CN106706692A - Pesticide toxicity evaluation method based on metabonomical technique - Google Patents
Pesticide toxicity evaluation method based on metabonomical technique Download PDFInfo
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- CN106706692A CN106706692A CN201611252940.5A CN201611252940A CN106706692A CN 106706692 A CN106706692 A CN 106706692A CN 201611252940 A CN201611252940 A CN 201611252940A CN 106706692 A CN106706692 A CN 106706692A
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- metabolin
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
- G01N24/08—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using nuclear magnetic resonance
- G01N24/088—Assessment or manipulation of a chemical or biochemical reaction, e.g. verification whether a chemical reaction occurred or whether a ligand binds to a receptor in drug screening or assessing reaction kinetics
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
Abstract
The invention discloses a pesticide toxicity evaluation method based on a metabonomical technique. The pesticide toxicity evaluation method comprises the following steps: by using a metabonomical method based on a nuclear magnetic resonance technique, performing contamination testing on goldfish as a model animal, taking a tissue sample, performing nuclear magnetic resonance detection so as to obtain a nuclear magnetic resonance spectrum signal of the sample, identifying metabolin of the sample according to the nuclear magnetic resonance spectrum, calculating the multiplying power of the metabolin after contamination, screening differential expression metabolin as indexes of pesticide toxicity evaluation, and finally, performing metabolic pathway analysis, recognizing a changed metabolic pathway, and analyzing the action mode of pesticide toxicity. By adopting the pesticide toxicity evaluation method, complex toxicity and toxication mechanisms of a water body contaminated by pesticide can be tested and analyzed, and comprehensive and accurate biological parameters and indexes can be provided. Compared with a common toxicity evaluation method, the pesticide toxicity evaluation method is relatively comprehensive and sensitive, and can provide a basis for evaluation on pesticide ecology and human body health risk.
Description
Technical field
The present invention relates to a kind of toxicity of pesticide evaluation method, specifically a kind of agriculture based on nuclear-magnetism metabonomic technology
Medicine toxicity evaluation method, more specifically a kind of nuclear-magnetism metabonomic technology global analysis agricultural chemicals that is based on is to biological systemic metabolism
Path disturbance and its toxicity assessment method of complicated mechanism of toxication.
Background technology
Increasing both production and income and economic development of the agricultural chemicals to modern agriculture have played very big booster action, but pesticide abuse is also resulted in
Serious problem of environmental pollution.Therefore, it is badly in need of a kind of comprehensive, accurate, sensitive water body toxicity analytical technology and method, deeply
Analysis is predicted its potential human health risk by the toxic action and mechanism of pollution by pesticides aquatic organism.
Existing water toxicity assessment method is mainly biological test method, including vitro detection and In vivo detection.These inspections
Survey method reflects the toxicity of pollutant by biological respinse terminal (such as behaviouristics, fatal rate, stress reaction, oxidative damage)
Effect, with simple and rapid advantage, but there is also deficiency：(1) organism or the other biochemical work(of histoorgan can only be reflected
Energy and state, lack overall, system toxicity assessment index；(2) index sensitivity for being detected is low, micro in water body
The toxic action responsiveness of pollutant is low to be can't detect, and descriptive index is more and specific index is few, points out toxic mechanism
Index is few, it is difficult to the comprehensive toxicity and mechanism of toxication of accurate evaluation water body.
In recent years, metabolism group quickly developed into after genomics, transcription group and proteomic techniques it
The fourth-largest omics technology afterwards.When the toxic action of the environmental contaminants such as agricultural chemicals is examined or check, it is considered merely to genome and is turned
The influence of the upper strata such as record group hereditary information, ignores that the change of terminal metabolism group.The hereditary information of organism is from bottom code
(information of genome and transcript profile) arrives middle mechanism (protein group), final all to embody the change feelings for having arrived metabolism group
Come in condition.The analytical technology of nuclear magnetic resonance have it is quick, without deflection, the characteristics of carrying out cylinder metabolism-ure and detect of free of losses,
More and more extensive effect has been played in pharma-toxicology research.
The content of the invention
For deficiency of the existing agricultural chemicals water body toxicity detection analysis method in terms of sensitivity, globality and accuracy,
The present invention provides a kind of toxicity of pesticide evaluation method based on metabonomic technology, and the method is using nuclear-magnetism metabolism group to by agriculture
The toxicity and mechanism of toxication of chemicals contamination aquatic organism carry out test analysis, there is provided comprehensive and accurate metabolism group parameter and index, deep
Enter and excavate potential biological information, the toxic effect mechanism of insecticide pollution is illustrated more truly, exactly, it is determined that reflecting its water
The biomarker of toxigenicity effect and its metabolic pathway of influence, analyze the mechanism of toxication of insecticide pollution.
Technical scheme is as follows：
A kind of toxicity of pesticide evaluation method based on metabonomic technology, comprises the following steps that：
(1) exposure experiment：Using pesticide sample as study subject, used as blank, choose goldfish is drinking public water supply
Model animal, contamination group and control group are respectively provided with the repeating groups of equivalent, after laboratory raises and train 4 weeks, carry out exposure experiment；
(2) sample collection：After exposure experiment terminates, collection liver, kidney and brain tissue extract total metabolism thing, are stored in minus 80
Degree；
(3) it is metabolized analyte detection：The phosphate that the total metabolism thing of contamination group and control group is separately added into deuterated heavy water preparation delays
Fliud flushing, centrifuging and taking supernatant, magnetic resonance detection hydrogen signal obtains the hydrogen nuclear magnetic spectrogram of the total metabolism thing of each repeating groups；
(4) data pre-processing：By the hydrogen signal system of identical metabolin in the hydrogen nuclear magnetic spectrogram of the total metabolism thing of each repeating groups
One, to same chemical displacement value, obtains the proton magnetic spectrum stacking chart of total metabolism thing, and the proton magnetic spectrum stacking chart of total metabolism thing is entered
Row subsection integral, normalized and normalized obtains the integration data of each metabolin；
(5) difference metabolin screening：After the integration data of each metabolin that will be obtained carries out variance analysis, each metabolism is obtained
The change multiplying power and p value of thing, will change the metabolin screening that multiplying power is more than 1.5 times and p value is less than 0.05 is differential expression generation
Thank to thing；
(6) metabolic pathway identification：For the metabolin of the p value less than 0.05 of variance analysis, using online software, generation is carried out
Thank to path analysis, it is determined that the metabolic pathway of reflection toxicity of pesticide.
Traditional toxicity of pesticide detection method is relatively low to its concentration-response degree, and poor sensitivity, the agricultural chemicals of long-time high dose is sudden and violent
Dew often cannot also detect fairly obvious changes in histopathology, point out the index of toxic mechanism few, it is impossible to reflect agricultural chemicals
To biological effect, it is difficult to the comprehensive toxicity and mechanism of toxication of accurate evaluation water body.The present invention is based on nuclear-magnetism metabonomic technology,
There is provided one kind application nuclear magnetic resonance technique, from small molecule metabolites level carry out quick toxicity of pesticide, sensitive bioanalysis and
Evaluation method, filters out the new biomarkers of identification toxicity of pesticide effect, and these biomarkers can both explain agricultural chemicals
The bio-chemical reaction mechanism of poisonous effect, again can will be interrelated between pollution by pesticides and biological effect, it is dirty for Pesticide environment
The exploration of dye and rapid screening.
Present invention employs self-adapting intelligent subsection integral method, the integration at equal intervals for generally using at present is effectively overcome
It is all that positive and negative coherent signal is cumulative in method, Weak characteristic signal is blanked, the mistake of non-characteristic signal is known and signal to noise ratio declines etc.
Many defects.For noise and the inapparent signal area of statistical discrepancy, Adaptive Integral uses larger integration interval, Ke Yiyou
Effect ground suppresses noise, is more beneficial for follow-up statistical analysis and the identification of characteristic metabolic thing so that spectrogram signal to noise ratio is obtained after integration
To enhancing, the resolution of metabolin spectral peak is improved, and effectively reduces the error brought by peak overlap so that
The interpretation of PLS-DA load diagrams is stronger, screens the potential source biomolecule mark for obtaining and has more biological significance.
The present invention can compose comprehensive accurate evaluation agricultural chemicals complexity toxicity from the final metabolic phenotype of biological activity, can be simpler
Just the different poisonous effects of agricultural chemicals, effectively, quickly, are sensitively detected, can be to sensitive and important water using result of the present invention
The raw ecosystem carries out daily monitoring, and can be as the early prediction system of pollutant long term toxicity effect, for human environment
The risk assessment of health.
Brief description of the drawings
Fig. 1 is flow chart of the invention.
Fig. 2 is embodiment liver multi-variate statistical analysis result.
Fig. 3 is embodiment kidney multi-variate statistical analysis result.
Fig. 4 is embodiment brain multi-variate statistical analysis result.
Fig. 5 is embodiment liver kidney brain section testing result.
Fig. 6 is embodiment Biochemical Indices In Serum testing result.
Specific embodiment
The present invention is further illustrated below by way of embodiments and drawings.
In the embodiment of the present invention by taking glyphosate as an example, metabolism group evaluation is carried out to its toxicity using the inventive method.
Embodiment：
A kind of method that application metabonomic technology carries out glyphosate toxicity evaluation, evaluates glyphosate pesticide aquatic toxicity,
Step is as follows：
(1) exposure experiment：Goldfish exposure experiment is carried out with glyphosate pesticide sample and is contaminated, with drinking public water supply as blank
Control, animal subject is Male Goldfish (Carassius auratis), and body is about 10cm, and body weight about 30g, laboratory is raised and train 4 weeks
Afterwards, physique healthy and strong is selected, disease-free without wound, the consistent individuality of specification is randomly divided into contamination group and control group, often as experimental subjects
Group 15, feeds running water containing agricultural chemicals and drinking public water supply respectively, and the contamination cycle is 90 days.
(2) sample collection：After contamination 90 days, contamination group and control group goldfish, solution takes liver kidney brain tissue, with the second of precooling
Nitrile：Water=1:1 (v/v) is Extraction solvent, and tissue metabolism's thing is extracted under condition of ice bath, and extract solution is by after freeze-drying, protecting
It is stored in minus 80 degree of refrigerators.
(3) it is metabolized analyte detection：Contamination group and control group freeze thyraden sample, the pH for adding 550 μ L to be prepared by heavy water
7.0 phosphate buffer, the μ L of supernatant liquid of centrifuging and taking 500 after being well mixed carries out magnetic resonance detection, sampling nuclear-magnetism used
Pulse train is CPMG (Carr-Purcell-Meiboom-Gill, RD- pi/2-(- τ-π-τ -)n- ACQ) sequence, test of pulse
Preceding stand-by period (RD) is 2s, and spin echo time (2n τ) is 100ms.With presaturation method suppress water signal, pressure the water time be
1.5s.One-dimensional spectrum width 10kHz, sampled point 32k, add up 128 times, and Fourier transform simultaneously adds Gaussian window functions to obtain preferably
Resolution ratio and signal to noise ratio.
(4) data pre-processing：By the hydrogen signal system of identical metabolin in the hydrogen nuclear magnetic spectrogram of the total metabolism thing of each repeating groups
One, to same chemical displacement value (ppm), obtains the proton magnetic spectrum stacking chart of total metabolism thing, and the proton magnetic spectrum of total metabolism thing is superimposed
Figure carries out self-adapting intelligent subsection integral, and does Pareto Criterion and the normalized treatment of probability business, obtains each metabolin
Integration data.Then integration data is input into R softwares, sets up PLS-DA multivariate analyses Mathematical Modeling (Fig. 2), obtain all repetitions
Score value (shot chart) of the sample in principal component 1 and principal component 2, and the covariance value and relevance values of each metabolin (are carried
Lotus is schemed).Two groups of samples are substantially divided into two classes on shot chart, and obvious metabolic alterations are there occurs in goldfish body after illustrating to contaminate.
Some difference metabolins obtained by PLS-DA multivariate statistical model automatic screenings can be obtained from load diagram, these are by PLS-
The difference metabolin that DA multivariate statistical model automatic screenings are obtained can only be considered potential difference metabolin, and whether each metabolin
For difference metabolin is finally required for being tested by variance analysis.
(5) differential expression metabolin screening：After the integration data of each metabolin that will be obtained carries out variance analysis, obtain each
The change multiplying power and p value of metabolin, will change the metabolin screening that multiplying power is more than 1.5 times and p value is less than 0.05 is difference table
Up to metabolin.8 differential expression metabolins closely related with glyphosate aquatic toxicity are selected altogether：Lysine, a word used in person's names propylhomoserin, bright ammonia
Acid, alanine, hypoxanthine, GTP, oxidized coenzyme 1 and adenosine monophosphate.By detecting this 8 in goldfish body
Metabolin, it is possible to exploration and rapid screening for glyphosate water environment pollution, to sensitive and important aquatic ecosystem
Daily monitoring is carried out, and can be as the early warning signal of glyphosate long term toxicity effect, for the risk of human environment health
Property evaluate.
(7) metabolic pathway analysis：It is after the integration data of each metabolin is carried out into variance analysis, the p value of variance analysis is small
Metabolin in 0.05 is input into the online softwares of MetaboAnalyst 3.0, and 9 metabolic pathways of significant changes are calculated altogether (such as
Shown in table 1), including：ArAA anabolism path, branched-chain amino acid anabolism path, Metabolism of Ascorbic Acid path,
Ala-Asp-glutamic acid metabolism path, nitrogen metabolism path, aminoacyl tRNA biosynthesis pathway, arginine-dried meat ammonia
Acid metabolic path, TCA cyclic metabolisms path and galactose metabolism path.These metabolic pathways are exactly the poison that can reveal that glyphosate
The biochemical metabolism path of property mechanism.
The goldfish metabolic pathway that the glyphosate sample toxic action of table 1 is significantly affected
The concentration of tested glyphosate is the concentration in environmental test, under this concentration level, traditional toxicity detection
Method bad response.Histopathology result does not find that glyphosate causes the lesion (Fig. 5) of goldfish brain, while serum biochemistry
Indexs measure result does not find that glyphosate causes the change (Fig. 6) of brain pathological index yet.Using disposable detection simultaneously of the invention
The biochemical pathway of brain liver kidney metabolic disorder and its various toxic actions is caused to goldfish to glyphosate pollution, and sensitivity is high,
It is with the obvious advantage.
In sum, the present invention can be from the water body toxicity of the organism terminal end comprehensive accurate evaluation glyphosate of metabolic phenotype
Effect, it is disposable to detect various toxicity simultaneously, and new biomarkers are provided.Additionally, the method is to water body glyphosate agriculture
Chemicals contamination response is sensitive, and more traditional toxicological evaluation method advantage is fairly obvious.
Claims (1)
1. a kind of toxicity of pesticide evaluation method based on metabonomic technology, it is characterised in that comprise the following steps that：
(1) exposure experiment：Using pesticide sample as study subject, used as blank, selection goldfish is pattern to drinking public water supply
Animal, contamination group and control group are respectively provided with the repeating groups of equivalent, after laboratory raises and train 4 weeks, carry out exposure experiment；
(2) sample collection：After exposure experiment terminates, collection liver, kidney and brain tissue extract total metabolism thing, are stored in minus 80 degree；
(3) it is metabolized analyte detection：The total metabolism thing of contamination group and control group is separately added into the phosphate buffer that deuterated heavy water is prepared,
Centrifuging and taking supernatant, magnetic resonance detection hydrogen signal obtains the hydrogen nuclear magnetic spectrogram of the total metabolism thing of each repeating groups；
(4) data pre-processing：By the hydrogen signal of identical metabolin in the hydrogen nuclear magnetic spectrogram of the total metabolism thing of each repeating groups unify to
Same chemical displacement value, obtains the proton magnetic spectrum stacking chart of total metabolism thing, and the proton magnetic spectrum stacking chart of total metabolism thing is divided
Duan Jifen, normalized and normalized obtains the integration data of each metabolin；
(5) difference metabolin screening：After the integration data of each metabolin that will be obtained carries out variance analysis, each metabolin is obtained
Change multiplying power and p value, will change the metabolin screening that multiplying power is more than 1.5 times and p value is less than 0.05 is differential expression metabolin；
(6) metabolic pathway identification：For the metabolin of the p value less than 0.05 of variance analysis, using online software, metabolism is carried out logical
Road is analyzed, it is determined that the metabolic pathway of reflection toxicity of pesticide.
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| CN107907610A (en) * | 2017-11-14 | 2018-04-13 | 湖南省药品检验研究院(湖南药用辅料检验检测中心) | Blood serum metabolism biological marker for acute allergic reaction cavy |
| CN108508055A (en) * | 2018-03-27 | 2018-09-07 | 广西医科大学 | A kind of potential marker metabolic pathway of Guangxi Yao Shan Sweet tea anti-diabetics and research method based on metabolism group |
| CN111210876A (en) * | 2020-01-06 | 2020-05-29 | 厦门大学 | Disturbed metabolic pathway determination method and system |
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| CN107907610A (en) * | 2017-11-14 | 2018-04-13 | 湖南省药品检验研究院(湖南药用辅料检验检测中心) | Blood serum metabolism biological marker for acute allergic reaction cavy |
| CN108508055A (en) * | 2018-03-27 | 2018-09-07 | 广西医科大学 | A kind of potential marker metabolic pathway of Guangxi Yao Shan Sweet tea anti-diabetics and research method based on metabolism group |
| CN111210876A (en) * | 2020-01-06 | 2020-05-29 | 厦门大学 | Disturbed metabolic pathway determination method and system |
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Application publication date: 20170524 |