母猪蛋白限制及糖皮质激素预处理对猪肾上腺皮质醇分泌能力的影响及机制探讨
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摘要
以往的研究表明,母体妊娠期应激可能使发育中的胚胎暴露在较高的糖皮质激素环境中,从而程序化地改变出生后肾上腺皮质醇分泌能力。本实验室以往的研究表明,中国地方猪种太湖猪肾上腺皮质醇分泌能力比国外猪种强,但发生机制尚不清楚。.由于太湖猪长期以来在低蛋白日粮的条件下饲养,而母猪蛋白限制也可能作为一种营养应激导致母体糖皮质激素升高,因此我们提出如下假说,即太湖猪较高的肾上腺皮质醇分泌能力是由于母猪妊娠期蛋白缺乏引起,而皮质醇参与介导这种程序化作用。本研究通过在体和离体两部分实验来验证这一假说。
1母猪蛋白限制对新生仔猪皮质醇分泌能力的影响
研究表明妊娠期蛋白限饲可作为一种应激源使母体血液皮质醇水平升高,从而程序化地影响后代下丘脑-垂体-肾上腺轴(Hypothalamic-pituitary-adrenal axis, HPA)功能。为研究梅山猪母猪妊娠期蛋白限制是否通过皮质醇影响后代仔猪肾上腺皮质功能,我们将梅山猪母猪分为对照组和蛋白限饲组,从配种到分娩全程饲喂标准蛋白水平日粮和蛋白缺乏日粮,限饲组日粮蛋白水平为对照组的50%。待母猪分娩后,采集母猪血清、0日龄仔猪血清和肾上腺。放免测定血清皮质醇水平,实时荧光RT-PCR定量检测0日龄仔猪肾上腺皮质细胞类固醇合成关键调节因子和酶的基因表达,包括类固醇生成急性调节蛋白(Steroidogenic acute regulatory protein, StAR)、胆固醇侧链裂解酶(Cholesterol side-chain cleavage cytochrome P450, P450scc)、17α-羟化酶(17α-hydroxylase cytochrome P450, P45017a)、21-羟化酶(21-hydroxylase cytochrome P450, P450c21). western-blotting方法分析0日龄仔猪肾上腺皮质糖皮质激素受体(Glucocorticoid receptor, GR)蛋白的表达。结果显示,蛋白限饲并未导致母猪皮质醇水平显著变化,新生仔猪皮质醇水平存在性别差异,但并没有表现组间差异。此外,新生仔猪肾上腺皮质中StAR、P450-17a、P450-scc、P450-c21 mRNA和GR的蛋白表达在两组间均未见显著差异,提示梅山猪新生仔猪肾上腺皮质的类固醇分泌能力并未受母体蛋白限制影响。
2糖皮质激素预处理对梅山猪肾上腺皮质细胞皮质醇分泌能力的影响及其机制
本实验以体外培养的原代猪肾上腺皮质细胞为模型,用糖皮质激素(皮质醇,地塞米松)预处理细胞48小时后,检测细胞在基础和应激状态下(ACTH刺激24小时)肾上腺皮质细胞分泌皮质醇的能力。试验分为六组：(1)空白预处理+基础分泌组；(2)空白预处理+ACTH刺激组；(3)皮质醇预处理+基础分泌组；(4)皮质醇预处理+ACTH刺激组；(5)地塞米松预处理+基础分泌组；(6)地塞米松预处理+ACTH刺激组。处理结束后收集培养液并提取细胞蛋白,放射免疫法测定各组细胞培养液的皮质醇水平,并用western-blotting方法分析各组细胞中类固醇合成酶的表达差异。结果显示,糖皮质激素预处理对细胞基础状态下皮质醇的分泌没有明显影响,但显著提高应激状态下(ACTH刺激)皮质醇水平。Western-blotting结果表明,糖皮质激素预处理显著增强肾上腺皮质细胞中类固醇合成关键因子StAR、P450scc以及黑皮素受体-2(Melanocortin type 2 receptor, MC2R)蛋白的表达,同时伴随GR蛋白水平显著上调。以上结果表明糖皮质激素预处理可以通过上调GR和类固醇合成关键因子的蛋白表达而增强猪肾上腺皮质细胞在ACTH刺激下分泌皮质醇的能力。
Previous studies indicated that maternal stress during pregnancy may program the postnatal capacity of glucocorticoid secretion from adrenal cortex of offspring, through prenatal exposure to high level of glucocorticoid. We found in our earlier studies that Chinese indigenous pig breed, Taihu pigs, possess significantly higher adrenocortical steroidogenic capacity compared to Western pig breed, leading to higher basal and stressed serum levels of cortisol. However the mechanisms underlying this difference are elusive. Since Taihu pigs have been traditionally raised under low protein diet and protein deficiency during pregnacy is considered as a stress which is able to raise plasma cortisol levels, we came up with a hypothesis that maternal protein restriction may increase adrenocortical steroidogenic capacity of the offspring through the mediation of cortisol. To test this, we conducted the following in vivo and in vitro experiments.
1 Effect of maternal protein restriction on adrenocortical steroidogenesis in newborn offspring pigs
Previous studies indicated that protein restriction during pregnancy may act as a stressor to elevate plasma cortisol levels of the mother which cause alterations in the function of HPA-axis in offspring. To investigate the effect of maternal protein restriction on adrenocortical cortisol secretion of the newborn piglets, Meishan sows were allocated to two groups, one fed low protein diet containing 50% crude protein of the standard diet, and the other fed standard diet from conception to parturition. The blood and adrenal of the newborn piglets, as well as the blood of sows were collected. Serum concentration of cortisol was measured with radioimmunoassay, adrenal expression of steroidogenic regulatory factors/enzymes were determined with Real-time RT-PCR, and the GR protein content was determined with Western blot analysis. The results showed that maternal protein restriction did not induce changes of serum cortisol concentrations in sows or piglets, although differences were observed between genders in newborn piglets. Furthermore, no differences were detected between control and maternal protein restriction groups in adrenal protein content of GR or mRNA abundances of StAR、P450-17a、P450scc and P450-c21 in newborn piglets. These results indicate that the adrenocortical steroidogenic capacity in new born piglets was not affected by maternal protein restriction in Meishan pigs.
2 Effect of glucocorticoid pretreatment on steroidogenic capacity of adrenocortical cells isolated from Meishan piglets and mechanisms involved
The present in vitro experiment was designed to test whether 48 h of pretreatment with glucocorticoid, cortisol or dexamethasone, would affect the basal and ACTH-stimulated (24 h) cortisol secretion from primary cultures of pig adrenocortical cells. Cells were divided into six groups:1, blank pretreatment+basal secretion; 2, blank pretreatment+ACTH challenge; 3, cotisol pretreatment+basal secretion; 4, cotisol pretreatment+ACTH challenge;5, dexamethasone pretreatment+basal secretion; 6, dexamethasone pretreatment +ACTH challenge. The culture medium and cells were collected at the end of treatment. Cortisol concentration in medium was measured with radioimmunoassay, protein contents of GR and key regulatory factors for steroidogenesis were detected with Western blot analysis. The results showed that glucocorticoid pretreatment did not affect cortisol secretion under basal condition, but significantly enhanced ACTH-stimulated cortisol secretion. Furthermore, the protein contents of GR, MC2R, StAR, and P450scc were all increased in groups pretreated with glucocorticoid. These results indicate that adrenocortical cells pretreated with glucocorticoid are more responsive to stress showing higher steroidogenic capacity under ACTH challenge, through up-regulation of GR and other steroidogenic regulatory factors.
1母猪蛋白限制对新生仔猪皮质醇分泌能力的影响
研究表明妊娠期蛋白限饲可作为一种应激源使母体血液皮质醇水平升高,从而程序化地影响后代下丘脑-垂体-肾上腺轴(Hypothalamic-pituitary-adrenal axis, HPA)功能。为研究梅山猪母猪妊娠期蛋白限制是否通过皮质醇影响后代仔猪肾上腺皮质功能,我们将梅山猪母猪分为对照组和蛋白限饲组,从配种到分娩全程饲喂标准蛋白水平日粮和蛋白缺乏日粮,限饲组日粮蛋白水平为对照组的50%。待母猪分娩后,采集母猪血清、0日龄仔猪血清和肾上腺。放免测定血清皮质醇水平,实时荧光RT-PCR定量检测0日龄仔猪肾上腺皮质细胞类固醇合成关键调节因子和酶的基因表达,包括类固醇生成急性调节蛋白(Steroidogenic acute regulatory protein, StAR)、胆固醇侧链裂解酶(Cholesterol side-chain cleavage cytochrome P450, P450scc)、17α-羟化酶(17α-hydroxylase cytochrome P450, P45017a)、21-羟化酶(21-hydroxylase cytochrome P450, P450c21). western-blotting方法分析0日龄仔猪肾上腺皮质糖皮质激素受体(Glucocorticoid receptor, GR)蛋白的表达。结果显示,蛋白限饲并未导致母猪皮质醇水平显著变化,新生仔猪皮质醇水平存在性别差异,但并没有表现组间差异。此外,新生仔猪肾上腺皮质中StAR、P450-17a、P450-scc、P450-c21 mRNA和GR的蛋白表达在两组间均未见显著差异,提示梅山猪新生仔猪肾上腺皮质的类固醇分泌能力并未受母体蛋白限制影响。
2糖皮质激素预处理对梅山猪肾上腺皮质细胞皮质醇分泌能力的影响及其机制
本实验以体外培养的原代猪肾上腺皮质细胞为模型,用糖皮质激素(皮质醇,地塞米松)预处理细胞48小时后,检测细胞在基础和应激状态下(ACTH刺激24小时)肾上腺皮质细胞分泌皮质醇的能力。试验分为六组：(1)空白预处理+基础分泌组；(2)空白预处理+ACTH刺激组；(3)皮质醇预处理+基础分泌组；(4)皮质醇预处理+ACTH刺激组；(5)地塞米松预处理+基础分泌组；(6)地塞米松预处理+ACTH刺激组。处理结束后收集培养液并提取细胞蛋白,放射免疫法测定各组细胞培养液的皮质醇水平,并用western-blotting方法分析各组细胞中类固醇合成酶的表达差异。结果显示,糖皮质激素预处理对细胞基础状态下皮质醇的分泌没有明显影响,但显著提高应激状态下(ACTH刺激)皮质醇水平。Western-blotting结果表明,糖皮质激素预处理显著增强肾上腺皮质细胞中类固醇合成关键因子StAR、P450scc以及黑皮素受体-2(Melanocortin type 2 receptor, MC2R)蛋白的表达,同时伴随GR蛋白水平显著上调。以上结果表明糖皮质激素预处理可以通过上调GR和类固醇合成关键因子的蛋白表达而增强猪肾上腺皮质细胞在ACTH刺激下分泌皮质醇的能力。
Previous studies indicated that maternal stress during pregnancy may program the postnatal capacity of glucocorticoid secretion from adrenal cortex of offspring, through prenatal exposure to high level of glucocorticoid. We found in our earlier studies that Chinese indigenous pig breed, Taihu pigs, possess significantly higher adrenocortical steroidogenic capacity compared to Western pig breed, leading to higher basal and stressed serum levels of cortisol. However the mechanisms underlying this difference are elusive. Since Taihu pigs have been traditionally raised under low protein diet and protein deficiency during pregnacy is considered as a stress which is able to raise plasma cortisol levels, we came up with a hypothesis that maternal protein restriction may increase adrenocortical steroidogenic capacity of the offspring through the mediation of cortisol. To test this, we conducted the following in vivo and in vitro experiments.
1 Effect of maternal protein restriction on adrenocortical steroidogenesis in newborn offspring pigs
Previous studies indicated that protein restriction during pregnancy may act as a stressor to elevate plasma cortisol levels of the mother which cause alterations in the function of HPA-axis in offspring. To investigate the effect of maternal protein restriction on adrenocortical cortisol secretion of the newborn piglets, Meishan sows were allocated to two groups, one fed low protein diet containing 50% crude protein of the standard diet, and the other fed standard diet from conception to parturition. The blood and adrenal of the newborn piglets, as well as the blood of sows were collected. Serum concentration of cortisol was measured with radioimmunoassay, adrenal expression of steroidogenic regulatory factors/enzymes were determined with Real-time RT-PCR, and the GR protein content was determined with Western blot analysis. The results showed that maternal protein restriction did not induce changes of serum cortisol concentrations in sows or piglets, although differences were observed between genders in newborn piglets. Furthermore, no differences were detected between control and maternal protein restriction groups in adrenal protein content of GR or mRNA abundances of StAR、P450-17a、P450scc and P450-c21 in newborn piglets. These results indicate that the adrenocortical steroidogenic capacity in new born piglets was not affected by maternal protein restriction in Meishan pigs.
2 Effect of glucocorticoid pretreatment on steroidogenic capacity of adrenocortical cells isolated from Meishan piglets and mechanisms involved
The present in vitro experiment was designed to test whether 48 h of pretreatment with glucocorticoid, cortisol or dexamethasone, would affect the basal and ACTH-stimulated (24 h) cortisol secretion from primary cultures of pig adrenocortical cells. Cells were divided into six groups:1, blank pretreatment+basal secretion; 2, blank pretreatment+ACTH challenge; 3, cotisol pretreatment+basal secretion; 4, cotisol pretreatment+ACTH challenge;5, dexamethasone pretreatment+basal secretion; 6, dexamethasone pretreatment +ACTH challenge. The culture medium and cells were collected at the end of treatment. Cortisol concentration in medium was measured with radioimmunoassay, protein contents of GR and key regulatory factors for steroidogenesis were detected with Western blot analysis. The results showed that glucocorticoid pretreatment did not affect cortisol secretion under basal condition, but significantly enhanced ACTH-stimulated cortisol secretion. Furthermore, the protein contents of GR, MC2R, StAR, and P450scc were all increased in groups pretreated with glucocorticoid. These results indicate that adrenocortical cells pretreated with glucocorticoid are more responsive to stress showing higher steroidogenic capacity under ACTH challenge, through up-regulation of GR and other steroidogenic regulatory factors.
引文
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[1]Fetoui H, Garoui M, Zeghal N. Protein restriction in pregnant-and lactating rats-induced oxidative stress and hypohomocysteinaemia in their offspring. J Anim Physiol Anim Nutr (Berl) 2009; 93: 263-270.
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[13]Haussmann MF, Carroll JA, Weesner GD, Daniels MJ, Matteri RL, Lay Jr DC. Administration of ACTH to restrained, pregnant sows alters their pigs hypothalamic-pituitary-adrenal (HPA) axis. J Anim Sci 2000;78:2399-2411.
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[16]Kanitz E, Otten W, Tuchscherer M, Manteuffel G. Effects of prenatal stress on corticosteroid receptors and monoamine concentrations in limbic areas of suckling piglets (Sus scrofa) at different ages. J Vet Med A 2003; 50:132-139.
[17]Kapoor A, Dunn E, Kostaki A. Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and Glucocorticoids. The Journal of physiology 2006; 572:31-34.
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[1]Huang H S, Wu M C, Li P H. Expression of steroidogenic enzyme messenger ribonucleic acid and cortisol production in adrenocortical cells isolated from halothane-sensitive and halothane-resistant pigs. J. Cell Biochem.2000; 79:58-70.
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[3]Darbeida H, Durand P. Glucocorticoid enhancement of adrenocorticotropin-induced 3',5'-cyclic adenosine monophosphate production by cultured ovine adrenocortical cells. Endocrinology 1987; 121:1051-1055.
[4]Feltus FA, Cote S, Melner MH. Glucocorticoids enhance activation of the human type Ⅱ 3beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerase gene. J Steroid Biochem 2003; 82: 55-63.
[5]Carsia RV, Malamed S. Glucocorticoid control of steroidogenesis in isolated rat adrenocortical cells. Biochim Biophys Acta 1983; 763:83-89.
[6]Carsia RV, Malamed S. Acute self-suppression of corticosteroidogenesis in isolated adrenocortical cells. Endocrinology 1979; 105:911-914.
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