T3DB: Tetrachlorobisphenol A

Identification Taxonomy Biological Properties Physical Properties Toxicity Profile Spectra Concentrations Links References Gene Regulation Targets (9)XML

Targets (9)

Record Information

Version

2.0

Creation Date

2014-08-12 17:44:32 UTC

Update Date

2014-12-24 20:26:34 UTC

Accession Number

T3D3948

Identification

Common Name

Tetrachlorobisphenol A

Class

Small Molecule

Description

Tetrachlorobisphenol A is estrogen receptor(ER) alpha agonists, antagonists for androgen receptor(AR), progesterone receptor(PR) antagonists. It exhibits the ability to reverse the ERR inhibition induced by 4-hydroxytamoxifen.

Compound Type

Industrial/Workplace Toxin
Organic Compound
Organochloride
Synthetic Compound

Chemical Structure

MOL SDF PDB SMILES InChI

Synonyms

Synonym
2,2-Bis(4-hydroxy-3,5-dichlorophenyl)propane
3,3',5,5'-Tetrachlorobisphenol a
Tetrachlorobisphenol a
Tetrachlorodian

Chemical Formula

C₁₅H₁₂Cl₄O₂

Average Molecular Mass

366.067 g/mol

Monoisotopic Mass

363.959 g/mol

CAS Registry Number

79-95-8

IUPAC Name

2,6-dichloro-4-[2-(3,5-dichloro-4-hydroxyphenyl)propan-2-yl]phenol

Traditional Name

tetrachlorobisphenol A

SMILES

CC(C)(C1=CC(Cl)=C(O)C(Cl)=C1)C1=CC(Cl)=C(O)C(Cl)=C1

InChI Identifier

InChI=1S/C15H12Cl4O2/c1-15(2,7-3-9(16)13(20)10(17)4-7)8-5-11(18)14(21)12(19)6-8/h3-6,20-21H,1-2H3

InChI Key

InChIKey=KYPYTERUKNKOLP-UHFFFAOYSA-N

Chemical Taxonomy

Description

belongs to the class of organic compounds known as bisphenols. These are methylenediphenols, HOC6H4CH2C6H4OH, commonly p,p-methylenediphenol, and their substitution products (generally derived from condensation of two equivalent amounts of a phenol with an aldehyde or ketone).

Kingdom

Organic compounds

Super Class

Benzenoids

Class

Benzene and substituted derivatives

Sub Class

Diphenylmethanes

Direct Parent

Bisphenols

Alternative Parents

Substituents

Bisphenol
Phenylpropane
1,3-dichlorobenzene
2-halophenol
2-chlorophenol
Chlorobenzene
Halobenzene
Phenol
Aryl halide
Aryl chloride
Hydrocarbon derivative
Organic oxygen compound
Organooxygen compound
Organohalogen compound
Organochloride
Aromatic homomonocyclic compound

Molecular Framework

Aromatic homomonocyclic compounds

External Descriptors

bisphenol (CHEBI:35004 )

Biological Properties

Status

Detected and Not Quantified

Origin

Exogenous

Cellular Locations

Membrane

Biofluid Locations

Not Available

Tissue Locations

Not Available

Pathways

Not Available

Applications

Not Available

Biological Roles

Not Available

Chemical Roles

Not Available

Physical Properties

State

Solid

Appearance

Solid.

Experimental Properties

Property	Value
Melting Point	130-132°C (lit.)
Boiling Point	Not Available
Solubility	DMSO and Methanol
LogP	Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0005 g/L	ALOGPS
logP	7.22	ALOGPS
logP	6.46	ChemAxon
logS	-5.9	ALOGPS
pKa (Strongest Acidic)	6.27	ChemAxon
pKa (Strongest Basic)	-7.5	ChemAxon
Physiological Charge	-1	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	2	ChemAxon
Polar Surface Area	40.46 Å²	ChemAxon
Rotatable Bond Count	2	ChemAxon
Refractivity	98.49 m³·mol⁻¹	ChemAxon
Polarizability	34.18 Å³	ChemAxon
Number of Rings	2	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Spectra

Spectrum Type	Description	Splash Key	Deposition Date	View
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	splash10-0udi-0129000000-d11faa3074c258e0bb4e	2021-09-24	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positive	Not Available	2021-10-12	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_1_1) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TMS_2_1) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TBDMS_1_1) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
Predicted GC-MS	Predicted GC-MS Spectrum - GC-MS (TBDMS_2_1) - 70eV, Positive	Not Available	2021-11-05	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 45V, Negative	splash10-0w29-0092000000-17853fe903a3975e5f90	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 60V, Negative	splash10-0002-0090000000-2772dcd617aaa92b1f6c	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 30V, Negative	splash10-03di-0019000000-ba2de1df5989b335615e	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 15V, Negative	splash10-03di-0009000000-f35b14b05fa85968fee8	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 75V, Negative	splash10-001j-0190000000-04aba6d56eb8a7f85072	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 90V, Negative	splash10-001i-1190000000-700b9d5cef5b6b06d83e	2021-09-20	View Spectrum
LC-MS/MS	LC-MS/MS Spectrum - 45V, Positive	splash10-0w29-0092000000-51a18251a74cd7430645	2021-09-20	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Positive	splash10-03di-0009000000-05964ea61258d00fd8ab	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Positive	splash10-03di-0009000000-6ac1db351cc0fded9281	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Positive	splash10-0hha-0439000000-94f5c9202b1187d29d99	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 10V, Negative	splash10-03di-0009000000-94363d558a1a5e2576b0	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 20V, Negative	splash10-03di-0009000000-caeb72dcd7861497e33d	2016-08-03	View Spectrum
Predicted LC-MS/MS	Predicted LC-MS/MS Spectrum - 40V, Negative	splash10-03di-0719000000-05ef1cc3f3e40642b2ef	2016-08-03	View Spectrum
MS	Mass Spectrum (Electron Ionization)	splash10-0udi-2419000000-f720422fd1ffc745c38f	2014-09-20	View Spectrum
1D NMR	¹H NMR Spectrum (1D, 90 MHz, CDCl₃, experimental)	Not Available	2014-09-20	View Spectrum

Toxicity Profile

Route of Exposure

Not Available

Mechanism of Toxicity

Not Available

Metabolism

Not Available

Toxicity Values

Not Available

Lethal Dose

Not Available

Carcinogenicity (IARC Classification)

No indication of carcinogenicity to humans (not listed by IARC).

Uses/Sources

Not Available

Minimum Risk Level

Not Available

Health Effects

Not Available

Symptoms

Not Available

Treatment

Not Available

Normal Concentrations

Not Available

Abnormal Concentrations

Not Available

External Links

DrugBank ID

Not Available

HMDB ID

Not Available

PubChem Compound ID

ChEMBL ID

ChemSpider ID

KEGG ID

UniProt ID

Not Available

OMIM ID

ChEBI ID

Not Available

BioCyc ID

Not Available

CTD ID

Not Available

Stitch ID

Not Available

PDB ID

Not Available

ACToR ID

Not Available

Wikipedia Link

Not Available

References

Synthesis Reference

Not Available

MSDS

T3D3948.pdf

General References

Li J, Ma M, Wang Z: In vitro profiling of endocrine disrupting effects of phenols. Toxicol In Vitro. 2010 Feb;24(1):201-7. doi: 10.1016/j.tiv.2009.09.008. Epub 2009 Sep 16. [19765641 ]

Gene Regulation

Up-Regulated Genes

Not Available

Down-Regulated Genes

Not Available

Targets

Target Details

1. Progesterone receptor

General Function:: Zinc ion binding
Specific Function:: The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Progesterone receptor isoform B (PRB) is involved activation of c-SRC/MAPK signaling on hormone stimulation.Isoform A: inactive in stimulating c-Src/MAPK signaling on hormone stimulation.Isoform 4: Increases mitochondrial membrane potential and cellular respiration upon stimulation by progesterone.
Gene Name:: PGR
Uniprot ID:: P06401
Molecular Weight:: 98979.96 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	1.19 uM	NVS_NR_hPR	Novascreen

References

Li J, Ma M, Wang Z: In vitro profiling of endocrine disrupting effects of phenols. Toxicol In Vitro. 2010 Feb;24(1):201-7. doi: 10.1016/j.tiv.2009.09.008. Epub 2009 Sep 16. [19765641 ]
Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

Target Details

2. Peroxisome proliferator-activated receptor gamma

General Function:: Zinc ion binding
Specific Function:: Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (By similarity).
Gene Name:: PPARG
Uniprot ID:: P37231
Molecular Weight:: 57619.58 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	1.27 uM	NVS_NR_hPPARg	Novascreen

References

Riu A, Grimaldi M, le Maire A, Bey G, Phillips K, Boulahtouf A, Perdu E, Zalko D, Bourguet W, Balaguer P: Peroxisome proliferator-activated receptor gamma is a target for halogenated analogs of bisphenol A. Environ Health Perspect. 2011 Sep;119(9):1227-32. doi: 10.1289/ehp.1003328. Epub 2011 May 11. [21561829 ]
Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

Target Details

3. Estrogen receptor

General Function:: Zinc ion binding
Specific Function:: Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Ligand-dependent nuclear transactivation involves either direct homodimer binding to a palindromic estrogen response element (ERE) sequence or association with other DNA-binding transcription factors, such as AP-1/c-Jun, c-Fos, ATF-2, Sp1 and Sp3, to mediate ERE-independent signaling. Ligand binding induces a conformational change allowing subsequent or combinatorial association with multiprotein coactivator complexes through LXXLL motifs of their respective components. Mutual transrepression occurs between the estrogen receptor (ER) and NF-kappa-B in a cell-type specific manner. Decreases NF-kappa-B DNA-binding activity and inhibits NF-kappa-B-mediated transcription from the IL6 promoter and displace RELA/p65 and associated coregulators from the promoter. Recruited to the NF-kappa-B response element of the CCL2 and IL8 promoters and can displace CREBBP. Present with NF-kappa-B components RELA/p65 and NFKB1/p50 on ERE sequences. Can also act synergistically with NF-kappa-B to activate transcription involving respective recruitment adjacent response elements; the function involves CREBBP. Can activate the transcriptional activity of TFF1. Also mediates membrane-initiated estrogen signaling involving various kinase cascades. Isoform 3 is involved in activation of NOS3 and endothelial nitric oxide production. Isoforms lacking one or several functional domains are thought to modulate transcriptional activity by competitive ligand or DNA binding and/or heterodimerization with the full length receptor. Essential for MTA1-mediated transcriptional regulation of BRCA1 and BCAS3. Isoform 3 can bind to ERE and inhibit isoform 1.
Gene Name:: ESR1
Uniprot ID:: P03372
Molecular Weight:: 66215.45 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	7.31 uM	ATG_ERa_TRANS	Attagene
AC50	5.23 uM	ATG_ERE_CIS	Attagene
AC50	1.42 uM	NVS_NR_hER	Novascreen

References

Li J, Ma M, Wang Z: In vitro profiling of endocrine disrupting effects of phenols. Toxicol In Vitro. 2010 Feb;24(1):201-7. doi: 10.1016/j.tiv.2009.09.008. Epub 2009 Sep 16. [19765641 ]
Riu A, le Maire A, Grimaldi M, Audebert M, Hillenweck A, Bourguet W, Balaguer P, Zalko D: Characterization of novel ligands of ERalpha, Erbeta, and PPARgamma: the case of halogenated bisphenol A and their conjugated metabolites. Toxicol Sci. 2011 Aug;122(2):372-82. doi: 10.1093/toxsci/kfr132. Epub 2011 May 27. [21622942 ]
Molina-Molina JM, Amaya E, Grimaldi M, Saenz JM, Real M, Fernandez MF, Balaguer P, Olea N: In vitro study on the agonistic and antagonistic activities of bisphenol-S and other bisphenol-A congeners and derivatives via nuclear receptors. Toxicol Appl Pharmacol. 2013 Oct 1;272(1):127-36. doi: 10.1016/j.taap.2013.05.015. Epub 2013 May 25. [23714657 ]
Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

Target Details

4. Nuclear receptor subfamily 1 group I member 2

General Function:: Zinc ion binding
Specific Function:: Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes.
Gene Name:: NR1I2
Uniprot ID:: O75469
Molecular Weight:: 49761.245 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	2.68 uM	ATG_PXR_TRANS	Attagene
AC50	3.54 uM	ATG_PXRE_CIS	Attagene
AC50	5.25 uM	NVS_NR_hPXR	Novascreen

References

Molina-Molina JM, Amaya E, Grimaldi M, Saenz JM, Real M, Fernandez MF, Balaguer P, Olea N: In vitro study on the agonistic and antagonistic activities of bisphenol-S and other bisphenol-A congeners and derivatives via nuclear receptors. Toxicol Appl Pharmacol. 2013 Oct 1;272(1):127-36. doi: 10.1016/j.taap.2013.05.015. Epub 2013 May 25. [23714657 ]
Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

Target Details

5. Androgen receptor

General Function:: Zinc ion binding
Specific Function:: Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Transcription factor activity is modulated by bound coactivator and corepressor proteins. Transcription activation is down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3.
Gene Name:: AR
Uniprot ID:: P10275
Molecular Weight:: 98987.9 Da

References

Li J, Ma M, Wang Z: In vitro profiling of endocrine disrupting effects of phenols. Toxicol In Vitro. 2010 Feb;24(1):201-7. doi: 10.1016/j.tiv.2009.09.008. Epub 2009 Sep 16. [19765641 ]
Sun H, Xu LC, Chen JF, Song L, Wang XR: Effect of bisphenol A, tetrachlorobisphenol A and pentachlorophenol on the transcriptional activities of androgen receptor-mediated reporter gene. Food Chem Toxicol. 2006 Nov;44(11):1916-21. Epub 2006 Jul 4. [16893599 ]

Target Details

6. Estrogen receptor beta

General Function:: Zinc ion binding
Specific Function:: Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560). Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual.
Gene Name:: ESR2
Uniprot ID:: Q92731
Molecular Weight:: 59215.765 Da

References

Riu A, le Maire A, Grimaldi M, Audebert M, Hillenweck A, Bourguet W, Balaguer P, Zalko D: Characterization of novel ligands of ERalpha, Erbeta, and PPARgamma: the case of halogenated bisphenol A and their conjugated metabolites. Toxicol Sci. 2011 Aug;122(2):372-82. doi: 10.1093/toxsci/kfr132. Epub 2011 May 27. [21622942 ]

Target Details

7. Estrogen-related receptor gamma

General Function:: Zinc ion binding
Specific Function:: Orphan receptor that acts as transcription activator in the absence of bound ligand. Binds specifically to an estrogen response element and activates reporter genes controlled by estrogen response elements (By similarity). Induces the expression of PERM1 in the skeletal muscle.
Gene Name:: ESRRG
Uniprot ID:: P62508
Molecular Weight:: 51305.485 Da

References

Li J, Ma M, Wang Z: In vitro profiling of endocrine disrupting effects of phenols. Toxicol In Vitro. 2010 Feb;24(1):201-7. doi: 10.1016/j.tiv.2009.09.008. Epub 2009 Sep 16. [19765641 ]

Target Details

8. Transthyretin

General Function:: Identical protein binding
Specific Function:: Thyroid hormone-binding protein. Probably transports thyroxine from the bloodstream to the brain.
Gene Name:: TTR
Uniprot ID:: P02766
Molecular Weight:: 15886.88 Da

References

Meerts IA, van Zanden JJ, Luijks EA, van Leeuwen-Bol I, Marsh G, Jakobsson E, Bergman A, Brouwer A: Potent competitive interactions of some brominated flame retardants and related compounds with human transthyretin in vitro. Toxicol Sci. 2000 Jul;56(1):95-104. [10869457 ]

Target Details

9. Glucocorticoid receptor

General Function:: Zinc ion binding
Specific Function:: Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. May play a negative role in adipogenesis through the regulation of lipolytic and antilipogenic genes expression.
Gene Name:: NR3C1
Uniprot ID:: P04150
Molecular Weight:: 85658.57 Da

Binding/Activity Constants

Type	Value	Assay Type	Assay Source
AC50	5.16 uM	Tox21_GR_BLA_Antagonist_ratio	Tox21/NCGC

References

Sipes NS, Martin MT, Kothiya P, Reif DM, Judson RS, Richard AM, Houck KA, Dix DJ, Kavlock RJ, Knudsen TB: Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays. Chem Res Toxicol. 2013 Jun 17;26(6):878-95. doi: 10.1021/tx400021f. Epub 2013 May 16. [23611293 ]

Tetrachlorobisphenol A (T3D3948)

Structure for T3D3948: Tetrachlorobisphenol A

Targets

Binding/Activity Constants

References

Binding/Activity Constants

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Binding/Activity Constants

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Binding/Activity Constants

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