and Escherichia coli exonuclease III with bistranded abasic sites in DNA." The Journal of biological chemistry 272(25): 15650-15655.</a></p>
<p><a name="_ENREF_4">Collins, A. R. (2004). "The comet assay for DNA damage and repair: principles, applications, and limitations." Molecular biotechnology 26(3): 249-261.</a></p>
<p><a name="_ENREF_5">David, S. S., V. L. O'Shea, et al. (2007). "Base-excision repair of oxidative DNA damage." Nature 447(7147): 941-950.</a></p>
<p><a name="_ENREF_6">Dayal, D., S. M. Martin, et al. (2008). "Hydrogen peroxide mediates the radiation-induced mutator phenotype in mammalian cells." Biochem J 413(1): 185-191.</a></p>
<p><a name="_ENREF_7">Ge, J., S. Prasongtanakij, et al. (2014). "CometChip: a high-throughput 96-well platform for measuring DNA damage in microarrayed human cells." Journal of visualized experiments : JoVE(92): e50607.</a></p>
<p><a name="_ENREF_8">Gradzka, I. and T. Iwanenko (2005). "A non-radioactive, PFGE-based assay for low levels of DNA double-strand breaks in mammalian cells." DNA repair 4(10): 1129-1139.</a></p>
<p><a name="_ENREF_9">Haag, J. D., L. C. Hsu, et al. (1996). "Allelic imbalance in mammary carcinomas induced by either 7,12-dimethylbenz[a]anthracene or ionizing radiation in rats carrying genes conferring differential susceptibilities to mammary carcinogenesis." Mol Carcinog 17(3): 134-143.</a></p>
<p><a name="_ENREF_10">Kawashima, Y., N. Yamaguchi, et al. (2017). "Detection of DNA double-strand breaks by pulsed-field gel electrophoresis." Genes to cells : devoted to molecular & cellular mechanisms 22(1): 84-93.</a></p>
<p><a name="_ENREF_11">Kuhne, M., K. Rothkamm, et al. (2000). "No dose-dependence of DNA double-strand break misrejoining following alpha-particle irradiation." International journal of radiation biology 76(7): 891-900.</a></p>
<p><a name="_ENREF_12">Kutanzi, K. and O. Kovalchuk (2013). "Exposure to estrogen and ionizing radiation causes epigenetic dysregulation, activation of mitogen-activated protein kinase pathways, and genome instability in the mammary gland of ACI rats." Cancer Biol Ther 14(7): 564-573.</a></p>
<p><a name="_ENREF_13">Kuzminov, A. (2001). "Single-strand interruptions in replicating chromosomes cause double-strand breaks." Proceedings of the National Academy of Sciences of the United States of America 98(15): 8241-8246.</a></p>
<p><a name="_ENREF_14">Liu, X., Y. He, et al. (2015). "Caspase-3 promotes genetic instability and carcinogenesis." Mol Cell 58(2): 284-296.</a></p>
<p><a name="_ENREF_15">Lobrich, M., B. Rydberg, et al. (1995). "Repair of x-ray-induced DNA double-strand breaks in specific Not I restriction fragments in human fibroblasts: joining of correct and incorrect ends." Proceedings of the National Academy of Sciences of the United States of America 92(26): 12050-12054.</a></p>
<p><a name="_ENREF_16">Lorat, Y., C. U. Brunner, et al. (2015). "Nanoscale analysis of clustered DNA damage after high-LET irradiation by quantitative electron microscopy--the heavy burden to repair." DNA repair 28: 93-106.</a></p>
<p><a name="_ENREF_17">Lorat, Y., S. Timm, et al. (2016). "Clustered double-strand breaks in heterochromatin perturb DNA repair after high linear energy transfer irradiation." Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology 121(1): 154-161.</a></p>
<p><a name="_ENREF_18">Madugundu, G. S., J. Cadet, et al. (2014). "Hydroxyl-radical-induced oxidation of 5-methylcytosine in isolated and cellular DNA." Nucleic acids research 42(11): 7450-7460.</a></p>
<p><a name="_ENREF_19">Morishita, M., T. Muramatsu, et al. (2016). "Chromothripsis-like chromosomal rearrangements induced by ionizing radiation using proton microbeam irradiation system." Oncotarget 7(9): 10182-10192.</a></p>
<p><a name="_ENREF_20">Murnane, J. P. (2012). "Telomere dysfunction and chromosome instability." Mutation research 730(1-2): 28-36.</a></p>
<p><a name="_ENREF_21">Nikitaki, Z., V. Nikolov, et al. (2016). "Measurement of complex DNA damage induction and repair in human cellular systems after exposure to ionizing radiations of varying linear energy transfer (LET)." Free radical research 50(sup1): S64-S78.</a></p>
<p><a name="_ENREF_22">OECD (1997). Test No. 486: Unscheduled DNA Synthesis (UDS) Test with Mammalian Liver Cells in vivo.</a></p>
<p><a name="_ENREF_23">OECD (2016). Test No. 473: In Vitro Mammalian Chromosomal Aberration Test.</a></p>
<p><a name="_ENREF_24">OECD (2016). Test No. 475: Mammalian Bone Marrow Chromosomal Aberration Test.</a></p>
<p><a name="_ENREF_25">OECD (2016). Test No. 483: Mammalian Spermatogonial Chromosomal Aberration Test.</a></p>
<p><a name="_ENREF_26">OECD (2016). Test No. 487: In Vitro Mammalian Cell Micronucleus Test.</a></p>
<p><a name="_ENREF_27">OECD (2016). Test No. 489: In Vivo Mammalian Alkaline Comet Assay.</a></p>
<p><a name="_ENREF_28">OECD (Organisation for Economic Co-operation and Development) (2016). Overview of the set of OECD Genetic Toxicology Test Guidelines and updates performed in 2014–2015. No. 238.</a></p>
<p><a name="_ENREF_29">Ogawa, Y., T. Kobayashi, et al. (2003). "Radiation-induced oxidative DNA damage, 8-oxoguanine, in human peripheral T cells." International journal of molecular medicine 11(1): 27-32.</a></p>
<p><a name="_ENREF_30">Ojima, M., N. Ban, et al. (2008). "DNA double-strand breaks induced by very low X-ray doses are largely due to bystander effects." Radiation research 170(3): 365-371.</a></p>
<p><a name="_ENREF_31">Pernot, E., J. Hall, et al. (2012). "Ionizing radiation biomarkers for potential use in epidemiological studies." Mutation research 751(2): 258-286.</a></p>
<p><a name="_ENREF_32">Pinto, M., K. M. Prise, et al. (2005). "Evidence for complexity at the nanometer scale of radiation-induced DNA DSBs as a determinant of rejoining kinetics." Radiation research 164(1): 73-85.</a></p>
<p><a name="_ENREF_33">Ponnaiya, B., M. N. Cornforth, et al. (1997). "Induction of chromosomal instability in human mammary cells by neutrons and gamma rays." Radiation research 147(3): 288-294.</a></p>
<p><a name="_ENREF_34">Ponnaiya, B., M. N. Cornforth, et al. (1997). "Radiation-induced chromosomal instability in BALB/c and C57BL/6 mice: the difference is as clear as black and white." Radiation research 147(2): 121-125.</a></p>
<p><a name="_ENREF_35">Ravanat, J. L., J. Breton, et al. (2014). "Radiation-mediated formation of complex damage to DNA: a chemical aspect overview." Br J Radiol 87(1035): 20130715.</a></p>
<p><a name="_ENREF_36">Regulus, P., B. Duroux, et al. (2007). "Oxidation of the sugar moiety of DNA by ionizing radiation or bleomycin could induce the formation of a cluster DNA lesion." Proceedings of the National Academy of Sciences of the United States of America 104(35): 14032-14037.</a></p>
<p><a name="_ENREF_37">Rothkamm, K. and M. Lobrich (2003). "Evidence for a lack of DNA double-strand break repair in human cells exposed to very low x-ray doses." Proceedings of the National Academy of Sciences of the United States of America 100(9): 5057-5062.</a></p>
<p><a name="_ENREF_38">Rydberg, B., B. Cooper, et al. (2005). "Dose-dependent misrejoining of radiation-induced DNA double-strand breaks in human fibroblasts: experimental and theoretical study for high- and low-LET radiation." Radiation research 163(5): 526-534.</a></p>
<p><a name="_ENREF_39">Sharma, V., L. B. Collins, et al. (2016). "Oxidative stress at low levels can induce clustered DNA lesions leading to NHEJ mediated mutations." Oncotarget 7(18): 25377-25390.</a></p>
<p><a name="_ENREF_40">Shiraishi, I., N. Shikazono, et al. (2017). "Efficiency of radiation-induced base lesion excision and the order of enzymatic treatment." International journal of radiation biology 93(3): 295-302.</a></p>
<p><a name="_ENREF_41">Sishc, B. J., C. B. Nelson, et al. (2015). "Telomeres and Telomerase in the Radiation Response: Implications for Instability, Reprograming, and Carcinogenesis." Front Oncol 5: 257.</a></p>
<p><a name="_ENREF_42">Stenerlow, B., E. Hoglund, et al. (2000). "Rejoining of DNA fragments produced by radiations of different linear energy transfer." International journal of radiation biology 76(4): 549-557.</a></p>
<p><a name="_ENREF_43">Sykora, P., K. L. Witt, et al. (2018). "Next generation high throughput DNA damage detection platform for genotoxic compound screening." Sci Rep 8(1): 2771.</a></p>
<p><a name="_ENREF_44">Unger, K., J. Wienberg, et al. (2010). "Novel gene rearrangements in transformed breast cells identified by high-resolution breakpoint analysis of chromosomal aberrations." Endocrine-related cancer 17(1): 87-98.</a></p>
<p><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></p>
<p><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></p>
<p><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></p>
<p><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></p>
<p><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></p>
2016-11-29T18:41:302019-05-08T12:28:46Damaging, MitochondriaDamaging, MitochondriaCellularCL:0000255eukaryotic cell2016-11-29T18:41:232017-09-27T16:05:28Activation, estrogen receptor alphaActivation, estrogen receptor alphaMolecular2016-11-29T18:41:292016-12-03T16:37:53Increased apoptosis, decreased number of adult Leydig Cells Increased apoptosis, decreased Leydig Cells CellularCL:0000178Leydig cell2016-11-29T18:41:252017-09-16T10:15:24ApoptosisApoptosisCellular<p>Apoptosis, the process of programmed cell death, is characterized by distinct morphology with DNA fragmentation and energy dependency [Elmore, 2007]. Apoptosis, also called “physiological cell death”, is involved in cell turnover, physiological involution, and atrophy of various tissues and organs [Kerr et al., 1972]. The formation of apoptotic bodies involves marked condensation of both nucleus and cytoplasm, nuclear fragmentation, and separation of protuberances [Kerr et al., 1972]. Apoptosis is characterized by DNA ladder and chromatin condensation. Several stimuli such as hypoxia, nucleotides deprivation, chemotherapeutical drugs, DNA damage, and mitotic spindle damage induce p53 activation, leading to p21 activation and cell cycle arrest [Pucci et al., 2000]. The SAHA or TSA treatment on neonatal human dermal fibroblasts (NHDFs) for 24 or 72 hrs inhibited proliferation of the NHDF cells [Glaser et al., 2003]. Considering that the acetylation of histone H4 was increased by the treatment of SAHA for 4 hrs, histone deacetylase inhibition may be involved in the inhibition of the cell proliferation [Glaser et al., 2003]. The impaired proliferation was observed in HDAC1<sup>-/-</sup> ES cells, which was rescued with the reintroduction of HDAC1 [Zupkovitz et al., 2010]. The present AOP focuses on the p21 pathway leading to apoptosis, however, alternative pathways such as NF-kappaB signaling pathways may be involved in the apoptosis of spermatocytes [Wang et al., 2017].</p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Apoptosis is characterized by many morphological and biochemical changes <span style="color:black">such as homogenous condensation of chromatin to one side or the periphery of the nuclei, membrane blebbing and formation of apoptotic bodies with fragmented nuclei, DNA fragmentation, enzymatic activation of pro-caspases, or phosphatidylserine translocation that can be measured using electron and cytochemical optical microscopy, proteomic and genomic methods, and spectroscopic techniques [Archana et al., 2013; Martinez et al., 2010; Taatjes et al., 2008; Yasuhara et al., 2003].</span></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・<span style="color:black">DNA fragmentation can be quantified with comet assay using electrophoresis, where the tail length, head size, tail intensity, and head intensity of the comet are measured [Yasuhara et al., 2003].</span></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・The apoptosis is detected with the expression alteration of procaspases 7 and 3 by Western blotting using antibodies [Parajuli<span style="color:black"> et al.</span>, 2014].</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・The apoptosis is measured with down-regulation of anti-apoptotic gene baculoviral inhibitor of apoptosis protein repeat containing 2 (BIRC2, or cIAP1) [Parajuli<span style="color:black"> et al.</span>, 2014].</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・Apoptotic nucleosomes are detected using Cell Death Detection ELISA kit, which was calculated as absorbance subtraction at 405 nm and 490 nm [Parajuli<span style="color:black"> et al.</span>, 2014].</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・Cleavage of PARP is detected with Western blotting [Parajuli<span style="color:black"> et al.</span>, 2014].</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・Caspase-3 and caspase-9 activity is measured with the enzyme-catalyzed release of p-nitroanilide (pNA) and quantified at 405 nm [Wu<span style="color:black"> et al.</span>, 2016].</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・Apoptosis is measured with Annexin V-FITC probes, and the relative percentage of Annexin V-FITC-positive/PI-negative cells is analyzed by flow cytometry [Wu et al., 2016].</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・Apoptosis is detected with the Terminal dUTP Nick End-Labeling (TUNEL) method to assay the endonuclease cleavage products by enzymatically end-labeling the DNA strand breaks [Kressel and Groscurth, 1994].</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">・For the detection of apoptosis, the testes are fixed in neutral buffered formalin and embedded in paraffin. Germ cell death is visualized in testis sections by Terminal dUTP Nick End-Labeling (TUNEL) staining method [Wade et al., 2008]. The incidence of TUNEL-positive cells is expressed as the number of positive cells per tubule examined for one entire testis section per animal [Wade et al., 2008].</span></span></p>
<ul>
<li><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Apoptosis is detected with the </span></span><span style="font-size:8.0pt"><span style="font-family:"Times New Roman",serif">Annexin V test</span></span></li>
</ul>
<p>・Apoptosis is induced in human prostate cancer cell lines (<em>Homo sapiens</em>) [Parajuli et al., 2014].</p>
<p>・Apoptosis occurs in B6C3F1 mouse (<em>Mus musculus</em>) [Elmore, 2007].</p>
<p>・Apoptosis occurs in Sprague-Dawley rat (<em>Rattus norvegicus</em>) [Elmore, 2007].</p>
<p>・Apoptosis occurs in the nematode (<em>Caenorhabditis elegans</em>) [Elmore, 2007].</p>
<ul>
<li>Apoptosis occurs in breast cancer cells, human and mouse</li>
</ul>
<p> </p>
<p> </p>
UBERON:0000062organCL:0000000cellHighUnspecificHighNot Otherwise SpecifiedHighHighHighHigh<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Archana, M. et al. (2013), "Various methods available for detection of apoptotic cells", Indian J Cancer 50:274-283</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Elmore, S. (2007), "Apoptosis: a review of programmed cell death", Toxicol Pathol 35:495-516</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Glaser, K.B. et al. (2003), "Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines", Mol Cancer Ther 2:151-163</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Kerr, J.F.R. et al. (1972), "Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics", Br J Cancer 26:239-257</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Kressel, M. and Groscurth, P. (1994), "Distinction of apoptotic and necrotic cell death by in situ labelling of fragmented DNA", Cell Tissue Res 278:549-556</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Martinez, M.M. et al. (2010), "Detection of apoptosis: A review of conventioinal and novel techniques", Anal Methods 2:996-1004</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Parajuli, K.R. et al. (2014), "Methoxyacetic acid suppresses prostate cancer cell growth by inducing growth arrest and apoptosis", Am J Clin Exp Urol 2:300-313</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Pucci, B. et al. (2000), "Cell cycle and apoptosis", Neoplasia 2:291-299</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Taatjes, D.J. et al. (2008), "Morphological and cytochemical determination of cell death by apoptosis", Histochem Cell Biol 129:33-43</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Wade, M.G. et al. (2008), "Methoxyacetic acid-induced spermatocyte death is associated with histone hyperacetylation in rats", Biol Reprod 78:822-831</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Wang, C. et al. (2017), "CD147 regulates extrinsic apoptosis in spermatocytes by modulating NFkB signaling pathways", Oncotarget 8:3132-3143</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Wu, R. et al. (2016), "microRNA-497 induces apoptosis and suppressed proliferation via the Bcl-2/Bax-caspase9-caspase 3 pathway and cyclin D2 protein in HUVECs", PLoS One 11:e0167052</span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif"><span style="color:black">Yasuhara, S. et al. (2003), </span>"<span style="color:black">Comparison of comet assay, electron microscopy, and flow cytometry for detection of apoptosis</span>"<span style="color:black">, J Histochem Cytochem 51:873-885</span></span></span></p>
<p><span style="font-size:16px"><span style="font-family:Arial,Helvetica,sans-serif">Zupkovitz, G. et al. (2010), "The cyclin-dependent kinase inhibitor p21 is a crucial target for histone deacetylase 1 as a regulator of cellular proliferation", Mol Cell Biol 30:1171-1181</span></span></p>
2017-02-07T13:21:502022-12-20T08:33:23Increased glycolipid levels in testisIncreased, glycolipid levels in testisOrgan2022-12-13T21:08:392022-12-13T21:08:39Impaired, blood testis barrierImpaired, blood testis barrierOrgan2022-12-13T21:12:242022-12-13T21:12:24Reduction, testosterone levelReduction, testosterone levelTissue<p><strong>Biological state</strong></p>
<p>Testosterone (T) is a steroid hormone from the androgen group. T serves as a substrate for two metabolic pathways that produce antagonistic sex steroids.</p>
<p><strong>Biological compartments</strong></p>
<p>Testosterone is synthesized by the gonads and other steroidogenic tissues (e.g., brain, adipose), acts locally and/or is transported to other tissues via blood circulation. Leydig cells are the testosterone-producing cells of the testis.</p>
<p><strong>General role in biology</strong></p>
<p>Androgens, the main male sex steroids, are the critical factors responsible for the development of the male phenotype during embryogenesis and for the achievement of sexual maturation at puberty. In adulthood, androgens remain essential for the maintenance of male reproductive function and behaviour. Apart from their effects on reproduction, androgens affect a wide variety of non-reproductive tissues such as skin, bone, muscle, and brain (Heemers, Verhoeven, & Swinnen, 2006). Androgens, principally T and 5α-dihydrotestosterone (DHT), exert most of their effects by interacting with a specific receptor, the androgen receptor (AR), for review see (Murashima, Kishigami, Thomson, & Yamada, 2015). On the one hand, testosterone can be reduced by 5α-reductase to produce 5α dihydrotestosterone (DHT). On the other hand, testosterone can be aromatized to generate estrogens. Testosterone effects can also be classified by the age of usual occurrence, postnatal effects in both males and females are mostly dependent on the levels and duration of circulating free testosterone.</p>
<p>Testosterone can be measured by immunoassays and by isotope-dilution gas chromatography-mass spectrometry in serum (Taieb et al., 2003), (Paduch et al., 2014). Testosterone levels are measured i.a. in: Fish Lifecycle Toxicity Test (FLCTT) (US EPA OPPTS 850.1500), Male pubertal assay (PP Male Assay) (US EPA OPPTS 890.1500), OECD TG 441: Hershberger Bioassay in Rats (H Assay).</p>
<p>Key enzymes needed for testosterone production first appear in the common ancestor of amphioxus and vertebrates (Baker 2011). Consequently, this key event is applicable to most vertebrates, including humans.</p>
UBERON:0000178bloodHighHighHigh<p>Heemers, H. V, Verhoeven, G., & Swinnen, J. V. (2006). Androgen activation of the sterol regulatory element-binding protein pathway: Current insights. Molecular Endocrinology (Baltimore, Md.), 20(10), 2265–77. doi:10.1210/me.2005-0479</p>
<p>Murashima, A., Kishigami, S., Thomson, A., & Yamada, G. (2015). Androgens and mammalian male reproductive tract development. Biochimica et Biophysica Acta, 1849(2), 163–170. doi:10.1016/j.bbagrm.2014.05.020</p>
<p>Paduch, D. A., Brannigan, R. E., Fuchs, E. F., Kim, E. D., Marmar, J. L., & Sandlow, J. I. (2014). The laboratory diagnosis of testosterone deficiency. Urology, 83(5), 980–8. doi:10.1016/j.urology.2013.12.024</p>
<p>Taieb, J., Mathian, B., Millot, F., Patricot, M.-C., Mathieu, E., Queyrel, N., … Boudou, P. (2003). Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children. Clinical Chemistry, 49(8), 1381–95.</p>
2016-11-29T18:41:242017-09-16T10:14:33Decreased sperm quantity or quality in the adult, Decreased fertility Decreased sperm quantity or quality in the adult, Decreased fertility Individual2016-11-29T18:41:252016-12-03T16:37:50anogenital distance (AGD), decreasedAGD, decreasedTissue<p>The anogenital distance (AGD) refers to the distance between anus and the external genitalia. In rodents and humans, the male AGD is approximately twice the length as the female AGD (<a href="#_ENREF_39" title="Salazar-Martinez, 2004 #8">Salazar-Martinez et al, 2004</a>; <a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). This sexual dimorphisms is a consequence of sex hormone-dependent development of secondary sexual characteristics (<a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). In males, it is believed that androgens (primarily DHT) activate AR-positive cells in non-myotic cells in the fetal perineum region to initiate differentiation of the perineal <em>levator ani</em> and <em>bulbocavernosus </em>(LABC) muscle complex (<a href="#_ENREF_18" title="Ipulan, 2014 #185">Ipulan et al, 2014</a>). This AR-dependent process occurs within a critical window of development, around gestational days 15-18 in rats (<a href="#_ENREF_26" title="MacLeod, 2010 #27">MacLeod et al, 2010</a>). In females, the absence of DHT prevents this masculinization effect from occurring.</p>
<p>The involvement of androgens in masculinization of the male fetus, including the perineum, has been known for a very long time (<a href="#_ENREF_20" title="Jost, 1953 #151">Jost, 1953</a>), and AGD has historically been used to, for instance, sex newborn kittens. It is now well established that the AGD in newborns is a proxy readout for the intrauterine sex hormone milieu the fetus was developing. Too low androgen levels in XY fetuses makes the male AGD shorter, whereas excess (ectopic) androgen levels in XX fetuses makes the female AGD longer, in humans and rodents (<a href="#_ENREF_41" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>).</p>
<p>The AGD is a morphometric measurement carried out by trained technicians (rodents) or medical staff (humans).</p>
<p>In rodent studies AGD is assessed as the distance between the genital papilla and the anus, and measured using a stereomicroscope with a micrometer eyepiece. The AGD index (AGDi) is often calculated by dividing AGD by the cube root of the body weight. It is important in statistical analysis to use litter as the statistical unit. This is done when more than one pup from each litter is examined. Statistical analyses is adjusted using litter as an independent, random and nested factor. AGD are analysed using body weight as covariate as recommended in Guidance Document 151 (<a href="#_ENREF_37" title="OECD, 2013 #30">OECD, 2013</a>).</p>
<p> </p>
<p>A short AGD in male offspring is a marker of insufficient androgen action during critical fetal developmental stages (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>; <a href="#_ENREF_49" title="Welsh, 2008 #23">Welsh et al, 2008</a>). A short AGD is thus a sign of undervirilization, which is also associated with a series of male reproductive disorders, including genital malformations and infertility in humans (<a href="#_ENREF_21" title="Juul, 2014 #3">Juul et al, 2014</a>; <a href="#_ENREF_44" title="Skakkebaek, 2001 #9">Skakkebaek et al, 2001</a>).</p>
<p>There are numerous human epidemiological studies showing associations with intrauterine exposure to anti-androgenic chemicals and short AGD in newborn boys alongside other reproductive disorders (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>). This underscores the human relevance of this AO. However, in reproductive toxicity studies and chemical risk assessment, rodents (rats and mice) are what is tested on. The list of chemicals inducing short male AGD in male rat offspring is extensive, as evidenced by the ‘stressor’ list and reviewed by (<a href="#_ENREF_42" title="Schwartz, 2019 #252">Schwartz et al, 2019</a>).</p>
UBERON:0002356perineumHighMaleHighFoetalModerateHighHigh<p><a name="_ENREF_1">Aydoğan Ahbab M, Barlas N (2015) Influence of in utero di-n-hexyl phthalate and dicyclohexyl phthalate on fetal testicular development in rats. <em>Toxicol Lett</em> <strong>233:</strong> 125-137</a></p>
<p><a name="_ENREF_2">Boberg J, Axelstad M, Svingen T, Mandrup K, Christiansen S, Vinggaard AM, Hass U (2016) Multiple endocrine disrupting effects in rats perinatally exposed to butylparaben. <em>Toxicol Sci</em> <strong>152:</strong> 244-256</a></p>
<p><a name="_ENREF_3">Boberg J, Metzdorff S, Wortziger R, Axelstad M, Brokken L, Vinggaard AM, Dalgaard M, Nellemann C (2008) Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats. <em>Toxicology</em> <strong>250:</strong> 75-81</a></p>
<p><a name="_ENREF_4">Bowman CJ, Barlow NJ, Turner KJ, Wallace DG, Foster PM (2003) Effects of in utero exposure to finasteride on androgen-dependent reproductive development in the male rat. <em>Toxicol Sci</em> <strong>74:</strong> 393-406</a></p>
<p><a name="_ENREF_5">Christiansen S, Boberg J, Axelstad M, Dalgaard M, Vinggaard AM, Metzdorff SB, Hass U (2010) Low-dose perinatal exposure to di(2-ethylhexyl) phthalate induces anti-androgenic effects in male rats. <em>Reprod Toxicol</em> <strong>30:</strong> 313-321</a></p>
<p><a name="_ENREF_6">Christiansen S, Scholze M, Dalgaard M, Vinggaard AM, Axelstad M, Kortenkamp A, Hass U (2009) Synergistic disruption of external male sex organ development by a mixture of four antiandrogens. <em>Environ Health Perspect</em> <strong>117:</strong> 1839-1846</a></p>
<p><a name="_ENREF_7">Draskau MK, Boberg J, Taxvig C, Pedersen M, Frandsen HL, Christiansen S, Svingen T (2019) In vitro and in vivo endocrine disrupting effects of the azole fungicides triticonazole and flusilazole. <em>Environ Pollut</em> <strong>255:</strong> 113309</a></p>
<p><a name="_ENREF_8">Ema M, Miyawaki E (2002) Effects on development of the reproductive system in male offspring of rats given butyl benzyl phthalate during late pregnancy. <em>Reprod Toxicol</em> <strong>16:</strong> 71-76</a></p>
<p><a name="_ENREF_9">Ema M, Miyawaki E, Hirose A, Kamata E (2003) Decreased anogenital distance and increased incidence of undescended testes in fetuses of rats given monobenzyl phthalate, a major metabolite of butyl benzyl phthalate. <em>Reprod Toxicol</em> <strong>17:</strong> 407-412</a></p>
<p><a name="_ENREF_10">Foster PM, Harris MW (2005) Changes in androgen-mediated reproductive development in male rat offspring following exposure to a single oral dose of flutamide at different gestational ages. <em>Toxicol Sci</em> <strong>85:</strong> 1024-1032</a></p>
<p><a name="_ENREF_11">Gray LE, Jr., Ostby J, Furr J, Price M, Veeramachaneni DN, Parks L (2000) Perinatal exposure to the phthalates DEHP, BBP, and DINP, but not DEP, DMP, or DOTP, alters sexual differentiation of the male rat. <em>Toxicol Sci</em> <strong>58:</strong> 350-365</a></p>
<p><a name="_ENREF_12">Gray LEJ, Ostby JS, Kelce WR (1994) Developmental effects of an environmental antiandrogen: the fungicide vinclozolin alters sex differentiation of the male rat. <em>Toxicol Appl Pharmacol</em> <strong>129:</strong> 46-52</a></p>
<p><a name="_ENREF_13">Hass U, Boberg J, Christiansen S, Jacobsen PR, Vinggaard AM, Taxvig C, Poulsen ME, Herrmann SS, Jensen BH, Petersen A, Clemmensen LH, Axelstad M (2012) Adverse effects on sexual development in rat offspring after low dose exposure to a mixture of endocrine disrupting pesticides. <em>Reprod Toxicol</em> <strong>34:</strong> 261-274</a></p>
<p><a name="_ENREF_14">Hass U, Scholze M, Christiansen S, Dalgaard M, Vinggaard AM, Axelstad M, Metzdorff SB, Kortenkamp A (2007) Combined exposure to anti-androgens exacerbates disruption of sexual differentiation in the rat. <em>Environ Health Perspect</em> <strong>115 Suppl. 1:</strong> 122-128</a></p>
<p><a name="_ENREF_15">Hoshino N, Iwai M, Okazaki Y (2005) A two-generation reproductive toxicity study of dicyclohexyl phthalate in rats. <em>J Toxicol Sci</em> <strong>30 Spec No:</strong> 79-96</a></p>
<p><a name="_ENREF_16">Hotchkiss AK, Parks-Saldutti LG, Ostby JS, Lambright C, Furr J, Vandenbergh JG, Gray LEJ (2004) A mixture of the "antiandrogens" linuron and butyl benzyl phthalate alters sexual differentiation of the male rat in a cumulative fashion. <em>Biol Reprod</em> <strong>71:</strong> 1852-1861</a></p>
<p><a name="_ENREF_17">Howdeshell KL, Furr J, Lambright CR, Rider CV, Wilson VS, Gray LE, Jr. (2007) Cumulative effects of dibutyl phthalate and diethylhexyl phthalate on male rat reproductive tract development: altered fetal steroid hormones and genes. <em>Toxicol Sci</em> <strong>99:</strong> 190-202</a></p>
<p><a name="_ENREF_18">Ipulan LA, Suzuki K, Sakamoto Y, Murashima A, Imai Y, Omori A, Nakagata N, Nishinakamura R, Valasek P, Yamada G (2014) Nonmyocytic androgen receptor regulates the sexually dimorphic development of the embryonic bulbocavernosus muscle. <em>Endocrinology</em> <strong>155:</strong> 2467-2479</a></p>
<p><a name="_ENREF_19">Jarfelt K, Dalgaard M, Hass U, Borch J, Jacobsen H, Ladefoged O (2005) Antiandrogenic effects in male rats perinatally exposed to a mixture of di(2-ethylhexyl) phthalate and di(2-ethylhexyl) adipate. <em>Reprod Toxicol</em> <strong>19:</strong> 505-515</a></p>
<p><a name="_ENREF_20">Jost A (1953) Problems of fetal endocrinology: The gonadal and hypophyseal hormones. <em>Recent Prog Horm Res</em> <strong>8:</strong> 379-418</a></p>
<p><a name="_ENREF_21">Juul A, Almstrup K, Andersson AM, Jensen TK, Jorgensen N, Main KM, Rajpert-De Meyts E, Toppari J, Skakkebaek NE (2014) Possible fetal determinants of male infertility. <em>Nat Rev Endocrinol</em> <strong>10:</strong> 553-562</a></p>
<p><a name="_ENREF_22">Kita DH, Meyer KB, Venturelli AC, Adams R, Machado DL, Morais RN, Swan SH, Gennings C, Martino-Andrade AJ (2016) Manipulation of pre and postnatal androgen environments and anogenital distance in rats. <em>Toxicology</em> <strong>368-369:</strong> 152-161</a></p>
<p><a name="_ENREF_23">Laier P, Metzdorff SB, Borch J, Hagen ML, Hass U, Christiansen S, Axelstad M, Kledal T, Dalgaard M, McKinnell C, Brokken LJ, Vinggaard AM (2006) Mechanisms of action underlying the antiandrogenic effects of the fungicide prochloraz. <em>Toxicol Appl Pharmacol</em> <strong>213:</strong> 2</a></p>
<p><a name="_ENREF_24">Li M, Qiu L, Zhang Y, Hua Y, Tu S, He Y, Wen S, Wang Q, Wei G (2013) Dose-related effect by maternal exposure to di-(2-ethylhexyl) phthalate plasticizer on inducing hypospadiac male rats. <em>Environ Toxicol Pharmacol</em> <strong>35:</strong> 55-60</a></p>
<p><a name="_ENREF_25">Lin H, Lian QQ, Hu GX, Jin Y, Zhang Y, Hardy DO, Chen GR, Lu ZQ, Sottas CM, Hardy MP, Ge RS (2009) In utero and lactational exposures to diethylhexyl-phthalate affect two populations of Leydig cells in male Long-Evans rats. <em>Biol Reprod</em> <strong>80:</strong> 882-888</a></p>
<p><a name="_ENREF_26">Loeffler IK, Peterson RE (1999) Interactive effects of TCDD and p,p'-DDE on male reproductive tract development in in utero and lactationally exposed rats. <em>Toxicol Appl Pharmacol</em> <strong>154:</strong> 28-39</a></p>
<p><a name="_ENREF_27">MacLeod DJ, Sharpe RM, Welsh M, Fisken M, Scott HM, Hutchison GR, Drake AJ, van den Driesche S (2010) Androgen action in the masculinization programming window and development of male reproductive organs. <em>Int J Androl</em> <strong>33:</strong> 279-287</a></p>
<p><a name="_ENREF_28">Matsuura I, Saitoh T, Ashina M, Wako Y, Iwata H, Toyota N, Ishizuka Y, Namiki M, Hoshino N, Tsuchitani M (2005) Evaluation of a two-generation reproduction toxicity study adding endpoints to detect endocrine disrupting activity using vinclozolin. <em>J Toxicol Sci</em> <strong>30 Spec No:</strong> 163-168</a></p>
<p><a name="_ENREF_29">McIntyre BS, Barlow NJ, Foster PM (2001) Androgen-mediated development in male rat offspring exposed to flutamide in utero: permanence and correlation of early postnatal changes in anogenital distance and nipple retention with malformations in androgen-dependent tissues. <em>Toxicol Sci</em> <strong>62:</strong> 236-249</a></p>
<p><a name="_ENREF_30">McIntyre BS, Barlow NJ, Sar M, Wallace DG, Foster PM (2002) Effects of in utero linuron exposure on rat Wolffian duct development. <em>Reprod Toxicol</em> <strong>16:</strong> 131-139</a></p>
<p><a name="_ENREF_31">Melching-Kollmuss S, Fussell KC, Schneider S, Buesen R, Groeters S, Strauss V, van Ravenzwaay B (2017) Comparing effect levels of regulatory studies with endpoints derived in targeted anti-androgenic studies: example prochloraz. <em>Arch Toxicol</em> <strong>91:</strong> 143-162</a></p>
<p><a name="_ENREF_32">Moore RW, Rudy TA, Lin TM, Ko K, Peterson RE (2001) Abnormalities of sexual development in male rats with in utero and lactational exposure to the antiandrogenic plasticizer Di(2-ethylhexyl) phthalate. <em>Environ Health Perspect</em> <strong>109:</strong> 229-237</a></p>
<p><a name="_ENREF_33">Mylchreest E, Sar M, Cattley RC, Foster PM (1999) Disruption of androgen-regulated male reproductive development by di(n-butyl) phthalate during late gestation in rats is different from flutamide. <em>Toxicol Appl Pharmacol</em> <strong>156:</strong> 81-95</a></p>
<p><a name="_ENREF_34">Nagao T, Ohta R, Marumo H, Shindo T, Yoshimura S, Ono H (2000) Effect of butyl benzyl phthalate in Sprague-Dawley rats after gavage administration: a two-generation reproductive study. <em>Reprod Toxicol</em> <strong>14:</strong> 513-532</a></p>
<p><a name="_ENREF_35">Nardelli TC, Albert O, Lalancette C, Culty M, Hales BF, Robaire B (2017) In utero and lactational exposure study in rats to identify replacements for di(2-ethylhexyl) phthalate. <em>Sci Rep</em> <strong>7:</strong> 3862</a></p>
<p><a name="_ENREF_36">Noriega NC, Ostby J, Lambright C, Wilson VS, Gray LE, Jr. (2005) Late gestational exposure to the fungicide prochloraz delays the onset of parturition and causes reproductive malformations in male but not female rat offspring. <em>Biol Reprod</em> <strong>72:</strong> 1324-1335</a></p>
<p><a name="_ENREF_37">OECD. (2013) Guidance document in support of the test guideline on the extended one generation reproductive toxicity study No. 151.</a></p>
<p><a name="_ENREF_38">Ostby J, Kelce WR, Lambright C, Wolf CJ, Mann P, Gray CLJ (1999) The fungicide procymidone alters sexual differentiation in the male rat by acting as an androgen-receptor antagonist in vivo and in vitro. <em>Toxicol Ind Health</em> <strong>15:</strong> 80-93</a></p>
<p><a name="_ENREF_39">Saillenfait AM, Gallissot F, Sabaté JP (2009a) Differential developmental toxicities of di-n-hexyl phthalate and dicyclohexyl phthalate administered orally to rats. <em>J Appl Toxicol</em> <strong>29:</strong> 510-521</a></p>
<p><a name="_ENREF_40">Saillenfait AM, Roudot AC, Gallissot F, Sabaté JP (2011) Prenatal developmental toxicity studies on di-n-heptyl and di-n-octyl phthalates in Sprague-Dawley rats. <em>Reprod Toxicol</em> <strong>32:</strong> 268-276</a></p>
<p><a name="_ENREF_41">Saillenfait AM, Sabaté JP, Gallissot F (2009b) Effects of in utero exposure to di-n-hexyl phthalate on the reproductive development of the male rat. <em>Reprod Toxicol</em> <strong>28:</strong> 468-476</a></p>
<p><a name="_ENREF_42">Salazar-Martinez E, Romano-Riquer P, Yanez-Marquez E, Longnecker MP, Hernandez-Avila M (2004) Anogenital distance in human male and female newborns: a descriptive, cross-sectional study. <em>Environ Health</em> <strong>3:</strong> 8</a></p>
<p><a name="_ENREF_43">Schneider S, Kaufmann W, Strauss V, van Ravenzwaay B (2011) Vinclozolin: a feasibility and sensitivity study of the ILSI-HESI F1-extended one-generation rat reproduction protocol. <em>Regulatory Toxicology and Pharmacology</em> <strong>59:</strong> 91-100</a></p>
<p><a name="_ENREF_44">Schwartz CL, Christiansen S, Vinggaard AM, Axelstad M, Hass U, Svingen T (2019) Anogenital distance as a toxicological or clinical marker for fetal androgen action and risk for reproductive disorders. <em>Arch Toxicol</em> <strong>93:</strong> 253-272</a></p>
<p><a name="_ENREF_45">Scott HM, Hutchison GR, Mahood IK, Hallmark N, Welsh M, De Gendt K, Verhoeven H, O'Shaughnessy P, Sharpe RM (2007) Role of androgens in fetal testis development and dysgenesis. <em>Endocrinology</em> <strong>148:</strong> 2027-2036</a></p>
<p><a name="_ENREF_46">Skakkebaek NE, Rajpert-De Meyts E, Main KM (2001) Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. <em>Hum Reprod</em> <strong>16:</strong> 972-978</a></p>
<p><a name="_ENREF_47">Taxvig C, Vinggaard AM, Hass U, Axelstad M, Metzdorff S, Nellemann C (2008) Endocrine-disrupting properties in vivo of widely used azole fungicides. <em>Int J Androl</em> <strong>31:</strong> 170-177</a></p>
<p><a name="_ENREF_48">Turner KJ, Barlow NJ, Struve MF, Wallace DG, Gaido KW, Dorman DC, Foster PM (2002) Effects of in utero exposure to the organophosphate insecticide fenitrothion on androgen-dependent reproductive development in the Crl:CD(SD)BR rat. <em>Toxicol Sci</em> <strong>68:</strong> 174-183</a></p>
<p><a name="_ENREF_49">Tyl RW, Myers CB, Marr MC, Fail PA, Seely JC, Brine DR, Barter RA, Butala JH (2004) Reproductive toxicity evaluation of dietary butyl benzyl phthalate (BBP) in rats. <em>Reprod Toxicol</em> <strong>18:</strong> 241-264</a></p>
<p><a name="_ENREF_50">Van den Driesche S, Kolovos P, Platts S, Drake AJ, Sharpe RM (2012) Inter-relationship between testicular dysgenesis and Leydig cell function in the masculinization programming window in the rat. <em>PloS one</em> <strong>7:</strong> e30111</a></p>
<p><a name="_ENREF_51">Welsh M, Saunders PT, Fisken M, Scott HM, Hutchison GR, Smith LB, Sharpe RM (2008) Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism. <em>J Clin Invest</em> <strong>118:</strong> 1479-1490</a></p>
<p><a name="_ENREF_52">Welsh M, Saunders PT, Sharpe RM (2007) The critical time window for androgen-dependent development of the Wolffian duct in the rat. <em>Endocrinology</em> <strong>148:</strong> 3185-3195</a></p>
<p><a name="_ENREF_53">Wolf CJ, LeBlanc GA, Gray LE, Jr. (2004) Interactive effects of vinclozolin and testosterone propionate on pregnancy and sexual differentiation of the male and female SD rat. <em>Toxicol Sci</em> <strong>78:</strong> 135-143</a></p>
<p><a name="_ENREF_54">Wolf CJJ, Lambright C, Mann P, Price M, Cooper RL, Ostby J, Gray CLJ (1999) Administration of potentially antiandrogenic pesticides (procymidone, linuron, iprodione, chlozolinate, p,p'-DDE, and ketoconazole) and toxic substances (dibutyl- and diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) during sexual differentiation produces diverse profiles of reproductive malformations in the male rat. <em>Toxicol Ind Health</em> <strong>15:</strong> 94-118</a></p>
<p><a name="_ENREF_55">Zhang L, Dong L, Ding S, Qiao P, Wang C, Zhang M, Zhang L, Du Q, Li Y, Tang N, Chang B (2014) Effects of n-butylparaben on steroidogenesis and spermatogenesis through changed E₂ levels in male rat offspring. <em>Environ Toxicol Pharmacol</em> <strong>37:</strong> 705-717</a></p>
2019-08-30T04:20:562022-12-22T05:18:24Malformation, cryptorchidism - maldescended testisMalformation, cryptorchidismOrgan<p style="text-align: justify;"><span style="font-family:times new roman,times,serif"><span style="font-size:14px">Undescended testis is a testicular disorder syndrome known as cryptorchidism. Testis migration is a major event in male fetus development, as it will directly affect his reproductive health.</span></span></p>
<p style="text-align: justify;"><span style="font-family:times new roman,times,serif"><span style="font-size:14px">Cryptorchidism can defined itself as the insertion of the testis in another position than the scrotum. Although the events leading to this pathology occurred during development, cryptorchidism can only be defined after birth though clinical examination as palpation.</span></span></p>
<p style="text-align: justify;"><span style="font-family:times new roman,times,serif"><span style="font-size:14px">Cryptorchidism can be either uni- or bilateral and has been reported to increase in incidence over the decades (Denmark, UK, India…). The maldescended testis will experiment heat stress (37 against 33C outside the body) interfering with testicular physiology and development of germ cells into spermatogonia. Germ cells maturation failure will induce a non-reversible reduction in fertility power of the individual. Cryptorchidism is an established risk factor for infertility and is known to increase the incidence of testicular germ cell tumors (TGCT) <sup>123</sup></span></span></p>
<p style="text-align: justify;"> </p>
<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">Remark: </span></span></p>
<table>
<tbody>
<tr>
<td colspan="1" rowspan="1">
<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">Cryptorchidism is the first AO of a larger list including raise in testicular cancer and germ cell tumor incidence, as well as reduced fertility due to impairment in germ cells maturation.</span></span></p>
</td>
</tr>
</tbody>
</table>
<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif">Cryptorchidism is a birth defect that can be highlighted by a clinical examination. The aim of this palpation is to locate the gonad and determine its lowest position without causing painful traction on the spermatic cord. <sup>4</sup></span></span></p>
<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif"><sup>1</sup> Hutson J.M., Li R., Southwell B.R., Newgreen D., and Cousinery M. (2015) Regulation of testicular descent. Pediatric Surgery International, 31(4): 317-325. <a href="https://www.google.com/url?q=https://doi.org/10.1007/s00383-015-3673-4&sa=D&ust=1554891396648000">https://doi.org/10.1007/s00383-015-3673-4</a> </span></span></p>
<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif"><sup>2</sup> Boisen K.A., Kaleva M., Main K.M., Virtanen H.E., Haavisto A.M., Schmidt I.M., Chellakooty M., Damgaard I.N., Mau C., Reunanen M., Skakkebaek N.E. and Toppari J. (2004) Difference in prevalence of congenital cryptorchidism in infants between two Nordic countries. Lancet, 17;363(9417):1264-9 <a href="https://www.google.com/url?q=https://doi.org/10.1016/S0140-6736(04)15998-9&sa=D&ust=1554891396649000">https://doi.org/10.1016/S0140-6736(04)15998-9</a> </span></span></p>
<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif"><sup>3</sup> Acerini C.L., Miles H.L., Dunger D.B., Ong K.K. and Hughes I.A. (2009) The descriptive epidemiology of congenital and acquired cryptorchidism in a UK infant cohort. Archives of disease in childhood, 94(11):868-72 https://doi.org10.1136/adc.2008.150219 </span></span></p>
<p style="text-align: justify;"><span style="font-size:14px"><span style="font-family:times new roman,times,serif"><sup>4</sup> Hutson J.M., et al. (2015) Cryptorchidism and Hypospadias. Endotext<a href="https://www.google.com/url?q=https://www.ncbi.nlm.nih.gov/books/NBK279106/&sa=D&ust=1554891396651000">https://www.ncbi.nlm.nih.gov/books/NBK279106/</a> </span></span></p>
2019-04-10T05:06:572019-04-10T05:27:42Decrease, ReproductionDecrease, ReproductionIndividual2021-04-11T08:21:372021-04-11T17:38:35Adverse Outcome Pathways diagram related to PBDEs associated male reproductive toxicityAdverse Outcome Pathways diagram related to PBDEs associated male reproductive toxicityUnder development: Not open for comment. Do not cite<p>In regulatory toxicology, the AGD is mandatory inclusions in OECD test guidelines used to test for developmental and reproductive toxicity of chemicals. Guidelines include ‘TG 443 extended one-generation study’, ‘TG 421/422 reproductive toxicity screening studies’ and ‘TG 414 developmental toxicity study’.</p>
2022-12-13T21:19:442023-04-29T13:02:21