Molecular Mechanisms of Toxicity of Dioxin-like Chemicals

The molecular mechanism of the toxicity of dioxins was reviewed. Zhang Zhiren, Xu Shunqing (Department of Environmental Monitoring, Institute of Environmental Medicine, Tongji Medical University, Wuhan 430030, China) received widespread attention. Many scholars have also carried out extensive research on this topic. The review of its toxic mechanism from the perspective of molecular biology mainly includes: Protein phosphorylation mediated by aryl hydrocarbon receptors through aryl hydrocarbon receptor-mediated gene expression. The molecular mechanism of nutrient metabolism.

The generic term for a wide range of substances that bind to aromatic hydrocarbon receptors (Ah-R) and lead to various biochemical changes, including: polychlorinated dibenzodioxins, polychlorinated bromine Benzofurans and coplanar polychlorinated biphenyls, of which the most studied and most typical and most toxic substance are 2,3,7,8-tetrachlorodibenzodioxime (2,3,7,8- Tetrachlorodibenzo-oxin, TCDD) have the common feature of being able to bind to Ah-R, produce dioxin-like toxicity, and are difficult to degrade in the environment. They are easily bio-enriched and can produce a wide range of toxic effects in rodents. Include: Acne, exhaustion syndrome, hepatotoxicity, teratogenicity, reproductive and developmental toxicity, carcinogenicity, neurological and behavioral toxicity, immunosuppression, induction of multiple metabolic enzymes in vivo (eg P4501A1), endocrine disruption, etc. The toxic effect of dioxin-like chemical substances is low, such as the dose of carcinogenicity in mice can be as low as 0.00卟g/kg.dm. It is widely found in the environment. It is difficult to degrade and is easy to bio-concentrate and produce various toxic effects. , therefore caused people Our great concern has been the extensive evaluation of the toxicity of dioxin-like chemicals. However, due to the complexity of the toxic mechanism of dioxins, the mechanism of action of these substances has not yet been fully understood. It leads to different evaluation methods adopted by various countries, and the conclusions obtained are also not the same, and there is no good method for prevention and control. This review of the molecular mechanism of toxicity of dioxin-like chemicals is provided for toxicity assessment and toxicological control of the substance.

Fund Project: This project is supported by the National Natural Science Foundation of China (29877020), a 98-degree postgraduate student, and focuses on the application of light-sensing technology and reporter genes in environmental monitoring. After more than 20 years of research, people also have their own mechanisms. Certainly, in general, dioxins are not responsible for the effects of chemical substances. Dioxin-like chemicals do not form adducts with proteins and nucleic acids, nor do they directly damage cellular DNA. Mainly through the aryl hydrocarbon receptor induced gene expression, changes in kinase activity, changes in protein function and so on.

1 Aromatic Receptor-mediated Gene Expression Through aryl hydrocarbon receptor-mediated gene expression (eg, P4501A1) is the most important and most basic mechanism of action of dioxin-like chemicals. The aryl hydrocarbon receptor is a high-molecular-weight protein. (110-150KD), with reversible high affinity for dioxin-like chemicals, mainly in the cytoplasm (also a small fraction in the nucleus). Its mode of action is similar to steroid receptors, but it is also different. . The protein belongs to the basichelix-loop-ielix PAS (Per-Arnt-Stim) superfamily, which is a transcription factor and contains two functional sites: basichelix4oop-helix site and PAS functional site, transcription of the activation gene in the family of proteins. It is of great significance that all aromatic hydrocarbon receptors have obvious interspecies, intraspecific and organizational differences, and the molecular characteristics of some aromatic hydrocarbon receptors are shown in Table 1+6! The aryl hydrocarbon receptor is present in the cytoplasm in a 380 kD complex inactive form, with 3-4 proteins in addition to itself, and only a 90 kD heat shock protein (HSP90) was identified. The protein has an important influence on the activity of receptors. The basic processes involved in aryl hydrocarbon receptor-mediated gene expression can distinguish between the following basic processes: 1 Dioxin-like chemicals enter the cell; 2 Compounds bind to aryl hydrocarbon receptors 3 ligand receptor complexes bind to DNA recognition sites; 4 transcription and translation of specific genes; 5 expression of proteins play a role. In the five processes, the 3-step study is relatively clear, and the 4-5 steps are not yet very clear. Table 1 Molecular characteristics of several aryl hydrocarbon receptors Settlement coefficient radius (nm) Molecular weight (kDa) Frictional amount f Axis-dosed (a/b) rat hepatocyte cytoplasm 2. Spit 0. 2 persons 5. C57BL mouse liver cytoplasm in ft solution 2. 2 persons mouse liver llcc7 cell removal only one of two slightly different effects! All of the body forming capacity 1 1 1 were removed from the white cf in the cytoplasm specifically combined with the aromatic aryl hydrocarbon receptor/complex i.neEnan et al. 1.1 Dioxin-like chemical substances entering the cell are generally considered dioxins-like chemicals passed Passive diffusion into the cytoplasm (due to the fact that dioxins are fat-soluble substances), but several studies have shown that passive diffusion does not fully explain the toxic effects of dioxin-like chemicals such as: Such substances can stimulate the liver Cell growth and fat infiltration, hyperplasia of epithelial cells, these observations suggest that cell membranes play a role in the toxic effects of dioxins-like chemicals 1.2 Dioxin-like chemicals and aromatic hydrocarbon receptors bind dioxins After entering the cytoplasm, the chemical species binds to the aryl hydrocarbon receptors in the cytoplasm. This binding process will lead to the activation of aryl hydrocarbon receptors. However, the physical and chemical changes caused by this combination are not currently clear. Miller et al.'s experiments show that the formation of ligand-aromatic complexes does not bind to the DNA binding site and is not sufficient to cause biological reactions, indicating that receptor activation is a multi-step process in vitro. Activation plays an important role. The complex formed at 4C does not bind to the gene locus correctly. However, the complex formed at 20C has biological activity, indicating that this process requires temperature-dependent activation. 1.3 Ligand Receptors The binding of complexes to DNA and the binding of dioxins to aromatic hydrocarbon receptors activates the aromatic receptors, and then the ligand-receptor complexes are transferred into the cell, where they aggregate in the nucleus before binding to DNA. Must be combined with a protein in the nucleus, ie aromatic protein, ARNT) to obtain DNA-binding energy. 9 The protein has a molecular weight of 87 kDa and also belongs to the basichelix-loop-ielix PAS (Per-Arnt-Stim) superfamily, which contains two Functional sites are: basichelix4oop-heKx (bHLH) sites and PAS functional sites. It forms heterodimers with aryl hydrocarbon receptors belonging to the same family. It is important for DNA binding. It only retains the bHLH and PAS sites of the nuclear receptor translocator of aromatic hydrocarbons, and it can store ARNTs to form dimers and DNA. The ability of binding, where two a-helilx structures at the bHLH site are involved in the formation of dimers, while the basic structure is only associated with the binding of DNA; the PAS site includes two substructures, namely PAS and PASB, which seriously affect the heterodimerization The formation capacity of the AhR/ARNT complex is then combined with the dioxin responsive element (XRE), an enhancer upstream of the specific gene, to activate transcription of the gene and transcription and translation of the specific gene of the dioxin exogenous reaction element 1.4. Dioxin-like chemical activation gene expression includes cytochrome P4501A1 and 1A2, glutathione S-transferase, methyl quinone oxidoreductase, aldehyde dehydroxylase and so on. Among them, cytochrome P4501A1 and 1A2 are the most important ones, and the most extensively studied AhR/ARNT complexes and enhancer core sequences have not been studied in any way to activate gene transcription. In general, binding of the AhR/ARNT complex to the enhancer core sequence can lead to bending of the DNA strand and cleavage of nuclear chromatin, thereby increasing the probability of activating the promoter and increasing the probability of initiation of CYP1A1 transcription, leading to cytochrome The aggregation of P4501A1 mRNA in the nucleus Roberton et al. found that there are nine cis-responsive elements between the 28950 bases upstream of the transcription start point of cytochrome P4501A1, three of which are dioxin-responsive elements and the other six. The role is unknown. However, when the AhR/ARNT complex binds to a dioxin-responsive element, the remaining reaction elements are more likely to bind to their respective protein action factors. It indicated that the transcription of the gene may be mainly through the Oozing method. The messenger RNA that is transcribed into the cell cytoplasm then binds to the ribosome to start protein translation.

1.5 The role of the expressed protein in this process is rarely studied, mainly in the study of cytochrome P4501A1 and A2 expression products, such as: aromatic hydroxylase, can convert pre-carcinogens to carcinogens, thereby promoting the body's cancer The occurrence of the above is the basic mode of dioxin-like chemical mediation of gene expression in the body. At present, the research on this process is still the main research direction of toxicity caused by dioxins.

2 aryl hydrocarbon receptor-mediated protein kinase pathway dioxin toxicity through the activation of the protein kinase, and then through the kinase pathway to produce a variety of biological activity. First discovered protein kinase tyrosine protein kinase Enan In W96, it was found that 2,3,7,8-TCDD can increase the activity of tyrosine protein kinase in the cytoplasm of adipocytes of guinea pigs under non-cellular conditions, and this effect is aryl hydrocarbon receptor-dependent. Soon they further discovered that tyrosine protein kinases can not only be activated by 2,3,7,8-TCDD, and that tyrosine considers tyrosine protein kinases to bind to aryl hydrocarbon receptor complexes in the cytosol when ligands The aryl hydrocarbon receptor binding releases the tyrosine protein kinase and is activated.

Thus, the degree of phosphorylation of the tyrosine residue of the intracellular protein is increased. This phosphorylation is important for the proliferation and differentiation of cells. Blankenshipinger L-Dualroles of the 90-monitoring and monitoring of the disinfection effect of public goods in public places in Changzhi City Wang Zhifang Yang Lan Zhang Yulian (Health and Epidemic Prevention Station of Changzhi City, Shanxi Province, 046011): R126. 4:C In order to improve the quality of supervision in public places, public supplies in various public places in Changzhi City were monitored.

According to the monitoring of public places in public places, aseptic operation. Gathered 202 samples of public towels, bed bedding, tea sets, beauty and hair tools, face (foot) basins, tubs, and slippers in 27 public places in Changzhi City. The inspection items include: the total number of bacteria, coliform bacteria, pathogenic bacteria, and Staphylococcus aureus were tested according to the national public place health monitoring standard test method. According to the corresponding standards in public places health standards evaluation. All indicators within the scope of the GB are qualified, one or more exceedances are unqualified.

Of the 202 samples tested, the pass rate was 90.1%. Among them, the pass rate of hotel industry was 90.%, the pass rate of beauty hairdressing tools was 88.6%, and the pass rate of cultural and entertainment venues supplies was 87.5%. All public bathroom supplies were qualified. There was no significant difference in the qualification rate of four types of inter-industry supplies (丨2=202, P>0.05). See Table 1 for the total effective data of 436 items detected in four items, 21 unqualified items, and the passing rate of 95.1%. As follows: 89.8% of total bacteria, 92.8% of coliform bacteria, 100% of Staphylococcus aureus, and 99.5% of pathogenic bacteria have very significant differences among the four items (i2=13.08, P).