本文選題：可吸入顆粒 + 妊娠��； 參考：《山東大學》2017年博士論文

【摘要】：研究背景空氣污染,又稱為大氣污染,通常是指由于人類活動或自然過程引起的某些有害物質(zhì)進入空氣中,并累積達到足夠的濃度,持續(xù)一定長的時間,由此危害了人類的健康和環(huán)境的現(xiàn)象。伴隨我國經(jīng)濟發(fā)展的一個重要社會問題是空氣污染,來源于自然因素如森林火災(zāi)和人為因素如工業(yè)廢氣排放、生活燃煤污染、汽車尾氣排放等對我國的環(huán)境造成嚴重的影響。2012年聯(lián)合國環(huán)境規(guī)劃署發(fā)布了《全球環(huán)境展望》中指出,空氣細顆粒物吸入會導(dǎo)致每年近200萬的過早死亡。2013世界衛(wèi)生組織下屬的國際癌癥研究機構(gòu)發(fā)布報告,首次指認大氣污染屬于環(huán)境致癌物之一。我國于2014年首次將霧霾天氣納入自然災(zāi)情進行通報并指出應(yīng)對霧霾污染、改善空氣質(zhì)量的首要任務(wù)是控制PM2.5,要從壓減燃煤、調(diào)整產(chǎn)業(yè)、嚴格控車、嚴格管理、聯(lián)防聯(lián)控、依法治理等方面,聚焦重點致污染領(lǐng)域,管理指標考核,加強環(huán)境執(zhí)法的監(jiān)管。可吸入細顆粒物PM2.5是指大氣總懸浮顆粒物中空氣動力學直徑≤2.5μ m的粒子,是空氣中各種氣態(tài)污染物經(jīng)化學反應(yīng)產(chǎn)生的二次粒子。PM2.5其成分主要為有機物、硫酸鹽、硝酸鹽以及地殼類元素,其中有機物已檢測出多環(huán)芳烴、聯(lián)苯類和含氮、硫、氧等原子的化合物,共110多種。其中多環(huán)芳烴是分子中含有兩個以上苯環(huán)的碳氫化合物,包括萘、蒽、菲、芘等150余種化合物,它一種可以致癌、致畸、致突變的物質(zhì),具有很強的毒性。多環(huán)芳烴還能通過胎盤與DNA結(jié)合,誘發(fā)胎兒DNA損傷,影響胎兒的生長發(fā)育。國內(nèi)外大量的流行病學研究表明PM2.5對機體健康有著不良影響。PM2.5表面吸附大量有毒有害物質(zhì),粒徑小,能通過呼吸作用進入呼吸道深部,沉積在終末細支氣管和肺泡,通過肺換氣進入血液循環(huán),改變循環(huán)系統(tǒng)功能,引發(fā)機體的一系列急性應(yīng)激反應(yīng),從而導(dǎo)致相關(guān)疾病的發(fā)生。PM2.5能影響細胞的生理生化過程,改變信號傳導(dǎo)通路,誘發(fā)蛋白質(zhì)合成和降解失調(diào)、抑癌基因突變失活,癌基因異常表達,誘導(dǎo)細胞癌變,增加肺癌等癌癥的發(fā)病率,并會導(dǎo)致某些職業(yè)暴露人群如交通警察、道路清潔工等的癌癥發(fā)病率增加。pM2.5暴露被報道與許多慢性疾病的發(fā)生發(fā)展有關(guān),如糖尿病、心血管疾病、哮喘等。長期暴露污染空氣可使機體對胰島素敏感性下降、胰島素抵抗增強,尤其是對于生活方式健康的人群更為明顯。胰島素抵抗是指外周組織和靶器官對內(nèi)和(或)外源性胰島素的敏感性和反應(yīng)性降低,胰島素抑制肝臟葡萄糖輸出及外周組織利用葡萄糖能力降低,血循環(huán)中葡萄糖利用減少,血糖升高。胰島素抵抗是2型糖尿病及代謝綜合征發(fā)病的關(guān)鍵環(huán)節(jié),是糖尿病患者發(fā)生心血管并發(fā)癥的獨立危險因素。PM2.5暴露會導(dǎo)致機體的胰島素抵抗水平增加和全身性炎癥狀態(tài)。大氣中PM2.5濃度每增加10μg/m3,糖尿病的發(fā)生率上升1%。PM2.5暴露小鼠顯示出異常的胰島素抵抗和全身炎癥反應(yīng)。PM2.5暴露下小鼠的骨骼肌葡萄糖轉(zhuǎn)運蛋白-4的表達水平顯著降低,提示PM2.5能通過抑制骨骼肌細胞葡萄糖的轉(zhuǎn)運,減少葡萄糖利用從而導(dǎo)致血糖水平升高,促進糖尿病的發(fā)生發(fā)展。妊娠期糖尿病(gestational diabetes mellitus,GDM)與2型糖尿病發(fā)病機制相似,有著類似的病理生理過程。妊娠是發(fā)生糖耐量異常的敏感階段,許多本身糖耐量正常的孕婦的胰島素抵抗狀態(tài)逐漸增強,大約有18%的孕婦會在妊娠期間出現(xiàn)糖耐量異常。近年來有研究發(fā)現(xiàn)PM2.5與妊娠婦女的糖耐量損害有關(guān),PM2.5進入機體后發(fā)生的氧化應(yīng)激反應(yīng)、全身及局部的炎癥反應(yīng),同樣也會發(fā)生在妊娠婦女身上。PM2.5持續(xù)暴露可導(dǎo)致機體組織AKT磷酸化水平改變,弱化胰島素信號通路,導(dǎo)致多器官組織的胰島素抵抗水平增強,促進糖代謝異常的發(fā)生發(fā)展,有研究認為污染空氣暴露會加速孕婦胰島素抵抗發(fā)生發(fā)展的病理生理過程。近年來,流行病學調(diào)查研究發(fā)現(xiàn)高濃度PM2.5孕期暴露與不良妊娠結(jié)局有關(guān)。早期胚胎由于細胞的增殖迅速,對營養(yǎng)和氧需求增加,空氣污染物暴露會引發(fā)胚胎功能性損傷甚至結(jié)構(gòu)異常。產(chǎn)前暴露于較嚴重的空氣污染會引發(fā)低出生體重、早產(chǎn)、流產(chǎn)等,并與出生缺陷的比率升高有關(guān)。許多污染物通過氣血交換進入母體血循環(huán),在母胎界面以簡單擴散等方式通過胎盤影響胎兒發(fā)育。眾所周知,胎兒的發(fā)育與胎盤的功能息息相關(guān)。胎盤是母體與胎兒之間的橋梁,母體通過胎盤向胎兒輸送氧氣和各種營養(yǎng)成分,胎兒通過胎盤向母體排出代謝廢物和二氧化碳。胎盤功能不良往往會引發(fā)多種不良妊娠結(jié)局如流產(chǎn)、胎死宮內(nèi)等。許多有害物質(zhì)能通過母胎血流在胎盤中蓄積,引發(fā)胎盤結(jié)構(gòu)與功能障礙,并導(dǎo)致不良妊娠結(jié)局發(fā)生。胎盤作為孕期母親與胎兒物質(zhì)與氣體的交換橋梁,其結(jié)構(gòu)、功能變化與胚胎發(fā)育乃至遠期預(yù)后密切相關(guān)。本課題組自2014年開始對孕期PM2.5暴露進行的系列的研究。我們通過觀察大鼠孕期PM2.5暴露對胎盤結(jié)構(gòu)的影響,以及孕鼠炎癥指標、凝血功能狀態(tài)、胎盤及仔鼠生長發(fā)育之間的相互關(guān)系,初步為研究孕期PM2.5暴露對胎兒生長發(fā)育造成的影響奠定基礎(chǔ)。為了探討PM2.5孕期暴露對母鼠及仔鼠的影響,對不同組織器官如胎盤和胰腺的作用及機制,我們設(shè)計并完成了以下二部分實驗:第一部分:溫州地區(qū)上半年P(guān)M2.5對妊娠期大鼠胎盤病理及圍產(chǎn)結(jié)局的影響方法:1.PM2.5顆粒采集、混懸液制備。使用大流量采樣器在交通主干道采樣,將采集好的PM2.5顆粒配成混懸液備用。2.妊娠大鼠造模。3.妊娠大鼠隨機分成2組,實驗組于妊娠10天、18天分別接受PM2.5(15mg/kg)經(jīng)氣管內(nèi)滴注,對照組同期接受同等劑量的生理鹽水。最后一次暴露后24小時,所有的妊娠大鼠麻醉下處死。4.剖宮取出仔鼠和胎盤。觀察仔鼠有無外觀畸形,記錄仔鼠數(shù)目并稱量體重。5.檢測血常規(guī)和血IL-6評估炎癥和凝血功能水平。6.檢測胎盤組織均漿液的谷胱甘肽過氧化物酶(Glutathione peroxidase,GSH-Px)和丙二醛(methane dicarboxylic aldehyde,MDA)含量評估胎盤組織的氧化損傷。7.胎盤組織行病理檢查。結(jié)果:1.孕期PM2.5暴露下的妊娠大鼠胚胎吸收率更高,孕期母鼠體重增加及仔鼠出生體重均低于對照組(p0.05)。2.PM2.5孕期暴露導(dǎo)致孕鼠白細胞、血小板、IL-6水平升高((P0.01)。3.兩組胎盤組織的GSH-Px和MDA水平無明顯區(qū)別(P0.05)。4.實驗組的胎盤組織病理檢查發(fā)現(xiàn)胎盤血管內(nèi)血栓形成及絨毛膜羊膜炎改變。結(jié)論:1.pM2.5孕期暴露會導(dǎo)致不良妊娠結(jié)局發(fā)生率明顯升高、胎盤組織發(fā)生明顯的病理改變。2.胎盤炎癥、高凝及血栓形成可能是PM2.5暴露致胎盤損傷的重要的作用機制。第二部分:溫州地區(qū)上半年P(guān)M2.5對血糖及胰腺葡萄糖轉(zhuǎn)運蛋白2(glucose transporter 2,GLUT2)表達的影響方法:1.PM2.5顆粒采集、混懸液制備。使用大流量采樣器在交通主干道采樣,將采集好的PM2.5顆粒配成混懸液備用。2.GDM大鼠造模。3.GDM大鼠隨機分成2組,實驗組于妊娠10天、18天分別接受PM2.5(15 mg/kg)經(jīng)氣管內(nèi)滴注,對照組同期接受同等劑量的生理鹽水。最后一次暴露后24小時,所有的GDM大鼠麻醉下處死。4.試驗期間,GDM大鼠每3天測量體重、每3天測尾血血糖并記錄。5.暴露結(jié)束后,檢測血常規(guī)和血IL-6來評估炎癥和凝血功能水平。6.胰腺勻漿液檢測GSH-Px和MDA含量評估胰腺組織的氧化損傷。7.檢測胰腺葡萄糖轉(zhuǎn)運蛋白2(GLUT2)水平。8.胰腺組織進行病理檢查。結(jié)果:1.PM2.5暴露組的孕期母鼠體重增加(P0.05)及仔鼠出生體重(P0.01)均低于對照組。2.PM2.5孕期暴露導(dǎo)致胚胎吸收率增高,血白細胞、血小板、IL-6水平升高(P0.01)。多次餐后隨機血糖水平高于對照組(P0.01)。3.PM2.5暴露組的胰腺經(jīng)病理檢查證實有明顯的胰腺導(dǎo)管周圍炎癥反應(yīng)。4.胰腺勻漿液的GSH-Px和MDA水平高于對照組(P0.01)。5.胰腺GLUT2蛋白水平明顯低于對照組(P0.05)。結(jié)論:1.PM2.5暴露可導(dǎo)致GDM大鼠胰腺GLUT2蛋白表達下降、血糖水平升高,胰腺組織有明顯的病理改變。2.氧化應(yīng)激反應(yīng)、炎癥反應(yīng)可能是PM2.5暴露引發(fā)胰腺損傷并加重GDM大鼠糖代謝異常的重要原因。
[Abstract]:Background air pollution, also known as air pollution, usually refers to the accumulation of certain harmful substances caused by human activities or natural processes into the air, and the accumulation of sufficient concentration, lasting a long period of time, thus endangering human health and the environment. An important social problem with the economic development of our country is empty. Gas pollution, derived from natural factors such as forest fires and human factors such as industrial exhaust emissions, living coal pollution, automobile exhaust emissions and so on, has a serious impact on the environment of our country. The United Nations Environment Programme issued the Global Environmental Outlook in.2012 that the inhalation of fine particles of air will lead to nearly 2 million premature death of.20 every year. 13 WHO, the International Cancer Research Institute, issued a report for the first time that air pollution is one of the environmental carcinogens. In 2014, our country first reported haze weather into the natural disaster and pointed out that the fog and haze pollution, the first task to improve the air quality was to control the PM2.5, to reduce the coal burning, to adjust the industry, and to strictly adjust the industry. Control car, strict management, joint prevention and control, management according to law, focus on pollution field, management index assessment, and strengthen the supervision of environmental law enforcement. The inhaled fine particulate matter PM2.5 is the particle of the air dynamics diameter less than 2.5 u m in the total suspended particulate matter of the atmosphere, and the two particle produced by the chemical reaction of various gaseous pollutants in the air. .PM2.5 is mainly composed of organic matter, sulfate, nitrate and crustal elements, in which polycyclic aromatic hydrocarbons, biphenyl and nitrogen, sulfur, oxygen and other atoms have been detected in more than 110 compounds. Polycyclic aromatic hydrocarbons are hydrocarbons containing more than two benzene rings, including naphthalene, anthracene, phenanthrene, pyrene and other 150 compounds. It can be carcinogenic, teratogenic, mutagenicity, and has strong toxicity. Polycyclic aromatic hydrocarbons can also be combined with DNA to induce fetal DNA damage and affect fetal growth and development. A large number of epidemiological studies at home and abroad have shown that PM2.5 has a bad effect on the body's health and adsorbs a large number of toxic and harmful substances on the surface of.PM2.5, which can pass through small size and can pass through Respiration enters the deep part of the respiratory tract, deposits in the terminal bronchioles and alveoli, enters the blood circulation through the lung ventilation, changes the function of the circulatory system and causes a series of acute stress responses of the body, which leads to the effect of.PM2.5 on the physiological and biochemical processes of the cells, the change of the signal transduction pathway, and the synthesis of protein and the synthesis of protein. Maladjustment, inactivation of tumor suppressor gene, abnormal expression of oncogene, induced canceration of cells, increasing the incidence of cancer such as lung cancer, and the increased incidence of cancer in some occupational exposures, such as traffic policemen, road cleaners, and.PM2.5 exposure are reported to be associated with the development of many chronic diseases, such as diabetes and cardiovascular disease. Prolonged exposure to air pollution can reduce the body's sensitivity to insulin and increase insulin resistance, especially in people with a healthy lifestyle. Insulin resistance is a reduction in the sensitivity and responsiveness of the peripheral and / or target organs to internal and / or exogenous insulin, and insulin inhibits the liver glucose output and The use of glucose in peripheral tissue decreases, glucose utilization decreases and blood glucose increases in blood circulation. Insulin resistance is a key link in the pathogenesis of type 2 diabetes and metabolic syndrome. It is an independent risk factor for cardiovascular complications in diabetic patients..PM2.5 exposure will lead to increased insulin resistance and systemic inflammatory symptoms in the body. The concentration of PM2.5 in the atmosphere increased by 10 mu g/m3, the incidence of diabetes increased in 1%.PM2.5 exposed mice and showed abnormal insulin resistance and systemic inflammatory response to.PM2.5 exposure. The expression level of glucose transporter -4 in skeletal muscle of mice decreased significantly, suggesting that PM2.5 could reduce the glucose transport of skeletal muscle cells and reduce the grapes. Sugar utilization can lead to higher levels of blood sugar and promote the development of diabetes. Gestational diabetes mellitus (GDM) is similar to the pathogenesis of type 2 diabetes and has a similar pathophysiological process. Pregnancy is a sensitive stage of impaired glucose tolerance, and a number of pregnant women with normal glucose tolerance are resistant to insulin. Gradually, about 18% of pregnant women have abnormal glucose tolerance during pregnancy. In recent years, studies have found that PM2.5 is associated with impaired glucose tolerance in pregnant women, oxidative stress after PM2.5 enters the body, systemic and local inflammatory reactions, and the persistent exposure to.PM2.5 in pregnant women can also lead to the body group. The changes in the level of phosphorylation of AKT and the weakening of insulin signaling pathway lead to the enhancement of insulin resistance in multiple organ tissues and the development of abnormal glucose metabolism. There is a study that polluted air exposure will accelerate the pathophysiological process of the development of insulin resistance in pregnant women. In recent years, the epidemiological investigation found that high concentration of PM2.5 pregnancy was found. Exposure to adverse pregnancy outcomes is associated with adverse pregnancy outcomes. Early embryos increase the demand for nutrition and oxygen due to rapid cell proliferation. Exposure to air pollutants may lead to functional damage and even structural abnormalities. Prenatal exposure to severe air pollution causes low birth weight, premature birth, abortion and so on, which is associated with a rise in birth defects. It is well known that the development of the fetus is closely related to the function of the placenta. It is well known that the fetal development is closely related to the function of the placenta. The placenta is a bridge between the mother and the fetus, the mother conveyed oxygen and various nutrients to the fetus through the placenta, and the fetus passed through the fetus. Disks discharge metabolic waste and carbon dioxide from the parent body. Abnormal placental function often causes a variety of bad pregnancy outcomes, such as abortion, fetal death, and so on. Many harmful substances can accumulate in the placenta by the maternal fetal blood flow, lead to placental structure and dysfunction, and lead to adverse pregnancy outcomes. Placenta is the mother and fetus of pregnancy. The exchange bridge of gas, its structure and function change closely related to embryo development and long term prognosis. The research group began a series of studies on PM2.5 exposure during pregnancy since 2014. We observed the effect of PM2.5 exposure on the placental structure during pregnancy, and the index of inflammation, the state of coagulation function, the growth and development of placenta and offspring. The relationship between birth and breeding lays a foundation for the study of the effects of PM2.5 exposure on fetal growth and development during pregnancy. In order to explore the effects of PM2.5 exposure on pregnant rats and offspring, and on the roles and mechanisms of different tissues and organs such as the placenta and pancreas, we have designed and completed the next two parts: the first part: the upper half of Wenzhou region The effect of PM2.5 on the placental pathology and perinatal outcome of pregnancy rats: 1.PM2.5 granule collection and suspension preparation. A large flow sampler was used to sample the main road of the traffic. The collected PM2.5 granules were divided into 2 groups of.3. gestation rats in a spare.2. pregnancy rat model. The experimental group received 10 days of pregnancy and 18 days to receive PM2., respectively. 5 (15mg/kg) was injected into the air tube, and the control group received the same dose of normal saline at the same time. 24 hours after the last exposure, all the pregnant rats were killed by.4. caesarean section to remove the offspring and placenta. The deformity of the offspring was observed and the number of the offspring was recorded and weighed by.5., and the blood routine and blood IL-6 were measured to evaluate the inflammation and coagulation function water. The levels of glutathione peroxidase (Glutathione peroxidase, GSH-Px) and malondialdehyde (methane dicarboxylic aldehyde, MDA) in placental tissues were measured by.6. in placental tissue to evaluate the pathological changes of placental tissue. The results showed that 1. pregnant rats exposed to PM2.5 were more absorbed in pregnant rats, and the weight of pregnant female rats increased. The birth weight of the mice was lower than that of the control group (P0.05). The exposure to.2.PM2.5 in pregnancy induced the leukocytes, platelets and IL-6 levels in the pregnant rats (P0.01) there was no significant difference between the GSH-Px and MDA levels of the placental tissue in.3. two groups (P0.05) the placental pathological examination of the.4. experimental group found the formation of intravascular thrombus in the fetal disc and the change of chorioamnionitis. Conclusion: 1.p Exposure to M2.5 during pregnancy could lead to a significant increase in the incidence of adverse pregnancy outcomes, placental tissue and pathological changes in.2. placenta inflammation. Hypercoagulability and thrombosis may be an important mechanism for placental injury induced by PM2.5 exposure. The second part: PM2.5 glucose and pancreatic glucose transporter 2 (glucose transporte) in the first half of the year in Wenzhou R 2, GLUT2) expression of the influence methods: 1.PM2.5 particles collection, suspension preparation. Using a large flow sampler sampling in the main road of the traffic,.3.GDM rats were randomly divided into 2 groups in the.2.GDM rat model of.2.GDM rats. The experimental group was treated with PM2.5 (15 mg/kg) in the air tube on the 18 day of pregnancy and the control group was the same as the control group. During the last 24 hours of the last exposure, 24 hours after the last exposure, all the GDM rats were killed in the.4. test, the GDM rats were measured every 3 days, the blood glucose was measured every 3 days and the.5. exposure was recorded. The blood routine and the blood IL-6 were detected to assess the levels of GSH-Px and MDA in the.6. pancreatic homogenate. To evaluate the oxidative damage of pancreatic tissue by.7., the pancreatic glucose transporter 2 (GLUT2) level.8. pancreatic tissue was examined. Results: the weight increase (P0.05) and the birth weight (P0.01) of the pregnant female rats in the 1.PM2.5 exposure group were lower than those of the control group, which resulted in the increase of the embryo absorption rate, blood leukocyte, platelet, IL-6 water during.2.PM2.5 pregnancy exposure. Ping Shenggao (P0.01). The level of postprandial random blood glucose was higher than that of the control group (P0.01).3.PM2.5 exposure group. The pancreatic duct pathological examination showed obvious pancreatic duct inflammatory response. The GSH-Px and MDA levels of.4. pancreatic homogenate were higher than those of the control group (P0.01).5. pancreatic GLUT2 protein water level was significantly lower than that of the control group (P0.05). Conclusion: 1.PM2.5 exposure can be found. The expression of GLUT2 protein in the pancreas of GDM rats decreased and the level of blood sugar increased. The pancreatic tissue had obvious pathological changes of.2. oxidative stress. The inflammatory reaction may be an important reason for the pancreatic injury caused by PM2.5 exposure and the aggravation of abnormal glucose metabolism in GDM rats.
【學位授予單位】：山東大學
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R714.2

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