T3D0443 - 2,2',6,6'-Tetrachlorobiphenyl
| Record Information | |
|---|---|
| Version | 1.0 |
| Creation Date | 2009-03-06 18:58:48 UTC |
| Update Date | 2013-04-25 08:34:17 UTC |
| Accession Number | T3D0443 |
| Identification | |
| Common Name | 2,2',6,6'-Tetrachlorobiphenyl |
| Description | 2,2',6,6'-Tetrachlorobiphenyl is one of 209 polychlorinated biphenyls (PCBs). PCBs are a group of synthetic organic compounds with 1-10 chlorine atoms attached to biphenyl. They were manufactured as commercial mixtures but banned in the 1970's because they were found to bioaccumulate and cause harmful health effects. However, PCBs do not break down readily and are still found in the environment. (R012) |
| Compound Type |
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| Chemical Structure |
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| Synonyms |
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| Chemical Formula | C12H6Cl4 |
| Average Molecular Weight | 291.988 |
| Monoisotopic Molecular Weight | 289.92236102 |
| Chemical IUPAC Name | 1,3-dichloro-2-(2,6-dichlorophenyl)benzene |
| CAS Registry Number | 15968-05-5 |
| SMILES | ClC1=CC=CC(Cl)=C1C1=C(Cl)C=CC=C1Cl |
| InChI Identifier | InChI=1S/C12H6Cl4/c13-7-3-1-4-8(14)11(7)12-9(15)5-2-6-10(12)16/h1-6H |
| InChI Key | InChIKey=PXAGFNRKXSYIHU-UHFFFAOYSA-N |
| Chemical Taxonomy | |
| Kingdom | Organic Compounds |
| Super Class | Benzenoids |
| Class | Benzene and Substituted Derivatives |
| Sub Class | Biphenyls and Derivatives |
| Direct Parent | Chlorinated Biphenyls |
| Alternative Parents |
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| Molecular Framework | Aromatic Homopolycyclic Compounds |
| Substituents |
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| External Descriptors | Not Available |
| External Links | |
| DrugBank ID | Not Available |
| PubChem Compound ID | 27588  |
| KEGG ID | Not Available |
| UniProt ID | Not Available |
| OMIM ID | Not Available |
| ChEBI ID | Not Available |
| BioCyc ID | CPD-946 |
| CTD ID | Not Available |
| Stitch ID | 2,2',6,6'-Tetrachlorobiphenyl |
| PDB ID | Not Available |
| ACToR ID | Not Available |
| Wikipedia Link | Not Available |
| Physical Properties | |
| Appearance | Oily liquids or solids that are colorless to light yellow. |
| Melting Point | Not Available |
| Solubility | 1.19e-05 mg/mL at 25 oC [YALKOWSKY,SH & DANNENFELSER,RM (1992)] |
| Predicted LogP | 6.036649883333333 |
| Toxicity Profile | |
| Route of Exposure | Oral (R012) ; inhalation (R012) ; dermal (R012) |
| Mechanism of Action | The mechanism of action varies with the specific PCB. Dioxin-like PCBs bind to the aryl hydrocarbon receptor, which disrupts cell function by altering the transcription of genes, mainly be inducing the expression of hepatic Phase I and Phase II enzymes, especially of the cytochrome P450 family. Most of the toxic effects of PCBs are believed to be results of Ah receptor binding. Other PBCs are believed to interfere with calcium channels and/or change brain dopamine levels. PCBs can also cause endocrine disurption by altering the production of thyroid hormones and binding to estrogen receptors, which can stimulate the growth of certain cancer cells and produce other estrogenic effects, such as reproductive dysfunction. They will bioaccumulate by binding to receptor proteins such as uteroglobin. (R013, R015, R071, R203) |
| Metabolism | PCBs are absorbed via inhalation, oral, and dermal routes of exposure. They are trasported in the blood, often bound to albumin. Due to their lipophilic nature they tend to accumulate in lipid-rich tissues, such as the liver, adipose, and skin. Metabolism of PCBs is very slow and varies based on the degree and position of chlorination. PCBs are metabolized by the microsomal monooxygenase system catalyzed by cytochrome P-450 enzymes to polar metabolites that can undergo conjugation with glutathione and glucuronic acid. The major metabolites are hydroxylated products which are excreted in the bile and faeces. The slow metabolism of PCBs means they tend to accumulate in body tissues. (R012, R014) |
| Toxicity Values | LD50: 1010 mg/kg (Oral, Rat) (R263) LD50: 880 mg/kg (Intraperitoneal, Mouse) (R263) |
| Lethal Dose | Not Available |
| Carcinogenicity (IARC Classification) | 2A, probably carcinogenic to humans. (R264) |
| Uses/Sources | PCBs were used as coolants and lubricants in transformers, capacitors, and other electrical devices (such as fluorescent lights and refridgerators) produced before 1977. PCBs may contaminate the air and water near hazardous waste sites. In addition, PCBs bioaccumulate in the environment and may be found in fish, meat, and dairy products. (R012) |
| Minimum Risk Level | Intermediate Oral: 0.03 ug/kg/day (R260) |
| Health Effects | The most common health effects of PCBs are skin conditions such as chloracne and rashes. Chronic PCB exposure has also been shown to cause liver, stomach and kidney, damage, jaundice, edema, anemia, changes in the immune system, behavioral alterations, and impaired reproduction. (R012) |
| Symptoms | Chronic PCB exposure results in symptoms such as abdominal pain, nausea, vomiting, diarrhea, headache, dizziness, depression, nervousness, dermal and ocular lesions, fatigue, irregular menstrual cycles and a lowered immune response. (R013) |
| Treatment | There are no specific treatments for PCB poisoning, since it is not usually recognized until after substantial chronic exposure. Only preventing further exposure and treating the observed symptoms can be done. Acute inhalation can be treated by administering oxygen. (R012) |
| References | |
| General References |
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Targets
1. Aromatic-L-amino-acid decarboxylase
Catalyzes the decarboxylation of L-3,4-dihydroxyphenylalanine (DOPA) to dopamine, L-5-hydroxytryptophan to serotonin and L-tryptophan to tryptamine.
PCB inhibition of aromatic-L-amino-acid decarboxylase is believed to cause decreased dopamine synthesis. (R012)UniProt ID: P20711
Gene: DDC
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:
- R012 — ATSDR - Agency for Toxic Substances and Disease Registry (2000). Toxicological profile for polychlorinated biphenyls. U.S. Public Health Service in collaboration with U.S. Environmental Protection Agency (EPA). [Link]
2. Aryl hydrocarbon receptor
Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissues.
Dioxin-like PCBs bind to the aryl hydrocarbon receptor, which disrupts cell function by altering the transcription of genes, mainly be inducing the expression of hepatic Phase I and Phase II enzymes, especially of the cytochrome P450 family. (R015)UniProt ID: P35869
Gene: AHR
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:
- R015 — Safe S, Bandiera S, Sawyer T, Robertson L, Safe L, Parkinson A, Thomas PE, Ryan DE, Reik LM, Levin W, et al.: PCBs: structure-function relationships and mechanism of action. Environ Health Perspect. 1985 May;60:47-56.
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3. Estrogen receptor
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. Isoform 3 can bind to ERE and inhibit isoform 1.
Causes endocrine disruption in humans by binding to and inhibiting the estrogen receptor. (S301)UniProt ID: P03372
Gene: ESR1
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:
- S301 — Luft S, Milki E, Glustrom E, Ampiah-Bonney R, O'Hara P. Binding of Organochloride and Pyrethroid Pesticides To Estrogen Receptors ? and ?: A Fluorescence Polarization Assay. Biophysical Journal 2009;96(3):444a.
4. Estrogen receptor beta
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. 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.
Causes endocrine disruption in humans by binding to and inhibiting the estrogen receptor. (S301)UniProt ID: Q92731
Gene: ESR2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:
- S301 — Luft S, Milki E, Glustrom E, Ampiah-Bonney R, O'Hara P. Binding of Organochloride and Pyrethroid Pesticides To Estrogen Receptors ? and ?: A Fluorescence Polarization Assay. Biophysical Journal 2009;96(3):444a.
5. Estrogen sulfotransferase
Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of estradiol and estrone. May play a role in the regulation of estrogen receptor activity by metabolizing free estradiol. Maximally sulfates beta-estradiol and estrone at concentrations of 20 nM. Also sulfates dehydroepiandrosterone, pregnenolone, ethinylestradiol, equalenin, diethylstilbesterol and 1-naphthol, at significantly higher concentrations; however, cortisol, testosterone and dopamine are not sulfated.
PCBs can cause endocrine disurption by binding to estrogen sulfotransferase, which can stimulate the growth of certain cancer cells and produce other estrogenic effects, such as reproductive dysfunction. (R013, R203)UniProt ID: P49888
Gene: SULT1E1
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:
- R013 — Aoki Y: Polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans as endocrine disrupters--what we have learned from Yusho disease. Environ Res. 2001 May;86(1):2-11.
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6. Tyrosine 3-monooxygenase
Plays an important role in the physiology of adrenergic neurons.
PCB inhibition of tyrosine 3-monooxygenase is believed to cause decreased dopamine synthesis. (R012)UniProt ID: P07101
Gene: TH
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:
- R012 — ATSDR - Agency for Toxic Substances and Disease Registry (2000). Toxicological profile for polychlorinated biphenyls. U.S. Public Health Service in collaboration with U.S. Environmental Protection Agency (EPA). [Link]
7. Uteroglobin
Binds phosphatidylcholine, phosphatidylinositol, polychlorinated biphenyls (PCB) and weakly progesterone, potent inhibitor of phospholipase A2.
PCBs will bioaccumulate by binding to receptor proteins such as uteroglobin. (R071)UniProt ID: P11684
Gene: SCGB1A1
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:
- R071 — Troisi GM, Haraguchi K, Kaydoo DS, Nyman M, Aguilar A, Borrell A, Siebert U, Mason CF: Bioaccumulation of polychlorinated biphenyls (PCBs) and dichlorodiphenylethane (DDE) methyl sulfones in tissues of seal and dolphin morbillivirus epizootic victims. J Toxicol Environ Health A. 2001 Jan 12;62(1):1-8.
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