Biotin Status in Pregnancy

怀孕期间生物素的状况

• 批准号: 7728014
• 负责人: Donald M Mock
• 金额: $ 37.31万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7728014
• 关键词: Address; Animals; Biotin; Biotinylation; Blood; Congenital Abnormality; Consent; Control Groups; Correlation Studies; Creatinine; Enzymes; Excretory function; Funding; Gene Expression; Healthcare; Human; In Vitro; Intervention; Intervention Trial; Mammals; Normal Range; Peripheral Blood Lymphocyte; Phase; Placebo Control; Placebos; Pregnancy; Pregnant Women; Qualifying; Randomized; Rattus; Renal function; Research; Role; Sampling; Supplementation; Testing; Time; Urine; Venous blood sampling; Western Blotting; Woman; beta-hydroxyisovaleric acid; design; falls; holocarboxylase synthetases; human subject; indexing; methylmalonyl-CoA decarboxylase; pregnant; protein expression; public health relevance; urinary

DESCRIPTION (provided by applicant): Marginal biotin deficiency causes birth defects in some animals including mammals, raising concern that biotin deficiency causes human birth defects. We seek funding for a definitive study of biotin status during normal human pregnancy. Previous studies suggest that during pregnancy about half of women become marginally biotin deficient. However, confidence in this conclusion is limited because the best validated index of biotin status (urinary 3-hydroxyisovaleric acid, 3HIA) depends on renal function, which is altered by pregnancy per se. We propose to quantitate activity of the biotin-dependent enzyme propionyl-CoA carboxylase (PCC) in peripheral blood lymphocytes. This validated indicator of biotin status will be used to test the overall hypothesis that a significant number of women develop marginal biotin deficiency during normal gestation. The study will be conducted in two phases. In the first phase (Qualifying Phase), PCC activity will be determined for 104 women in early pregnancy. Mean PCC activity of the pregnancy group will be compared to a control group of women who are not pregnant to test the hypothesis that PCC activity is significantly decreased in early pregnancy, reflecting reduced biotin status. The second phase (Intervention Phase) will use a randomized, placebo-controlled design to test the hypothesis that the reduced PCC activity identified in the Qualifying Phase does indeed reflect biotin deficiency, rather than an effect of pregnancy per se. Twenty-six pregnant women with low PCC activity will be randomized to either biotin supplementation (300 5g daily supplement for 3 weeks) or placebo. Activity of PCC will be determined immediately before and at the end of the supplement period. We expect that PCC activity will increase significantly in the biotin-supplemented group and not change significantly in the placebo group, providing strong evidence of biotin deficiency. Urinary 3HIA will be used as a secondary indicator of biotin status in both the Qualifying Phase and the Intervention Phase. The proposed studies will also address mechanism. We will 1) investigate the role of accelerated biotin degradation (as assessed by increased urinary excretion of biotin metabolites) in causing biotin deficiency, and 2) confirm that a limited biotin supply is the cellular mechanism for the observed decrease in PCC activity by quantitating PCC and holocarboxylase synthetase gene expression, apo- and holo-PCC mass, and PCC in vitro activation coefficient. PUBLIC HEALTH RELEVANCE: We are concerned that marginal biotin deficiency causes human birth defects. Here we seek funding to demonstrate that marginal biotin deficiency is common in pregnancy. If so, then the next logical question would be "Does marginal biotin deficiency cause a substantial number of human birth defects?" Large-scale epidemiologic correlation studies, a large-scale biotin intervention trial or both would be needed to answer that question. Given the expense of such trials, the smaller study proposed here is an essential prerequisite in a line of research with substantial healthcare implications.

描述（由申请人提供）：边际生物素缺乏会导致某些动物（包括哺乳动物）的先天缺陷，这引起了人们对生物素缺乏会导致人类先天缺陷的担忧。我们寻求对正常人类怀孕期间生物素状态的确切研究的资金。先前的研究表明，在怀孕期间，大约一半的女性变得略有生物素缺乏。然而，对这一结论的信心受到限制，因为最佳验证的生物素状态指数（尿3-羟基甲甲酸，3HIA）取决于肾功能，肾功能是通过妊娠本身改变的。我们建议定量外周血淋巴细胞中生物素依赖性酶丙二酰羧酸酶（PCC）的活性。该验证的生物素状态指标将用于检验总体假设，即在正常妊娠期间，大量女性会出现边缘生物素缺乏症。该研究将分为两个阶段。在第一阶段（合格阶段），将在怀孕初期确定104名妇女的PCC活性。妊娠组的平均PCC活性将与未怀孕的女性对照组进行比较，以检验PCC活性在怀孕早期显着降低，这反映了生物素状态的降低。第二阶段（干预阶段）将使用随机的安慰剂对照设计来检验以下假设：在合格阶段鉴定的PCC活性减少确实反映了生物素缺乏症，而不是妊娠本身的影响。 PCC活性低的26名孕妇将被随机分配给补充生物素（300 5G每日补充3周）或安慰剂。 PCC的活性将在补充期之前和结束时立即确定。我们预计，在生物素供应的组中，PCC活性将大大增加，而安慰剂组则不会显着变化，从而提供了有力的生物素缺乏迹象。在合格阶段和干预阶段，尿液3HIA将被用作生物素状态的次要指标。拟议的研究还将解决机制。 We will 1) investigate the role of accelerated biotin degradation (as assessed by increased urinary excretion of biotin metabolites) in causing biotin deficiency, and 2) confirm that a limited biotin supply is the cellular mechanism for the observed decrease in PCC activity by quantitating PCC and holocarboxylase synthetase gene expression, apo- and holo-PCC mass, and PCC in vitro activation 系数。公共卫生相关性：我们担心边缘生物素缺乏会导致人类的先天缺陷。在这里，我们寻求资金证明边缘生物素缺乏症在怀孕中很常见。如果是这样，那么下一个合乎逻辑的问题将是“边际生物素缺乏会导致大量的人类出生缺陷？”大规模的流行病学相关研究，大规模生物素干预试验或两者都需要回答该问题。考虑到此类试验的费用，此处提出的较小的研究是具有重大医疗保健意义的研究线中的必要先决条件。