不同碘营养对哺乳期母—子碘代谢、甲状腺功能、仔代发育及乳腺调控机制的实验研究
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摘要
碘是合成甲状腺激素的必需原料。碘缺乏与碘过量均可导致甲状腺形态与功能发生变化,从而引发各种疾病。在脑发育期的临界期(即胎儿期和生后早期)缺碘而使甲状腺功能低下会导致脑发育受到不可逆转的损害。胎儿期和生后早期的婴幼儿(母乳喂养)的碘营养只能来源于母亲,因此孕妇和哺乳妇女的碘营养对于子代的生长发育尤其脑发育至关重要。由于神经发育在生后早期(即哺乳期)仍在进行,以及目前母乳喂养的大力提倡,因此哺乳期妇女的碘营养状况不容忽视。本课题以此作为立题依据,做了大量基础性研究工作,从多个角度和不同层面探讨哺乳期母亲及其乳腺是否对碘缺乏或碘过量存在一定代偿能力(即对婴幼儿的保护能力),为哺乳期妇女的碘预防工作提供实验依据。
在本研究中,我们在成功建立了不同程度碘缺乏与碘过量的Wistar大鼠动物模型的基础上,以哺乳期母鼠和仔鼠为研究对象,对不同碘供给量母、子两代的碘代谢、甲状腺功能与形态的变化进行了全面分析,然后对仔鼠生长发育的相应指标和小脑特异性的基因和蛋白进行了测定,最后对哺乳期乳腺的代偿机制进行了进一步的研究,为探讨哺乳期不同碘供给水平下母鼠乳腺的代偿调控机制及其对仔鼠保护作用提供了科学合理的解释,为指导哺乳期妇女科学补碘提供重要的理论意义。现将本实验的研究方法、结果及结论总结如下：
一、方法
按体重将4-6周龄健康Wistar雌性大鼠随机分为4组：重度缺碘组、轻度缺碘组、正常碘组和碘过量组,每组大鼠食用低碘鼠粮,饮用含不同IK浓度的自来水,使各组母鼠每天碘供应量分别为1.24μg、5μg、10μg、300μg。雄鼠按正常组条件饲养。条件喂养8周后交配,取哺乳期14和28天的母鼠及其仔鼠作为实验研究对象。砷铈催化分光光度法检测母鼠和仔鼠的(尿、血、乳汁)碘水平,化学发光免疫和竞争结合放射免疫分析方法检测血TSH和甲状腺激素水平,观察甲状腺形态以及仔鼠生长发育的状况,测量小脑外颗粒层的消长、实时荧光定量PCR检测髓鞘碱性蛋白和蒲肯野细胞蛋白-2mRNA的表达水平,蛋白免疫印迹杂交和免疫组织化学方法检测其蛋白表达水平,实时荧光定量PCR检测母鼠乳腺两种碘转运蛋白(钠碘转运体和氯碘转运体)mRNA水平,酶联接免疫吸附双抗体夹心法测定母鼠血清催乳素水平。
二、结果
1.不同碘供给量对哺乳期母鼠的影响
1.1重度碘缺乏
1.1.1尿碘排泄减少重度碘缺乏组母鼠尿碘与正常组相比始终处于极低的水平。
1.1.2体内碘水平很低重度碘缺乏组母鼠无论是血碘还是乳汁碘均明显低于正常组。
1.1.3甲状腺肿大重度碘缺乏组母鼠的甲状腺呈现明显的充血、肿大,甲状腺绝对重量和相对重量约为正常组的4倍。组织学研究显示,呈现典型的小滤泡增生性甲状腺肿。
1.1.4甲状腺功能减退重度碘缺乏组血清TT4及FT4水平下降,TT3及FT3水平在早期略呈代偿性增高后下降,呈现明显甲状腺功能减退及TSH刺激征象。
1.2轻度碘缺乏
1.2.1尿碘排泄减少轻度碘缺乏组母鼠尿碘与正常组相比始终处于较低水平,以保证体内接近正常的血碘水平。
1.2.2体内低碘状态得以缓解轻度碘缺乏组母鼠血碘为正常组的62.7%、哺乳14天乳汁碘是正常组的51.2%,均明显高于碘供应量的比例(为NI组的50%)。
1.2.3甲状腺肿大程度较轻轻度碘缺乏组母鼠的甲状腺呈现轻度肿大(其重量是正常组的1.5倍),组织学研究显示,出现个别小滤泡增生。
1.2.4甲状腺功能接近正常轻度碘缺乏组母鼠的血清激素水平接近甚至个别指标还超过了正常组。
1.3碘过量
碘过量组通过增加尿碘排泄量减少了体内碘含量：血碘含量是正常组的20倍。甲状腺摄碘相对减少,T3合成相对减少,T4合成相对增加,血清激素T4水平高于正常组,而T3水平及T3/T4均低于正常组。甲状腺组织学改变显示出多型性特征,但程度很轻。
2.不同碘供给量对哺乳期仔鼠的影响
2.1重度碘缺乏
2.1.1体内碘水平很低通过减少尿液碘的排泄,碘缺乏的状态得到部分缓解,但是由于摄入碘的含量太少,机体代偿能力还不足以缓解体内碘缺乏状态,仔鼠不可避免地出现了低血碘。
2.1.2甲状腺功能减退重度碘缺乏组仔鼠出现了甲状腺功能减退的表现,血TT4水平明显低于正常组,组织学观察发现甲状腺呈现同母鼠相似的典型的小滤泡增生性甲状腺肿。
2.1.3生长发育迟缓无论是代表体格生理指标的张耳、开眼、长毛以及身长、体重,还是代表神经反射的平面翻正成功率、负趋地成功率,以及代表肌肉发育的前肢悬挂时间,重度碘缺乏组均明显不如正常组。表明重度碘缺乏组仔鼠在生长发育上严重落后于正常组,反映出“克汀病”的呆、小、发育迟缓的明显特征。
2.1.4小脑发育不良重度碘缺乏组仔鼠小脑外颗粒层的增殖和消退明显延迟于正常组,髓鞘碱性蛋白和蒲肯野细胞蛋白-2的mRNA和蛋白表达也明显低于正常组,说明重度碘缺乏影响了小脑的正常发育。
2.2轻度碘缺乏
2.2.1体内碘水平略低通过减少尿液碘的排泄,仔鼠体内碘水平得到较好改善。
2.2.2甲状腺功能、小脑和生长发育均接近正常轻度碘缺乏组仔鼠的甲状腺激素水平接近于正常组,组织学形态也仅出现个别小滤泡的增生。仔鼠小脑外颗粒层的增殖和消退,髓鞘碱性蛋白和蒲肯野细胞蛋白-2的mRNA和蛋白表达与正常组相比,有轻度落后趋势,但无显著差异。
2.3碘过量
碘过量组仔鼠血碘仅为正常组的3-4倍,远远小于乳汁碘与正常组的比值,TT4水平、甲状腺组织形态与正常组没有明显的差异,小脑和生长发育的各项指标仅有轻度落后的趋势。
3.哺乳期母鼠乳腺对碘的代偿机制
3.1重度碘缺乏
乳腺摄碘能力下降严重碘缺乏组乳腺NIS和Pendrin mRNA表达降低；提示长期严重缺碘情况下乳腺的摄碘能力处于失代偿状态。
3.2轻度碘缺乏
乳腺摄碘能力代偿性增强轻度碘缺乏组乳腺NIS mRNA表达增高,而Pendrin mRNA表达降低,提示轻度缺碘情况下虽然抑制了Pendrin mRNA的表达,但是NIS的代偿作用起到主导地位。综合以上,轻度碘缺乏时乳腺摄碘能力增强。
3.3碘过量
乳腺的摄碘能力代偿性下降乳腺的NIS和Pendrin mRNA的表达减弱,乳腺的摄碘能力下降。
三、结论
综上所述,严重碘缺乏时母体进入失代偿状态,呈现明显甲状腺功能减退表现和TSH刺激征象,而导致明显的滤泡增生性甲状腺肿的形成,乳腺摄碘能力也随之下降,子代受碘缺乏的影响导致小脑和生长发育不良；轻度碘缺乏时,哺乳期母鼠通过机体多途径的代偿机制,可维持自身接近正常的甲状腺功能,同时乳腺摄碘能力增强保护子代少受或免受碘缺乏的影响；对于碘过量(正常碘的30倍),母鼠具有很强的代偿能力,能够维持自身基本正常的甲状腺功能,同时乳腺摄碘能力下降保护子代少受或免受碘过量的影响。但乳腺对子代的保护能力有限,主要通过仔鼠自身的代偿(增加尿碘排泄量等)来减轻碘异常的危害。
通过本实验还发现：哺乳期母亲自身对碘营养异常的代偿途径是多方面的,发挥主要作用的是肾脏、乳腺、甲状腺自身、以及下丘脑-腺垂体-甲状腺轴。结果提示我们：哺乳期妇女碘营养不容忽视,应科学、合理的补碘,及时纠正碘缺乏或碘过量,避免碘营养异常对哺乳期妇女及其后代的危害。
Iodine is an essential component for the synthesis of thyroid hormones. Iodine deficiency and iodine excess both lead to thyroid changes in morphology and function, causing various disorders. In the critical brain development period (ie, prenatal and early postnatal periods), thyroid hypofunction caused by iodine deficiency will lead to irreversible damage in brain development. Iodine nutrition of fetal and infants (breastfed) can only come from mother, therefore the iodine nutrition of pregnant and lactating women is essential for the offspring's physical growth and development, in particular brain development. Because infant's neural development is still in progress in early postnatal period (ie, breast-feeding), as well as a strong proponent of breast-feeding in current, the iodine status of lactating women can not be ignored. According to this, our study has done a great deal of research work, to explore whether breast-feeding mothers and their mammary gland have the compensatory ability to iodine deficiency or iodine excess (that is, the protection of infants and young children) in different aspects, providing experimental basis for iodine deficiency and iodine excess prevention of breast-feeding women.
In our study, we successfully established Wistar rat model of iodine deficiency and iodine excess in different degrees, and on the based of that, we studied the iodine metabolism, thyroid function and morphology changes of the mother and child in lactation, measured the growth and development status and cerebellum-specific gene and protein of child rat, and explored the compensatory mechanisms of the lactating mammary gland with different iodine supply, to explain the compensatory regulation mechanism of lactating mammary gland and its protection to child. The present experimental methods, findings and conclusions are summarized as follows:
Methods:
4-6 weeks healthy Wistar female rats were randomly divided into severe iodine deficiency (SID), mild iodine deficiency (MiID), normal iodine (NI) and excessive iodine (ExI) groups by body weight. All female rats were fed on an iodine deficient food and drinking water with different doses of KI for 8 weeks until to mating.The male rats were fed as NI. Lactating mother and their young rats on 14 and 28 days after birth were empirical studied. Iodine level in urine, blood and milk were detected in lactating mother and their young rats by As-Ce catalytic spectrophotometry. TSH and thyroid hormones (TH) in blood were detected by chemiluminascent immunoassay and competitive binding RIA methods. Thyroid morphology of mother and their young rats and the physical growth and nervous development of these off-springs were observed. The thickness of external granular layer in cerebellum was measured. The mRNA expression of myelin basic protein and Pcp-2 in cerebellum were detected by real-time fluorescence quantitative PCR, and the protein of those were detected by Western blot and immunohistochemical method. The mRNA expression of NIS and Pendrin were detected by real-time fluorescence quantitative PCR, too. The prolactin in blood of lactating rats was detected by enzyme-linked immunosorbnent assay.
Results:
1. The effect of different iodine supply on mother rats in lactation
1.1 Severe iodine deficiency
1.1.1 The urinary iodine excretion reduced:mother urine of severe iodine deficiency group had always been at a very low level compared with normal iodine group.
1.1.2 The low iodine level in vivo:iodine in blood and in milk of severe iodine deficiency group were significantly lower than that of normal iodine group
1.1.3 Thyroid goiter: thyroid of severe iodine deficiency group showed clear signs of hyperaemia, swelling. Thyroid absolute weight and relative weight were about 3 times more than the normal group. Histological studies have shown that a typical small follicular thyroid hyperplasia swollen.
1.1.4 Hypothyroidism:severe iodine deficiency decreased serum TT4 and FT4 levels, TT3 and FT3 levels in the early compensatory increased slightly and then decreased, showing a significantly hypothyroidism and TSH stimulated.
1.2 Mild iodine deficiency
1.2.1 Reduction of urinary iodine excretion:mother urine iodine level of mild iodine deficiency group has always been at a low level compared with the NI group in order to ensure a normal blood iodine levels in vivo.
1.2.2 Low iodine status of the body alleviated:the mild iodine deficiency group, iodine in blood was 62.7% of the normal group, milk iodine was 51.2% of the normal group at 14 day of breast feeding, were significantly higher than those the proportion of iodine supply (50% of NI).
1.2.3 A lesser goiter: mother rats of mild iodine deficiency group showed mild swelling of the thyroid (the thyroid weight was 1.5 times higher than the normal group), histological studies had shown individually small follicular hyperplasia.
1.2.4 Thyroid function almost normal:the serum thyroid hormone levels of mother rats with mild iodine deficiency were closed to the NI group.
1.3 Excessive iodine
Mother rat of excessive iodine group reduced the iodine content by increasing the urinary excretion of iodine:blood iodine content is 20 times higher than the NI group. Thyroid reduced iodine taking, T3 reduced synthesis, T4 relative increased in synthesis, serum T4 hormone level of ExI was higher, but T3 levels and T3/T4 were lower than the NI group. Changes in thyroid histology showed features of polymorphism, but the degree was light.
2. The effect of different iodine supply on child rats in lactation
2.1 Severe iodine deficiency
2.1.1 The low level of iodine in vivo:by reducing urine excretion of iodine, iodine deficiency status had been partial remission, but the iodine intake was too little, the compensatory ability of body is not enough to alleviate the status of iodine deficiency, the child rats showed low blood iodine level unavoidably.
2.1.2 Thyroid function reduced:child rat of severe iodine deficiency appeared hypothyroidism, serum TT4 levels were significantly lower than the normal group, thyroid histology observed with rats showed typical small goiter follicular hyperplasia similar to their mother.
2.1.3 The growth and development of child rat delayed:representative of the physiological indicators, such as, ear standing, eyes opening, hair growning and body length, weight, and on behalf of the success rate of turning over on the plane, the success rate of negative geotaxis, as well as the hanging time of forelimb, SID group were significantly lagging behind compared with NI group, reflecting the "Cretinism" features.
2.1.4 Cerebellar dysplasia: the proliferation and disappearance of EGL in SID were delayed, MBP and Pcp-2 mRNA and protein were significantly lower than NI group, that illustrated severe iodine deficiency that affects the normal development of cerebellum.
2.2 Mild iodine deficiency
2.2.1 Iodine level in vivo slightly lower: by reducing iodine urine excretion, iodine level in vivo of child rats of mild iodine deficiency group has been very good improvement.
2.2.2 Thyroid function, physical growth and cerebellum development were close to normal group child rats:thyroid hormone levels in child rats of mild iodine deficiency were closed to the NI group, the histological change was only small follicular hyperplasia individually. EGL proliferation and regression, MBP and Pcp-2 mRNA and protein expression of mild iodine deficiency were slightly behind but no significant differences with the normal group.
2.3 Excessive iodine
Blood iodine of child rat in excessive iodine was only 3-4 times of NI group, and the ratio was far less than the milk iodine. TT4 levels, thyroid morphology, were not significantly differences, but cerebellum, growth and development were slightly behind compared with the normal group.
3. The compensation of lactating mammary at different iodine supply
3.1 Severe iodine deficiency
Decreased ability of iodine intake of mammary gland:a serious decline of NIS and Pendrin mRNA expressions of severe iodine deficiency group indicated that the thyroid capacity of iodine intake was into decompensated status.
3.2 Mild iodine deficiency
Compensatory enhance in ability of iodine intake of mammary gland:NIS mRNA expression of mammary gland in lactation of mild iodine deficiency groups was increased. Although the expression of Pendrin mRNA was suppressed by low-iodine, but NIS has played a dominant position. Based on the above, the ability of breast taking in iodine of mild iodine deficiency groups was enhanced.
3.3 Excessive iodine
Compensatory reduce in ability of iodine intake of mammary gland:The NIS and Pendrin mRNA expressions of mammary gland were significantly reduced, the ability of breast taking in iodine was declined.
Conclusion:
In conclusion, in severe iodine deficiency, the mother was into the decompensated state finally, appeard a significantly thyroid hypofunction and signs of TSH stimulation, which led to a typical follicular hyperplasia goiter, and the ability of breast taken in iodine descended, which affected the postnatal growth and development of offspring rat; in mild iodine deficiency, the lactating rats maintained their own normal thyroid function through compensatory, at the same time the capacity of iodine taken in breast enhanced to protect the offspring from iodine deficiency; for excessive iodine, mother rats had a strong ability to compensate to maintain normal thyroid function itself, and the capacity of iodine taken in breast reduced to protect the offspring from iodine excessive. But the breast ability of iodine accommodatation is limited, mainly through the infant's compensation (increase urine iodine excretion etc.) to mitigate the harm of iodine excessive.
We also discovered:The compensatory way is various to abnormal iodine nutrition of the lactating mother. It exist certain regulation mechanism in mammary gland, but which plays the leading role are kidney, the mammary gland, the thyroid gland as well as the hypothalamus-gland pituitary gland- thyroid axis. Prompt us:it should not overlook iodine nutrition of breast-feeding women, supply iodine to them scientifically and rationally, and correct iodine deficiency or excessive iodine timely to prevent abnormal iodine nutrition on breast-feeding women and their offspring.
在本研究中,我们在成功建立了不同程度碘缺乏与碘过量的Wistar大鼠动物模型的基础上,以哺乳期母鼠和仔鼠为研究对象,对不同碘供给量母、子两代的碘代谢、甲状腺功能与形态的变化进行了全面分析,然后对仔鼠生长发育的相应指标和小脑特异性的基因和蛋白进行了测定,最后对哺乳期乳腺的代偿机制进行了进一步的研究,为探讨哺乳期不同碘供给水平下母鼠乳腺的代偿调控机制及其对仔鼠保护作用提供了科学合理的解释,为指导哺乳期妇女科学补碘提供重要的理论意义。现将本实验的研究方法、结果及结论总结如下：
一、方法
按体重将4-6周龄健康Wistar雌性大鼠随机分为4组：重度缺碘组、轻度缺碘组、正常碘组和碘过量组,每组大鼠食用低碘鼠粮,饮用含不同IK浓度的自来水,使各组母鼠每天碘供应量分别为1.24μg、5μg、10μg、300μg。雄鼠按正常组条件饲养。条件喂养8周后交配,取哺乳期14和28天的母鼠及其仔鼠作为实验研究对象。砷铈催化分光光度法检测母鼠和仔鼠的(尿、血、乳汁)碘水平,化学发光免疫和竞争结合放射免疫分析方法检测血TSH和甲状腺激素水平,观察甲状腺形态以及仔鼠生长发育的状况,测量小脑外颗粒层的消长、实时荧光定量PCR检测髓鞘碱性蛋白和蒲肯野细胞蛋白-2mRNA的表达水平,蛋白免疫印迹杂交和免疫组织化学方法检测其蛋白表达水平,实时荧光定量PCR检测母鼠乳腺两种碘转运蛋白(钠碘转运体和氯碘转运体)mRNA水平,酶联接免疫吸附双抗体夹心法测定母鼠血清催乳素水平。
二、结果
1.不同碘供给量对哺乳期母鼠的影响
1.1重度碘缺乏
1.1.1尿碘排泄减少重度碘缺乏组母鼠尿碘与正常组相比始终处于极低的水平。
1.1.2体内碘水平很低重度碘缺乏组母鼠无论是血碘还是乳汁碘均明显低于正常组。
1.1.3甲状腺肿大重度碘缺乏组母鼠的甲状腺呈现明显的充血、肿大,甲状腺绝对重量和相对重量约为正常组的4倍。组织学研究显示,呈现典型的小滤泡增生性甲状腺肿。
1.1.4甲状腺功能减退重度碘缺乏组血清TT4及FT4水平下降,TT3及FT3水平在早期略呈代偿性增高后下降,呈现明显甲状腺功能减退及TSH刺激征象。
1.2轻度碘缺乏
1.2.1尿碘排泄减少轻度碘缺乏组母鼠尿碘与正常组相比始终处于较低水平,以保证体内接近正常的血碘水平。
1.2.2体内低碘状态得以缓解轻度碘缺乏组母鼠血碘为正常组的62.7%、哺乳14天乳汁碘是正常组的51.2%,均明显高于碘供应量的比例(为NI组的50%)。
1.2.3甲状腺肿大程度较轻轻度碘缺乏组母鼠的甲状腺呈现轻度肿大(其重量是正常组的1.5倍),组织学研究显示,出现个别小滤泡增生。
1.2.4甲状腺功能接近正常轻度碘缺乏组母鼠的血清激素水平接近甚至个别指标还超过了正常组。
1.3碘过量
碘过量组通过增加尿碘排泄量减少了体内碘含量：血碘含量是正常组的20倍。甲状腺摄碘相对减少,T3合成相对减少,T4合成相对增加,血清激素T4水平高于正常组,而T3水平及T3/T4均低于正常组。甲状腺组织学改变显示出多型性特征,但程度很轻。
2.不同碘供给量对哺乳期仔鼠的影响
2.1重度碘缺乏
2.1.1体内碘水平很低通过减少尿液碘的排泄,碘缺乏的状态得到部分缓解,但是由于摄入碘的含量太少,机体代偿能力还不足以缓解体内碘缺乏状态,仔鼠不可避免地出现了低血碘。
2.1.2甲状腺功能减退重度碘缺乏组仔鼠出现了甲状腺功能减退的表现,血TT4水平明显低于正常组,组织学观察发现甲状腺呈现同母鼠相似的典型的小滤泡增生性甲状腺肿。
2.1.3生长发育迟缓无论是代表体格生理指标的张耳、开眼、长毛以及身长、体重,还是代表神经反射的平面翻正成功率、负趋地成功率,以及代表肌肉发育的前肢悬挂时间,重度碘缺乏组均明显不如正常组。表明重度碘缺乏组仔鼠在生长发育上严重落后于正常组,反映出“克汀病”的呆、小、发育迟缓的明显特征。
2.1.4小脑发育不良重度碘缺乏组仔鼠小脑外颗粒层的增殖和消退明显延迟于正常组,髓鞘碱性蛋白和蒲肯野细胞蛋白-2的mRNA和蛋白表达也明显低于正常组,说明重度碘缺乏影响了小脑的正常发育。
2.2轻度碘缺乏
2.2.1体内碘水平略低通过减少尿液碘的排泄,仔鼠体内碘水平得到较好改善。
2.2.2甲状腺功能、小脑和生长发育均接近正常轻度碘缺乏组仔鼠的甲状腺激素水平接近于正常组,组织学形态也仅出现个别小滤泡的增生。仔鼠小脑外颗粒层的增殖和消退,髓鞘碱性蛋白和蒲肯野细胞蛋白-2的mRNA和蛋白表达与正常组相比,有轻度落后趋势,但无显著差异。
2.3碘过量
碘过量组仔鼠血碘仅为正常组的3-4倍,远远小于乳汁碘与正常组的比值,TT4水平、甲状腺组织形态与正常组没有明显的差异,小脑和生长发育的各项指标仅有轻度落后的趋势。
3.哺乳期母鼠乳腺对碘的代偿机制
3.1重度碘缺乏
乳腺摄碘能力下降严重碘缺乏组乳腺NIS和Pendrin mRNA表达降低；提示长期严重缺碘情况下乳腺的摄碘能力处于失代偿状态。
3.2轻度碘缺乏
乳腺摄碘能力代偿性增强轻度碘缺乏组乳腺NIS mRNA表达增高,而Pendrin mRNA表达降低,提示轻度缺碘情况下虽然抑制了Pendrin mRNA的表达,但是NIS的代偿作用起到主导地位。综合以上,轻度碘缺乏时乳腺摄碘能力增强。
3.3碘过量
乳腺的摄碘能力代偿性下降乳腺的NIS和Pendrin mRNA的表达减弱,乳腺的摄碘能力下降。
三、结论
综上所述,严重碘缺乏时母体进入失代偿状态,呈现明显甲状腺功能减退表现和TSH刺激征象,而导致明显的滤泡增生性甲状腺肿的形成,乳腺摄碘能力也随之下降,子代受碘缺乏的影响导致小脑和生长发育不良；轻度碘缺乏时,哺乳期母鼠通过机体多途径的代偿机制,可维持自身接近正常的甲状腺功能,同时乳腺摄碘能力增强保护子代少受或免受碘缺乏的影响；对于碘过量(正常碘的30倍),母鼠具有很强的代偿能力,能够维持自身基本正常的甲状腺功能,同时乳腺摄碘能力下降保护子代少受或免受碘过量的影响。但乳腺对子代的保护能力有限,主要通过仔鼠自身的代偿(增加尿碘排泄量等)来减轻碘异常的危害。
通过本实验还发现：哺乳期母亲自身对碘营养异常的代偿途径是多方面的,发挥主要作用的是肾脏、乳腺、甲状腺自身、以及下丘脑-腺垂体-甲状腺轴。结果提示我们：哺乳期妇女碘营养不容忽视,应科学、合理的补碘,及时纠正碘缺乏或碘过量,避免碘营养异常对哺乳期妇女及其后代的危害。
Iodine is an essential component for the synthesis of thyroid hormones. Iodine deficiency and iodine excess both lead to thyroid changes in morphology and function, causing various disorders. In the critical brain development period (ie, prenatal and early postnatal periods), thyroid hypofunction caused by iodine deficiency will lead to irreversible damage in brain development. Iodine nutrition of fetal and infants (breastfed) can only come from mother, therefore the iodine nutrition of pregnant and lactating women is essential for the offspring's physical growth and development, in particular brain development. Because infant's neural development is still in progress in early postnatal period (ie, breast-feeding), as well as a strong proponent of breast-feeding in current, the iodine status of lactating women can not be ignored. According to this, our study has done a great deal of research work, to explore whether breast-feeding mothers and their mammary gland have the compensatory ability to iodine deficiency or iodine excess (that is, the protection of infants and young children) in different aspects, providing experimental basis for iodine deficiency and iodine excess prevention of breast-feeding women.
In our study, we successfully established Wistar rat model of iodine deficiency and iodine excess in different degrees, and on the based of that, we studied the iodine metabolism, thyroid function and morphology changes of the mother and child in lactation, measured the growth and development status and cerebellum-specific gene and protein of child rat, and explored the compensatory mechanisms of the lactating mammary gland with different iodine supply, to explain the compensatory regulation mechanism of lactating mammary gland and its protection to child. The present experimental methods, findings and conclusions are summarized as follows:
Methods:
4-6 weeks healthy Wistar female rats were randomly divided into severe iodine deficiency (SID), mild iodine deficiency (MiID), normal iodine (NI) and excessive iodine (ExI) groups by body weight. All female rats were fed on an iodine deficient food and drinking water with different doses of KI for 8 weeks until to mating.The male rats were fed as NI. Lactating mother and their young rats on 14 and 28 days after birth were empirical studied. Iodine level in urine, blood and milk were detected in lactating mother and their young rats by As-Ce catalytic spectrophotometry. TSH and thyroid hormones (TH) in blood were detected by chemiluminascent immunoassay and competitive binding RIA methods. Thyroid morphology of mother and their young rats and the physical growth and nervous development of these off-springs were observed. The thickness of external granular layer in cerebellum was measured. The mRNA expression of myelin basic protein and Pcp-2 in cerebellum were detected by real-time fluorescence quantitative PCR, and the protein of those were detected by Western blot and immunohistochemical method. The mRNA expression of NIS and Pendrin were detected by real-time fluorescence quantitative PCR, too. The prolactin in blood of lactating rats was detected by enzyme-linked immunosorbnent assay.
Results:
1. The effect of different iodine supply on mother rats in lactation
1.1 Severe iodine deficiency
1.1.1 The urinary iodine excretion reduced:mother urine of severe iodine deficiency group had always been at a very low level compared with normal iodine group.
1.1.2 The low iodine level in vivo:iodine in blood and in milk of severe iodine deficiency group were significantly lower than that of normal iodine group
1.1.3 Thyroid goiter: thyroid of severe iodine deficiency group showed clear signs of hyperaemia, swelling. Thyroid absolute weight and relative weight were about 3 times more than the normal group. Histological studies have shown that a typical small follicular thyroid hyperplasia swollen.
1.1.4 Hypothyroidism:severe iodine deficiency decreased serum TT4 and FT4 levels, TT3 and FT3 levels in the early compensatory increased slightly and then decreased, showing a significantly hypothyroidism and TSH stimulated.
1.2 Mild iodine deficiency
1.2.1 Reduction of urinary iodine excretion:mother urine iodine level of mild iodine deficiency group has always been at a low level compared with the NI group in order to ensure a normal blood iodine levels in vivo.
1.2.2 Low iodine status of the body alleviated:the mild iodine deficiency group, iodine in blood was 62.7% of the normal group, milk iodine was 51.2% of the normal group at 14 day of breast feeding, were significantly higher than those the proportion of iodine supply (50% of NI).
1.2.3 A lesser goiter: mother rats of mild iodine deficiency group showed mild swelling of the thyroid (the thyroid weight was 1.5 times higher than the normal group), histological studies had shown individually small follicular hyperplasia.
1.2.4 Thyroid function almost normal:the serum thyroid hormone levels of mother rats with mild iodine deficiency were closed to the NI group.
1.3 Excessive iodine
Mother rat of excessive iodine group reduced the iodine content by increasing the urinary excretion of iodine:blood iodine content is 20 times higher than the NI group. Thyroid reduced iodine taking, T3 reduced synthesis, T4 relative increased in synthesis, serum T4 hormone level of ExI was higher, but T3 levels and T3/T4 were lower than the NI group. Changes in thyroid histology showed features of polymorphism, but the degree was light.
2. The effect of different iodine supply on child rats in lactation
2.1 Severe iodine deficiency
2.1.1 The low level of iodine in vivo:by reducing urine excretion of iodine, iodine deficiency status had been partial remission, but the iodine intake was too little, the compensatory ability of body is not enough to alleviate the status of iodine deficiency, the child rats showed low blood iodine level unavoidably.
2.1.2 Thyroid function reduced:child rat of severe iodine deficiency appeared hypothyroidism, serum TT4 levels were significantly lower than the normal group, thyroid histology observed with rats showed typical small goiter follicular hyperplasia similar to their mother.
2.1.3 The growth and development of child rat delayed:representative of the physiological indicators, such as, ear standing, eyes opening, hair growning and body length, weight, and on behalf of the success rate of turning over on the plane, the success rate of negative geotaxis, as well as the hanging time of forelimb, SID group were significantly lagging behind compared with NI group, reflecting the "Cretinism" features.
2.1.4 Cerebellar dysplasia: the proliferation and disappearance of EGL in SID were delayed, MBP and Pcp-2 mRNA and protein were significantly lower than NI group, that illustrated severe iodine deficiency that affects the normal development of cerebellum.
2.2 Mild iodine deficiency
2.2.1 Iodine level in vivo slightly lower: by reducing iodine urine excretion, iodine level in vivo of child rats of mild iodine deficiency group has been very good improvement.
2.2.2 Thyroid function, physical growth and cerebellum development were close to normal group child rats:thyroid hormone levels in child rats of mild iodine deficiency were closed to the NI group, the histological change was only small follicular hyperplasia individually. EGL proliferation and regression, MBP and Pcp-2 mRNA and protein expression of mild iodine deficiency were slightly behind but no significant differences with the normal group.
2.3 Excessive iodine
Blood iodine of child rat in excessive iodine was only 3-4 times of NI group, and the ratio was far less than the milk iodine. TT4 levels, thyroid morphology, were not significantly differences, but cerebellum, growth and development were slightly behind compared with the normal group.
3. The compensation of lactating mammary at different iodine supply
3.1 Severe iodine deficiency
Decreased ability of iodine intake of mammary gland:a serious decline of NIS and Pendrin mRNA expressions of severe iodine deficiency group indicated that the thyroid capacity of iodine intake was into decompensated status.
3.2 Mild iodine deficiency
Compensatory enhance in ability of iodine intake of mammary gland:NIS mRNA expression of mammary gland in lactation of mild iodine deficiency groups was increased. Although the expression of Pendrin mRNA was suppressed by low-iodine, but NIS has played a dominant position. Based on the above, the ability of breast taking in iodine of mild iodine deficiency groups was enhanced.
3.3 Excessive iodine
Compensatory reduce in ability of iodine intake of mammary gland:The NIS and Pendrin mRNA expressions of mammary gland were significantly reduced, the ability of breast taking in iodine was declined.
Conclusion:
In conclusion, in severe iodine deficiency, the mother was into the decompensated state finally, appeard a significantly thyroid hypofunction and signs of TSH stimulation, which led to a typical follicular hyperplasia goiter, and the ability of breast taken in iodine descended, which affected the postnatal growth and development of offspring rat; in mild iodine deficiency, the lactating rats maintained their own normal thyroid function through compensatory, at the same time the capacity of iodine taken in breast enhanced to protect the offspring from iodine deficiency; for excessive iodine, mother rats had a strong ability to compensate to maintain normal thyroid function itself, and the capacity of iodine taken in breast reduced to protect the offspring from iodine excessive. But the breast ability of iodine accommodatation is limited, mainly through the infant's compensation (increase urine iodine excretion etc.) to mitigate the harm of iodine excessive.
We also discovered:The compensatory way is various to abnormal iodine nutrition of the lactating mother. It exist certain regulation mechanism in mammary gland, but which plays the leading role are kidney, the mammary gland, the thyroid gland as well as the hypothalamus-gland pituitary gland- thyroid axis. Prompt us:it should not overlook iodine nutrition of breast-feeding women, supply iodine to them scientifically and rationally, and correct iodine deficiency or excessive iodine timely to prevent abnormal iodine nutrition on breast-feeding women and their offspring.
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