NEURAL TUBE DEFECTS INDUCED BY ANIONS VIA INCREASED PHI

阴离子通过增加 PHI 引起的神经管缺陷

基本信息

批准号：
3465182
负责人：
MICHAEL David COLLINS
金额：
$ 9.3万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-07-01 至 1993-06-30
项目状态：
已结题

项目摘要

Specific organic aliphatic monocarboxylic acids (or their anions), such as the anticonvulsant valproic acid or the metabolites of environmental contaminants, 2-methoxyacetic acid and 2-ethylhexanoic acid, are teratogenic in more than a single species. These agents cause a wide variety of types of malformations depending on the gestational time at which the agent is administered. After determining that the embryonic intracellular pH (pHi) is increased following the administration of a teratogenic dose of 2-ethylhexanoic or valproic acid, but unchanged after a higher but non-teratogenic dose of 2-ethylhexanoic or valproic acid, but unchanged after a higher but non-teratogenic dose of the naturally occurring fatty acid, 1-octanoic acid, a hypothesis was formulated. The hypothesis was that increases in embryonic pHi were the mechanism of action by which the monocarboxylates induce congential malformations. This study will specifically analyzee the relationship of neural tube defects to increases in pHi because these agents are known to produce strain specific neural tube defects in vivo, the failure of neural tube closure can be readily detected in whole embryo culture, and valproic acid is a suspected human neural tube teratogen. The basic hypothesis will be analyzed from three perspectives. First, the strength of the association between neural tube teratogenicity and increased embryonic pHi will be determined by evaluating these parameters in teratogenic and non-teratogenic monocarboxylic acids. The association will also be evaluated via the use of inbred strains of mice, one of which has been found to be susceptibel to valproic acid-induced neural tube teratogenesis (SWV) while the other has been shown to be resistant (C57BL/6). Second, the mechanism by which the organic acids cause and increase in embryonic pHi will be explored. These studies will focus on the inhibition of three membrane transport processes which may be involved in the regulation of embryonic pHi, specifically, the Na+/H+ antiporter, the monocarboxylate/transporter, and the Cl-/HCO3- exchanger. Third, this proposal will explore several hypothesized biochemical pathways by which the increase in embryonic pHi may cuase defects. Analysis of one of these pathways suggests that an increase in glycolytic flux causes an increase in lactate which is teratogenic. Analysis of a second pathway suggests that an increase in glycolytic flux causes an increase in lactate which is teratogenic. Analysis of a second pathway suggests that the activation of Na+/K+ ATPase usurps the embryonic ATP supply inducing malformations.

特定的有机脂肪族单羧酸（或其阴离子），例如抗惊厥药丙戊酸或环境代谢物污染物，2-甲氧基乙酸和2-乙基己酸，对多个物种具有致畸作用。这些药剂会引起广泛的不同类型的畸形取决于妊娠时间施用该药剂。确定胚胎后施用 a 后细胞内 pH (pHi) 升高 2-乙基己酸或丙戊酸的致畸剂量，但在服用后没有变化较高但非致畸剂量的 2-乙基己酸或丙戊酸，但是在较高但非致畸剂量的天然药物后没有变化出现脂肪酸，1-辛酸，提出了一个假设。这假设胚胎 pHi 的增加是作用机制单羧酸盐可引起先天性畸形。这项研究下面将具体分析神经管缺陷与 pHi 增加，因为已知这些试剂会产生菌株特异性体内神经管缺陷，神经管闭合失败可在整个胚胎培养物中很容易检测到，丙戊酸是可疑的人类神经管致畸剂。基本假设将从三个角度进行分析。首先，神经管致畸性与相关性的强度胚胎 pHi 的增加将通过评估这些参数来确定致畸和非致畸一元羧酸。协会还将通过使用近交系小鼠进行评估，其中之一已发现对丙戊酸诱导的神经管敏感致畸（SWV），而另一种已被证明具有耐药性 (C57BL/6)。二、有机酸引起的机理将探讨胚胎 pHi 的增加。这些研究将集中于可能涉及的三个膜转运过程的抑制在胚胎 pHi 的调节中，特别是 Na+/H+ 反向转运蛋白，单羧酸盐/转运蛋白和 Cl-/HCO3- 交换蛋白。三、这个该提案将探索几种假设的生化途径胚胎 pHi 的增加可能会导致缺陷。分析其中之一途径表明，糖酵解通量的增加会导致乳酸，具有致畸作用。对第二条途径的分析表明糖酵解通量的增加导致乳酸增加，即致畸。对第二条途径的分析表明， Na+/K+ ATP 酶侵占胚胎 ATP 供应，导致畸形。