T3D0154 - Heptachlorodibenzo-p-dioxin
| Record Information | |
|---|---|
| Version | 1.0 |
| Creation Date | 2009-03-06 18:58:11 UTC |
| Update Date | 2013-04-25 08:33:04 UTC |
| Accession Number | T3D0154 |
| Identification | |
| Common Name | Heptachlorodibenzo-p-dioxin |
| Description | Heptachlorodibenzo-p-dioxins are chlorinated dibenzo-p-dioxin (CDD) congeners. CDDs are a class of manufactured chemicals that consist of dioxin skeletel structures with chlorine substituents. They are also persistent organic pollutants (POPs), thus their production is regulated in most areas. Dioxins occur as by-products from the manufacture of organochlorides, the bleaching of paper, chlorination by waste and drinking water treatment plants, municipal solid waste and industrial incinerators, and natural sources such as volcanoes and forest fires. (R346, R347) |
| Compound Type |
|
| Chemical Structure |
|
| Synonyms | Not Available |
| Chemical Formula | C13H24O |
| Average Molecular Weight | 196.3291 |
| Monoisotopic Molecular Weight | 196.18271539 |
| Chemical IUPAC Name | 4-(5-isopropyl-2-methylcyclopent-1-en-1-yl)butan-2-ol |
| CAS Registry Number | 37871-00-4 |
| SMILES | CC(O)CCC1=C(C)CCC1C(C)C |
| InChI Identifier | InChI=1S/C13H24O/c1-9(2)12-7-5-10(3)13(12)8-6-11(4)14/h9,11-12,14H,5-8H2,1-4H3 |
| InChI Key | InChIKey=MUQXEVWSOUHEOG-UHFFFAOYSA-N |
| Chemical Taxonomy | |
| Kingdom | Organic Compounds |
| Super Class | Lipids |
| Class | Prenol Lipids |
| Sub Class | Monoterpenes |
| Direct Parent | Iridoids and Derivatives |
| Alternative Parents |
|
| Molecular Framework | Aliphatic Homomonocyclic Compounds |
| Substituents |
|
| External Descriptors | Not Available |
| External Links | |
| DrugBank ID | Not Available |
| PubChem Compound ID | 235956  |
| KEGG ID | Not Available |
| UniProt ID | Not Available |
| OMIM ID | Not Available |
| ChEBI ID | Not Available |
| BioCyc ID | Not Available |
| CTD ID | Not Available |
| Stitch ID | Heptachlorodibenzo-p-dioxin |
| PDB ID | Not Available |
| ACToR ID | Not Available |
| Wikipedia Link | Not Available |
| Physical Properties | |
| Appearance | Colorless solid. |
| Melting Point | 264 C |
| Solubility | 1.41e-09 mg/mL at 23 °C [FRIESEN,KJ et al. (1990B)] |
| Predicted LogP | 3.2352848073333336 |
| Toxicity Profile | |
| Route of Exposure | Oral (R346) ; inhalation (R346) ; dermal (R346) |
| Mechanism of Action | CDDs cause their toxic effects by binding to the aryl hydrocarbon receptor and subsequently altering the trascription of certain genes. The affinity for the Ah receptor depends on the structure of the specific CDD. The change in gene expression may result from the direct interaction of the Ah receptor and its heterodimer-forming partner, the aryl hydrocarbon receptor nuclear translocator, with gene regulatory elements or the initiation of a phosphorylation/dephosphorylation cascade that subsequently activates other transcription factors. The affected genes include several oncogenes, growth factors, receptors, hormones, and drug-metabolizing enzymes. The change in transcription/translation of these genes is believed to be the cause of most of the toxic effects of CDDs. (R346) |
| Metabolism | CDDs are absorbed through oral, inhalation, and dermal routes of exposure. CDDs are carried in the plasma by serum lipids and lipoproteins, distributing mainly to the liver and adipose tissue. CDDs are very slowly metabolized by the microsomal monooxygenase system to polar metabolites that can undergo conjugation with glucuronic acid and glutathione. They may increase the rate of their own metabolism by inducing both phase I and phase II enzymes. The major routes of excretion of CDDs are the bile and the faeces, though smaller amounts are excreted in the urine and via lactation. (R346) |
| Toxicity Values | Not Available |
| Lethal Dose | Not Available |
| Carcinogenicity (IARC Classification) | 3, not classifiable as to its carcinogenicity to humans. (R264) |
| Uses/Sources | Dioxins occur as by-products from the manufacture of organochlorides, the bleaching of paper, chlorination by waste and drinking water treatment plants, municipal solid waste and industrial incinerators, and natural sources such as volcanoes and forest fires. (R346, R347) |
| Minimum Risk Level | Acute Oral: 0.0002 ug/kg/day (R260) Intermediate Oral: 0.00002 ug/kg/day (R260) Chronic Oral: 0.000001 ug/kg/day (R260) |
| Health Effects | Exposure to large amounts of CDDs causes chloracne, a severe skin disease with acne-like lesions that occur mainly on the face and upper body. CDDs may also cause liver damage and induce long-term alterations in glucose metabolism and subtle changes in hormonal levels. In addition, studies have shown that CDDs may disrupt the endocrine system and weaken the immune system, as well as cause reproductive damage and birth defects, central and peripheral nervous system pathology, thyroid disorders, endometriosis, and diabetes. (R346, R347) |
| Symptoms | In addition to chloracne, CDD exposure causes skin rashes, discoloration, and excessive body hair. (R346) |
| Treatment | Treatment of CDD exposure may include washing the area of contact, GI decontamination, administering an IV, or forced alkaline diuresis. (R622) |
| References | |
| General References |
|
Targets
1. 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.
Chlorinated dibenzo-p-dioxins cause their toxic effects by binding to the aryl hydrocarbon receptor and subsequently altering the trascription of certain genes. The affinity for the Ah receptor depends on the structure of the specific CDD. The change in gene expression may result from the direct interaction of the Ah receptor and its heterodimer-forming partner, the aryl hydrocarbon receptor nuclear translocator, with gene regulatory elements or the initiation of a phosphorylation/dephosphorylation cascade that subsequently activates other transcription factors. The affected genes include several oncogenes, growth factors, receptors, hormones, and drug-metabolizing enzymes. The change in transcription/translation of these genes is believed to be the cause of most of the toxic effects of CDDs. This includes 2,3,7,8-tetrachlorodibenzo-p-dioxin's carcinogenicity is thought to be the result of its ability to alter the capacity of both exogenous and endogenous substances to damage the DNA by inducing CYP1A1- and CYP1A2-dependent drug-metabolizing enzymes. (R346)UniProt ID: P35869
Gene: AHR
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report
References:
- R346 — ATSDR - Agency for Toxic Substances and Disease Registry (1998). Toxicological profile for chlorinated dibenzo-p-dioxins (CDDs). U.S. Public Health Service in collaboration with U.S. Environmental Protection Agency (EPA). [Link]
2. 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.
3. 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.