不同价态砷对大鼠砷代谢及甲基化生化指标的影响
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摘要
目的：观察不同价态、不同剂量砷染毒大鼠代谢相关生化指标的活力及大鼠肝脏中甲基转移酶mRNA的表达情况,寻找不同价态砷体内代谢间的差异,为进一步探讨砷的毒作用机制提供依据。方法：选用Wistar大鼠70只,随机分为对照组,对照组给予饮用去离子水,iAs3+高、中、低剂量组,分别给予20.0、6.7、2.2mg/kg的亚砷酸钠溶液,iAs5+高、中、低剂量组,分别给予20.0、6.7、2.2mg/kg的砷酸氢钠溶液,共7组。采用自由饮水法染毒,连续染毒90d。大鼠饲养至第3个月末,用颈椎脱臼法处死。应用酶联免疫吸附法(ELISA)测各组肝脏匀浆液中SAM, ARR,MTR的活力；酶联免疫吸附法测定血细胞中PK活力；实时荧光定量PCR测定各组肝脏基因组中甲基转移酶mRNA的表达。结果：1.iAs3+和iAs5+均可升高大鼠肝脏中SAM活力(P<0.05),且随着染砷剂量的增加,呈下降的趋势,相同剂量iAs3+组SAM活力低于iAs5+组,差别有统计学意义(P<0.05); 2.iAs3+和iAs5+可改变大鼠肝脏中的ARR活力,差别有统计学意义(P<0.05)；iAs3+高、中剂量组与低剂量组比较,差别有统计学意义(P<0.05), iAs5+高剂量组与低剂量组比较,差别有统计学意义(P<0.05); iAs3+和iAs5+各剂量组间比较,差别均有统计学意义(P<0.05); 3.MTR可改变iAs3+和iAs5+大鼠肝脏中的活力,差别有统计学意义(P<0.05)；相同受试物与低剂量组比较,差别均有统计学意义(P<0.05); iAs3+和iAs5+高剂量组间比较,差别有统计学意义(P<0.05); iAs3+和iAs5+低剂量组比较,差别有统计学意义(P<0.05)；4.高剂量iAs3+和iAs5+可降低大鼠血清中PK活性,iAs3+和iAs5+高剂量组中的比较差异有统计学意义(P<0.05),iAs3+和iAs5+在中剂量组与低剂量组比较时差异均无统计学意义(P均>0.05)；5.从荧光定量PCR的结果可见,iAs3+和iAs5+在大鼠肝脏中甲基化转移酶mRNA的基因表达与正常对照组相比均有统计学差异(P<0.05),随着染砷剂量的增加,iAs3+As3MT基因的mRNA表达呈上升趋势,iAs5+As3MT基因的mRNA表达呈下降趋势,iAs3+和iAs5+高剂量组比较差异有统计学意义(P<0.05)；随着染砷剂量的增加,iAs3+DNMT3A,3B基因的mRNA表达呈下降趋势,iAs5+DNMT3A,3B基因的mRNA表达呈上升趋势,iAs3+和iAs5+高、低剂量组比较差异有统计学意义(P<0.05)；DNMT1基因的mRNA表达中iAs3+和iAs5+高、中剂量组比较差异有统计学意义(P<0.05)。结论：1.iAs3+和iAs5+均可使大鼠肝脏组织中SAM的含量升高,通过SAM提供充足的甲基供体,增强机体的甲基化代谢能力。2.iAs3+或iAs5+可影响ARR的活力,还原酶的活性将直接影响甲基化的进程。3.iAs3+或iAs5+染毒大鼠可改变MTR的活力,通过影响叶酸的正常代谢、细胞内DNA甲基化反应以及脱氧核苷酸三磷酸盐的生物合成,进而影响砷的作用机制。4.长期摄入过量iAs3+或iAs5+可降低丙酮酸激酶的活力,通过糖酵解作用改变砷甲基化的程度。5.长期慢性染砷(iAs3+或iAs5+)可使As3MT的mRNA表达升高,并存在剂量关系,影响砷的甲基化程度；iAs3+或iAs5+可在大鼠肝脏中抑制DNMTs基因的mRNA的表达,表明不同价态的砷可通过DNMTs抑制mRNA的表达水平,影响表观遗传调控,从而诱导毒性作用的发生。
Objective:To investigate the mechanism of arsenic toxicology further and seek for the difference between sodium arsenite and sodium arsenate(different valence state arsenic), we studied the influence on activity of biochemical indicator and Methyltransferase in rats liver mRNA treated with sodium arsenite and sodium arsenate. Methods:Different valence state and doses of arsenic was administrated with drinking water to Wistar rats, rats were divided into 7 group randomly,10 rats each group, control group (C) administer-ated with demineralized water, Sodium Arsenite low dose group(AL), medial dose group (AM), high dose group (AH) administrated with different concentrations of sodium arsen ite:20.0,6.7,2.2mg/kg; Sodium Arsenate low dose group(BL), medial dose group(BM), high dose group(BH) administrated with different concentrations of sodium Arsenate:20.0, 6.7,2.2mg/kg. Exposed by the free water method. Continuous exposed for 90d. At the end of the 3 months execute the rats by cervical dislocation to collect the blood and Liver, the activity of SAM, ARR, MTR was detected by ELISA in Rats liver, the activity of PK was detected by ELISA in rats blood, the expression of methyltransferase was detected by real-time PCR in liver genome mRNA. Results:1.iAs3+and iAs5+ can increase the activity of SAM in rats liver (P<0.05), with the increasing dose of arsenic, the tendency is descendent, the activity of iAs3+ is lower than iAs5+ in identical dose, the difference was statistically significant (P<0.05);2.ARR can change the activity of iAs3+ and iAs5+, the difference was statistically significant (P<0.05); to compare high and medial dose group with low dose group of iAs3+, the difference was statistically significant (P<0.05); to compare high dose group with low dose group of iAs5+, the difference was statistically significant (P<0.05); to compare iAs+and iAs5+, the difference of each experimental group was statistically significant (Ali P<0.05);3.MTR can change the activity of iAs3+and iAs+,the difference was statistically significant (P<0.05); to compare identical the test matter with low dose group, the difference was statistically significant (P<0.05); the difference of high dose group of iAs3+ and iAs5+ was statistically significant(P<0.05); to compare iAs3+ and iAs5+, the difference of high dose group of was statistically significant (P<0.05);4.iAs3+ and iAs5+ can decrease the activity of PK in rats blood (P<0.05), the difference of high dose group was statistically significant (P<0.05),the medial dose and low dose group was not statistically significant (All P>0.05);5.The result of real-time PCR showed that the difference of methyltransferase expression was statistically signif-icant (P<0.05) with control group in rats liver mRNA on iAs3+ and iAs5+; with the increase of Arsenic dose, iAs3+ As3MT mRNA showed a ascendant trend, iAs5+ As3MT mRNA showed a descendant trend; to compere with iAs3+and iAs5+ of high dose group of As3MT, the difference was statistically significant (P<0.05); with the increase of Arsenic dose, iAs3+ DNMT3A,3B mRNA showed a descendant trend, iAs5+DNMT3A,3B mRNA showed a ascendant trend, to compere with iAs3+and iAs5+ of high and low dose groups of DNMT3A,3B, the difference was statistically significant (P<0.05);the difference of DNMT1 of iAs3+ and iAs5+ high, medial dose group was statistically significant (P<0.05); Conclusions:1.iAs3+and iAs5+ can make the content of SAM step-up in rats liver, SAM offer abundant methyl donor to enhance metabolic capability of methylation.2. iAs3+or iAs5+ affect the activity of ARR, the activity of reductases will affect the processes of methylation directly.3. iAs3+ or iAs5+ can modify the vitality of MTR in rats to affect normal metabolism of folic acid and intra-cellular DNA methylation reaction and biosynthesis of deoxynucleotide triphosphate, then impact arsenical mechanism of action.4. Long-term intake overdose iAs3+ or iAs5+can decrease the vitality of PK to pass glycolysis and modify arsenic methylated level.5. Long-term and chronicity expose to iAs3+or iAs5+ can step-up As3MT mRNA expression, and exis dosage relationships, it will impact arsenical methylation level; iAs3+or iAs5+ can inhibit DNMTs mRNA expression in rats liver that indicate different valence state arsenic may inhibit DNMTs mRNA expression level and affect epigenetic regulation, then induce toxic effect generation.
Objective:To investigate the mechanism of arsenic toxicology further and seek for the difference between sodium arsenite and sodium arsenate(different valence state arsenic), we studied the influence on activity of biochemical indicator and Methyltransferase in rats liver mRNA treated with sodium arsenite and sodium arsenate. Methods:Different valence state and doses of arsenic was administrated with drinking water to Wistar rats, rats were divided into 7 group randomly,10 rats each group, control group (C) administer-ated with demineralized water, Sodium Arsenite low dose group(AL), medial dose group (AM), high dose group (AH) administrated with different concentrations of sodium arsen ite:20.0,6.7,2.2mg/kg; Sodium Arsenate low dose group(BL), medial dose group(BM), high dose group(BH) administrated with different concentrations of sodium Arsenate:20.0, 6.7,2.2mg/kg. Exposed by the free water method. Continuous exposed for 90d. At the end of the 3 months execute the rats by cervical dislocation to collect the blood and Liver, the activity of SAM, ARR, MTR was detected by ELISA in Rats liver, the activity of PK was detected by ELISA in rats blood, the expression of methyltransferase was detected by real-time PCR in liver genome mRNA. Results:1.iAs3+and iAs5+ can increase the activity of SAM in rats liver (P<0.05), with the increasing dose of arsenic, the tendency is descendent, the activity of iAs3+ is lower than iAs5+ in identical dose, the difference was statistically significant (P<0.05);2.ARR can change the activity of iAs3+ and iAs5+, the difference was statistically significant (P<0.05); to compare high and medial dose group with low dose group of iAs3+, the difference was statistically significant (P<0.05); to compare high dose group with low dose group of iAs5+, the difference was statistically significant (P<0.05); to compare iAs+and iAs5+, the difference of each experimental group was statistically significant (Ali P<0.05);3.MTR can change the activity of iAs3+and iAs+,the difference was statistically significant (P<0.05); to compare identical the test matter with low dose group, the difference was statistically significant (P<0.05); the difference of high dose group of iAs3+ and iAs5+ was statistically significant(P<0.05); to compare iAs3+ and iAs5+, the difference of high dose group of was statistically significant (P<0.05);4.iAs3+ and iAs5+ can decrease the activity of PK in rats blood (P<0.05), the difference of high dose group was statistically significant (P<0.05),the medial dose and low dose group was not statistically significant (All P>0.05);5.The result of real-time PCR showed that the difference of methyltransferase expression was statistically signif-icant (P<0.05) with control group in rats liver mRNA on iAs3+ and iAs5+; with the increase of Arsenic dose, iAs3+ As3MT mRNA showed a ascendant trend, iAs5+ As3MT mRNA showed a descendant trend; to compere with iAs3+and iAs5+ of high dose group of As3MT, the difference was statistically significant (P<0.05); with the increase of Arsenic dose, iAs3+ DNMT3A,3B mRNA showed a descendant trend, iAs5+DNMT3A,3B mRNA showed a ascendant trend, to compere with iAs3+and iAs5+ of high and low dose groups of DNMT3A,3B, the difference was statistically significant (P<0.05);the difference of DNMT1 of iAs3+ and iAs5+ high, medial dose group was statistically significant (P<0.05); Conclusions:1.iAs3+and iAs5+ can make the content of SAM step-up in rats liver, SAM offer abundant methyl donor to enhance metabolic capability of methylation.2. iAs3+or iAs5+ affect the activity of ARR, the activity of reductases will affect the processes of methylation directly.3. iAs3+ or iAs5+ can modify the vitality of MTR in rats to affect normal metabolism of folic acid and intra-cellular DNA methylation reaction and biosynthesis of deoxynucleotide triphosphate, then impact arsenical mechanism of action.4. Long-term intake overdose iAs3+ or iAs5+can decrease the vitality of PK to pass glycolysis and modify arsenic methylated level.5. Long-term and chronicity expose to iAs3+or iAs5+ can step-up As3MT mRNA expression, and exis dosage relationships, it will impact arsenical methylation level; iAs3+or iAs5+ can inhibit DNMTs mRNA expression in rats liver that indicate different valence state arsenic may inhibit DNMTs mRNA expression level and affect epigenetic regulation, then induce toxic effect generation.
引文
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