宮內(nèi)TCDD暴露對(duì)子代印記基因及空間學(xué)習(xí)記憶影響的跨代遺傳研究
發(fā)布時(shí)間：2018-08-01 18:42
【摘要】：2,3,7,8-四氯代二苯并-對(duì)-二VA英(TCDD)可以通過(guò)胎盤和乳汁向下一代傳遞,在直接暴露的個(gè)體及其子代中引起嚴(yán)重的異常生理和功能性改變。已有研究證實(shí)了胎兒發(fā)育中的環(huán)境因素刺激可誘導(dǎo)基因組的表觀遺傳調(diào)控的長(zhǎng)期改變,造成表型的跨代遺傳效應(yīng)。目前宮內(nèi)TCDD暴露對(duì)大鼠體細(xì)胞組織印記基因改變的跨代遺傳效應(yīng)尚未有報(bào)道;宮內(nèi)TCDD暴露是否能夠造成子代的空間學(xué)習(xí)記憶損傷,該效應(yīng)是否能夠跨代傳遞,亦尚未有文獻(xiàn)報(bào)道。目的探索性腺性別決定期宮內(nèi)TCDD暴露對(duì)F1-F3代生長(zhǎng)發(fā)育,以及F1代和F3代雄鼠肝臟印記基因Igf2的影響,進(jìn)一步研究相關(guān)的表觀遺傳跨代調(diào)控機(jī)制;并對(duì)宮內(nèi)TCDD暴露對(duì)F1-F3代成年大鼠空間學(xué)習(xí)記憶能力的影響進(jìn)行研究。方法建立跨代遺傳大鼠模型,孕F0代雌性SD大鼠在性腺性別決定期(孕8-14天,GD 8-14)灌胃染毒TCDD,劑量分別為0,200,800 ng/kg bw。F1-F3代仔鼠圍產(chǎn)期間測(cè)量其頂臀長(zhǎng)和尾長(zhǎng);對(duì)肛門生殖孔距離(AGD)和體重增長(zhǎng)情況進(jìn)行測(cè)定。使用亞硫酸氫鈉測(cè)序法(BSP)法對(duì)F1和F3代雄鼠肝臟組織中Igf2/H19位點(diǎn)兩個(gè)差異性甲基化區(qū)域(ICR,DMR2)的甲基化狀態(tài)進(jìn)行測(cè)定;使用Real-time PCR法對(duì)F1代和F3代雄鼠肝臟印記基因胰島素樣生長(zhǎng)因子2(Igf2),DNA甲基轉(zhuǎn)移酶(DNMT1,DNMT3A,DNMT3B)的m RNA表達(dá)水平進(jìn)行測(cè)定;使用Morris水迷宮實(shí)驗(yàn)測(cè)試F1-F3代成年大鼠的空間學(xué)習(xí)記憶能力。結(jié)果1宮內(nèi)性腺性別決定期TCDD暴露未對(duì)F1-F3代窩大小和出生性別比例造成影響,但是造成了F1代雌鼠和雄鼠的出生存活率和哺乳存活率的顯著下降,圍產(chǎn)期頂臀長(zhǎng)和尾長(zhǎng)的縮短,圍產(chǎn)期和成年期的AGD縮短;這些效應(yīng)在F2代和F3代子代中仍持續(xù),但隨著傳代的進(jìn)行,效應(yīng)逐漸減弱;2宮內(nèi)性腺性別決定期TCDD暴露可顯著造成F1和F2代的低出生體重以及圍產(chǎn)期的體重增長(zhǎng)緩慢。體重增長(zhǎng)趨勢(shì)上,高劑量(800 ng/kg bw)TCDD宮內(nèi)暴露造成F1代大鼠體重持續(xù)低于對(duì)照組,并隨著傳代的進(jìn)行,直至F3代仍出現(xiàn)不同程度的體重增長(zhǎng)緩慢現(xiàn)象;而在低劑量(200 ng/kg bw)TCDD宮內(nèi)暴露后代中則出現(xiàn)了不同程度的體重增長(zhǎng)高于同期對(duì)照組的現(xiàn)象,并持續(xù)到F3代;3宮內(nèi)TCDD暴露可引起F1-F3代雄鼠(睪丸,附睪,前列腺)和雌鼠(卵巢)的生殖系統(tǒng)臟器重量和臟器系數(shù)的不同程度的改變,并隨著傳代該效應(yīng)衰減;同時(shí)也觀察到了宮內(nèi)TCDD暴露對(duì)F1-F3代一般臟器(脾臟,腎臟,心臟,肝臟)的重量和臟器系數(shù)的長(zhǎng)期影響;4宮內(nèi)TCDD暴露可造成子F1代和F3代雄鼠肝臟印記基因Igf2的m RNA表達(dá)下降。200和800 ng/kg bw TCDD組的F1代雄鼠Igf2的m RNA表達(dá)分別為對(duì)照組的0.81倍和0.39倍(P0.05);經(jīng)過(guò)兩代雄性生殖系的傳遞后,F3代Igf2的表達(dá)水平仍顯示了明顯的降低趨勢(shì),200和800 ng/kg bw TCDD組F3代雄鼠Igf2的m RNA表達(dá)分別為對(duì)照組的0.25和0.33倍(P0.05);5對(duì)印記基因Igf2的兩個(gè)差異性甲基化區(qū)域的甲基化程度的分析結(jié)果顯示,F1代ICR區(qū)域甲基化程度隨染毒劑量增加而上升,DMR2區(qū)域甲基化程度則隨劑量增加而下降;并且隨著傳代的進(jìn)行,宮內(nèi)TCDD暴露誘導(dǎo)的ICR和DMR2的甲基化模式的改變?cè)贔3代仍呈現(xiàn)相似的趨勢(shì);6伴隨著印記基因Igf2差異性甲基化區(qū)域甲基化模式的改變,建立和維持印記基因表達(dá)的DNMTs也受宮內(nèi)TCDD暴露的影響:F1代DNMT1,DNMT3A和DNMT3B的m RNA表達(dá)呈現(xiàn)非單調(diào)改變模式,并且該效應(yīng)在F3代仍凸顯;7 Morris水迷宮獲得性訓(xùn)練階段,TCDD宮內(nèi)暴露組F1-F3代雌雄成年大鼠的潛伏期和游泳路程與對(duì)照組相比,具有不同程度的延長(zhǎng)現(xiàn)象,該效應(yīng)持續(xù)到F3代仍顯示與對(duì)照組有微弱的差異;8 Morris水迷宮探查測(cè)試中,F1代的800 ng/kg bw TCDD組的雄鼠穿越原平臺(tái)的次數(shù)明顯減少,但是該效應(yīng)并沒(méi)有在F2,F3代中凸顯出來(lái),F1-F3代雌性后代也未出現(xiàn)差異;F1代800 ng/kg bw TCDD組的雌雄成年大鼠在目標(biāo)象限花費(fèi)的時(shí)間多于對(duì)照組;9 Morris水迷宮獲得性訓(xùn)練階段,宮內(nèi)TCDD作用造成的子代學(xué)習(xí)記憶能力具有明顯的性別差異。F2代TCDD組雄鼠相對(duì)于同劑量組的雌鼠花費(fèi)更長(zhǎng)的時(shí)間找到隱匿平臺(tái);并且在F1代和F2代中,TCDD組雄鼠表現(xiàn)差于對(duì)照組的雌鼠,顯示了一定程度的雌性化。上述性別差異經(jīng)歷兩代傳遞后衰減。結(jié)論1宮內(nèi)性腺性別決定期TCDD暴露對(duì)F1-F3代子代的一般生長(zhǎng)發(fā)育和AGD造成一定的影響,并隨著傳代的進(jìn)行,效應(yīng)逐漸減弱;2宮內(nèi)TCDD暴露對(duì)子代體重增長(zhǎng)的長(zhǎng)期影響可能呈現(xiàn)“倒U”現(xiàn)象:TCDD宮內(nèi)暴露子代體重的增長(zhǎng)可能在低劑量作用下得到刺激,出現(xiàn)代償性生長(zhǎng);而在較高劑量的作用下體重增長(zhǎng)受到抑制,該種現(xiàn)象可能會(huì)跨代傳遞;3性腺性別決定期TCDD宮內(nèi)暴露具有廣泛的發(fā)育毒性作用,可能擾亂器官形成,對(duì)子代生殖系統(tǒng),免疫系統(tǒng)造成影響,產(chǎn)生腎臟毒性,心臟毒性和肝臟毒性,一些效應(yīng)還能夠持續(xù)影響多代,增加疾病風(fēng)險(xiǎn);4宮內(nèi)TCDD暴露可能并不直接造成不良妊娠結(jié)局,相反的可能對(duì)于生長(zhǎng)和發(fā)育指標(biāo)產(chǎn)生長(zhǎng)久的細(xì)微的效應(yīng)或損傷。靶器官的跨代效應(yīng)影響可能也涉及表觀遺傳因素的影響,對(duì)于以后的TCDD跨代遺傳研究靶標(biāo)選擇上具有一定的提示作用;5性腺性別決定期TCDD宮內(nèi)暴露可通過(guò)擾亂印記基因Igf2的表觀遺傳修飾,從而造成印記基因表達(dá)的改變,并且該印記基因的異常甲基化模式可在傳代中逃避基因組的重新甲基化過(guò)程,進(jìn)行跨代遺傳;DNA甲基轉(zhuǎn)移酶在TCDD造成的印記基因甲基化模式的跨代遺傳傳遞中起一定的作用;6宮內(nèi)TCDD暴露可造成F1-F3代雌雄成年大鼠空間學(xué)習(xí)記憶能力的損傷,具有跨代遺傳效應(yīng);宮內(nèi)TCDD暴露誘導(dǎo)的空間學(xué)習(xí)記憶能力的改變具有性別差異。TCDD子代雄鼠顯示了“雌性化”表現(xiàn),提示TCDD可能通過(guò)激素紊亂效應(yīng)造成雄性子代的神經(jīng)行為的“去雄化”表現(xiàn),但是該效應(yīng)經(jīng)過(guò)兩代傳遞后逐漸衰減。
[Abstract]:2,3,7,8- four chloro two benzo benzo - two VA e (TCDD) can be transmitted through the placenta and milk to the next generation, causing severe abnormal physiological and functional changes in directly exposed individuals and their progenies. The intergenerational genetic effect of the intrauterine TCDD exposure has not yet been reported on the intergenerational effect of intrauterine exposure to the imprinted gene of the somatic tissue of the rat. Whether the intrauterine TCDD exposure can cause the spatial learning and memory damage of the offspring, whether the effect can be transmitted across the generation, and not yet be reported in the literature. Purpose to explore the intrauterine TCDD storm in the sex determination period of the gonadal gland. The effect of exposure on the growth and development of F1-F3 generation, as well as the liver imprinting gene Igf2 of F1 and F3 male rats, further study the related epigenetic cross generation regulation mechanism, and study the effect of TCDD exposure on the spatial learning and memory ability of the adult rats in the F1-F3 generation. Methods a cross generation rat model was established, and the female SD rats of F0 generation were in the gonads. The sex determination period (8-14 days of pregnancy, GD 8-14) was administered to the stomach of TCDD, and the dose of 0200800 ng/kg bw.F1-F3 offspring was measured in the perinatal period. The distance of the anal genital pore (AGD) and the weight growth were measured. The Igf2/H19 loci in the liver tissues of F1 and F3 male rats were two difference using the Sodium Bisulfite sequencing method (BSP) method. The methylation status of ICR (DMR2) was measured and the Real-time PCR method was used to determine the expression level of the expression level of insulin like growth factor 2 (Igf2), DNA methyltransferase (DNMT1, DNMT3A, DNMT3B) of the liver imprinted gene of the F1 and F3 male mice, and the spatial learning of adult rats in the water maze test was tested. Results in 1 intrauterine gonadal sex determination, TCDD exposure did not affect the size of F1-F3 nests and the proportion of birth sex, but resulted in a significant decrease in the birth and lactation survival rates of the F1 generation female rats and male rats, the shortening of the perinatal length and tail length, and the shortening of the perinatal and adult AGD; these effects were in the F2 and F3 generations. The offspring still continued, but with the passage of the passage, the effect gradually weakened; the sex determination period of the 2 intrauterine sex gland TCDD exposure could significantly cause the low birth weight of the F1 and F2 generation and the slow growth of the perinatal body weight. In the trend of weight growth, Gao Jiliang (800 ng/kg BW) TCDD intrauterine exposure resulted in the weight of the F1 generation rats lower than the control group, and along with the transmission. On behalf of the F3 generation, there were still different degrees of slow weight growth, while in the low dose (200 ng/kg BW) TCDD intrauterine offspring, the weight gain of different degrees was higher than that of the same control group, and continued to the F3 generation, and the 3 intrauterine TCDD exposure could cause the F1-F3 male male rats (testis, epididymis, prostate) and the female rats (ovaries). The changes in the organ weight and organ coefficient of the reproductive system were changed to varying degrees, and the effect of this effect was attenuated with the passage. The long-term effect of intrauterine TCDD exposure on the weight and organ coefficient of the F1-F3 generation general organs (spleen, kidney, heart, liver) was also observed; 4 intrauterine TCDD exposure could cause the liver imprinting gene Igf2 of the offspring F1 and F3 generations of the male rats. The expression of M RNA expression of F1 generation male rat Igf2 in M RNA expression and 800 ng/kg BW TCDD group was 0.81 times and 0.39 times (P0.05), respectively. After the transmission of male reproductive lines in two generations, the expression level of F3 generation was still obviously decreasing. 200 and 800 were the control group. 0.25 and 0.33 times (P0.05); 5 Analysis of the methylation degree of two differential methylation regions of the imprinting gene Igf2 showed that the degree of methylation in the F1 generation ICR region increased with the increase of the dose, and the degree of methylation in the DMR2 region decreased with the increase of the dose; and as the transmission was carried out, the TCDD exposure induced ICR and DMR2 in the intrauterine exposure. The changes in the F3 generation are similar in the F3 generation; with the alteration of the methylation pattern in the differential methylation region of the imprinting gene Igf2, the establishment and maintenance of the DNMTs of the imprinted gene expression is also affected by the intrauterine TCDD exposure: the F1 generation DNMT1, the m RNA expression of DNMT3A and DNMT3B present a non monotonic pattern, and the effect is still convex in the F3 generation. 7 Morris water maze acquired training stage, the incubation period and swimming distance of the F1-F3 generation adult rats in the TCDD intrauterine exposure group had different degrees of prolongation compared with the control group, and the effect continued until the F3 generation still showed a weak difference with the control group; in the 8 Morris test, the 800 ng/kg BW TCDD group of the F1 generation was male. The number of mice passed through the original platform significantly decreased, but the effect was not highlighted in the F2, F3 generation, and the female offspring of the F1-F3 generation did not differ. The time spent in the female and male adult rats of the F1 800 ng/kg BW TCDD group was more than the control group; the 9 Morris water maze acquired the sexual training stage and the offspring learning caused by the intrauterine TCDD action. The male rats of.F2 generation TCDD took longer time to find concealed platforms than the female rats in the same dose group; and in the F1 and F2 generations, the male rats in the group TCDD showed a certain degree of feminization. The above sex difference experienced two generations of transmission attenuation. Conclusion the 1 intrauterine gonads TCDD exposure in the sex determination period has a certain effect on the general growth and development of the F1-F3 generation and AGD, and the effect gradually diminished with the passage of the passage. 2 the long-term effect of TCDD exposure on the offspring's body weight may show "inverted U" phenomenon: the growth of TCDD intrauterine exposure progeny weight may be stimulated under the effect of low dose. Modern compensatory growth; and the growth of body weight under the high dose of inhibition, the phenomenon may pass through the generation; 3 sex determination of sex in the gonad period TCDD intrauterine exposure has extensive developmental toxicity, may disturb the formation of organs, the reproductive system of the progeny, the immune system, and produce renal toxicity, heart toxicity, and liver toxicity. Some effects can also continue to affect multiple generations and increase the risk of disease; 4 intrauterine TCDD exposure may not directly cause adverse pregnancy outcomes. On the contrary, it may have long and subtle effects or damage to growth and development indicators. The effect of the cross generation effect of target organs may also involve epigenetic factors, for the subsequent TCDD cross generation. The selection of genetic research targets has a certain suggestive effect; 5 the intrauterine exposure to TCDD in the sex determination period of sex glands can cause the epigenetic modification of the imprinted gene Igf2 to cause changes in the expression of the imprinting genes, and the abnormal methylation pattern of the imprinted gene can escape the process of the re methylation of the genome in the passage and carry out the cross generation. Heredity; DNA methyltransferase plays a certain role in the transgenerational transmission of the imprinted gene methylation pattern caused by TCDD; 6 intrauterine TCDD exposure can cause damage to the spatial learning and memory ability of the adult male and female adult rats of F1-F3 generation, and has a cross generation genetic effect; the changes of spatial learning and memory ability induced by intrauterine TCDD exposure have sex differences. The TCDD progeny male mice showed "feminization", suggesting that TCDD may result in the "derangement" of the neurobehavioral behavior of the male offspring through the hormonal disorder effect, but the effect gradually attenuates after two generations of transmission.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R714.5
[Abstract]:2,3,7,8- four chloro two benzo benzo - two VA e (TCDD) can be transmitted through the placenta and milk to the next generation, causing severe abnormal physiological and functional changes in directly exposed individuals and their progenies. The intergenerational genetic effect of the intrauterine TCDD exposure has not yet been reported on the intergenerational effect of intrauterine exposure to the imprinted gene of the somatic tissue of the rat. Whether the intrauterine TCDD exposure can cause the spatial learning and memory damage of the offspring, whether the effect can be transmitted across the generation, and not yet be reported in the literature. Purpose to explore the intrauterine TCDD storm in the sex determination period of the gonadal gland. The effect of exposure on the growth and development of F1-F3 generation, as well as the liver imprinting gene Igf2 of F1 and F3 male rats, further study the related epigenetic cross generation regulation mechanism, and study the effect of TCDD exposure on the spatial learning and memory ability of the adult rats in the F1-F3 generation. Methods a cross generation rat model was established, and the female SD rats of F0 generation were in the gonads. The sex determination period (8-14 days of pregnancy, GD 8-14) was administered to the stomach of TCDD, and the dose of 0200800 ng/kg bw.F1-F3 offspring was measured in the perinatal period. The distance of the anal genital pore (AGD) and the weight growth were measured. The Igf2/H19 loci in the liver tissues of F1 and F3 male rats were two difference using the Sodium Bisulfite sequencing method (BSP) method. The methylation status of ICR (DMR2) was measured and the Real-time PCR method was used to determine the expression level of the expression level of insulin like growth factor 2 (Igf2), DNA methyltransferase (DNMT1, DNMT3A, DNMT3B) of the liver imprinted gene of the F1 and F3 male mice, and the spatial learning of adult rats in the water maze test was tested. Results in 1 intrauterine gonadal sex determination, TCDD exposure did not affect the size of F1-F3 nests and the proportion of birth sex, but resulted in a significant decrease in the birth and lactation survival rates of the F1 generation female rats and male rats, the shortening of the perinatal length and tail length, and the shortening of the perinatal and adult AGD; these effects were in the F2 and F3 generations. The offspring still continued, but with the passage of the passage, the effect gradually weakened; the sex determination period of the 2 intrauterine sex gland TCDD exposure could significantly cause the low birth weight of the F1 and F2 generation and the slow growth of the perinatal body weight. In the trend of weight growth, Gao Jiliang (800 ng/kg BW) TCDD intrauterine exposure resulted in the weight of the F1 generation rats lower than the control group, and along with the transmission. On behalf of the F3 generation, there were still different degrees of slow weight growth, while in the low dose (200 ng/kg BW) TCDD intrauterine offspring, the weight gain of different degrees was higher than that of the same control group, and continued to the F3 generation, and the 3 intrauterine TCDD exposure could cause the F1-F3 male male rats (testis, epididymis, prostate) and the female rats (ovaries). The changes in the organ weight and organ coefficient of the reproductive system were changed to varying degrees, and the effect of this effect was attenuated with the passage. The long-term effect of intrauterine TCDD exposure on the weight and organ coefficient of the F1-F3 generation general organs (spleen, kidney, heart, liver) was also observed; 4 intrauterine TCDD exposure could cause the liver imprinting gene Igf2 of the offspring F1 and F3 generations of the male rats. The expression of M RNA expression of F1 generation male rat Igf2 in M RNA expression and 800 ng/kg BW TCDD group was 0.81 times and 0.39 times (P0.05), respectively. After the transmission of male reproductive lines in two generations, the expression level of F3 generation was still obviously decreasing. 200 and 800 were the control group. 0.25 and 0.33 times (P0.05); 5 Analysis of the methylation degree of two differential methylation regions of the imprinting gene Igf2 showed that the degree of methylation in the F1 generation ICR region increased with the increase of the dose, and the degree of methylation in the DMR2 region decreased with the increase of the dose; and as the transmission was carried out, the TCDD exposure induced ICR and DMR2 in the intrauterine exposure. The changes in the F3 generation are similar in the F3 generation; with the alteration of the methylation pattern in the differential methylation region of the imprinting gene Igf2, the establishment and maintenance of the DNMTs of the imprinted gene expression is also affected by the intrauterine TCDD exposure: the F1 generation DNMT1, the m RNA expression of DNMT3A and DNMT3B present a non monotonic pattern, and the effect is still convex in the F3 generation. 7 Morris water maze acquired training stage, the incubation period and swimming distance of the F1-F3 generation adult rats in the TCDD intrauterine exposure group had different degrees of prolongation compared with the control group, and the effect continued until the F3 generation still showed a weak difference with the control group; in the 8 Morris test, the 800 ng/kg BW TCDD group of the F1 generation was male. The number of mice passed through the original platform significantly decreased, but the effect was not highlighted in the F2, F3 generation, and the female offspring of the F1-F3 generation did not differ. The time spent in the female and male adult rats of the F1 800 ng/kg BW TCDD group was more than the control group; the 9 Morris water maze acquired the sexual training stage and the offspring learning caused by the intrauterine TCDD action. The male rats of.F2 generation TCDD took longer time to find concealed platforms than the female rats in the same dose group; and in the F1 and F2 generations, the male rats in the group TCDD showed a certain degree of feminization. The above sex difference experienced two generations of transmission attenuation. Conclusion the 1 intrauterine gonads TCDD exposure in the sex determination period has a certain effect on the general growth and development of the F1-F3 generation and AGD, and the effect gradually diminished with the passage of the passage. 2 the long-term effect of TCDD exposure on the offspring's body weight may show "inverted U" phenomenon: the growth of TCDD intrauterine exposure progeny weight may be stimulated under the effect of low dose. Modern compensatory growth; and the growth of body weight under the high dose of inhibition, the phenomenon may pass through the generation; 3 sex determination of sex in the gonad period TCDD intrauterine exposure has extensive developmental toxicity, may disturb the formation of organs, the reproductive system of the progeny, the immune system, and produce renal toxicity, heart toxicity, and liver toxicity. Some effects can also continue to affect multiple generations and increase the risk of disease; 4 intrauterine TCDD exposure may not directly cause adverse pregnancy outcomes. On the contrary, it may have long and subtle effects or damage to growth and development indicators. The effect of the cross generation effect of target organs may also involve epigenetic factors, for the subsequent TCDD cross generation. The selection of genetic research targets has a certain suggestive effect; 5 the intrauterine exposure to TCDD in the sex determination period of sex glands can cause the epigenetic modification of the imprinted gene Igf2 to cause changes in the expression of the imprinting genes, and the abnormal methylation pattern of the imprinted gene can escape the process of the re methylation of the genome in the passage and carry out the cross generation. Heredity; DNA methyltransferase plays a certain role in the transgenerational transmission of the imprinted gene methylation pattern caused by TCDD; 6 intrauterine TCDD exposure can cause damage to the spatial learning and memory ability of the adult male and female adult rats of F1-F3 generation, and has a cross generation genetic effect; the changes of spatial learning and memory ability induced by intrauterine TCDD exposure have sex differences. The TCDD progeny male mice showed "feminization", suggesting that TCDD may result in the "derangement" of the neurobehavioral behavior of the male offspring through the hormonal disorder effect, but the effect gradually attenuates after two generations of transmission.
【學(xué)位授予單位】：天津醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2014
【分類號(hào)】：R714.5
【共引文獻(xiàn)】
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