NEURAL TUBE DEFECTS INDUCED BY ANIONS VIA INCREASED PHI

特定的有机脂肪族单羧酸(或其阴离子)， 如抗惊厥剂丙戊酸或其代谢物 环境污染物2-甲氧基乙酸和2-甲氧基乙酸 乙基己酸，在不止一个物种中具有致畸作用。 这些物质会导致多种类型的畸形。 取决于代谢物的孕期 管理。在确定胚胎细胞内 服用致畸药物后，pH(Phi)升高 2-乙基己酸或丙戊酸的剂量，但在 高剂量但无致畸作用的2-乙基己酸或丙戊酸 酸，但在较高但无致畸作用的剂量后没有变化 自然产生的脂肪酸，1-辛酸，一个假说是 公式化的。假设是胚胎PHI的增加 是单羧酸盐的作用机制 诱发等位畸形。这项研究将具体地 分析神经管缺陷与生长发育迟缓的关系 PHI，因为已知这些制剂能产生特定的菌株 神经管在体缺陷，神经管闭合失败可 在整个胚胎培养中很容易检测到，丙戊酸是 疑似人类神经管畸形症患者。 基本假设将从三个角度进行分析。 第一，神经管之间的联系的强度 致畸性和胚胎PHI增加将通过以下方式确定 在致畸和非致畸中评估这些参数 一元羧酸。该协会还将通过以下方式进行评估 使用近亲繁殖的小鼠品系，其中一种已被发现 易患丙戊酸致神经管畸形 (SWV)，而另一株已被证明具有抗药性(C57BL/6)。 第二，有机酸引起和 胚胎PHI的增加将被探索。这些研究将 关注对三种膜转运过程的抑制 这可能参与了胚胎phi的调节， 具体地说，Na+/H+逆向转运蛋白 单羧酸盐/转运体和C1-/HCO3-交换体。 第三，这项建议将探索几个假想的生化 胚胎PHI升高可能导致的途径 缺陷。对其中一条途径的分析表明， 糖酵解通量的增加会导致乳酸的增加，这是 致畸胎。对第二条途径的分析表明， 糖酵解通量的增加会导致乳酸的增加，这是 致畸胎。对第二条途径的分析表明， Na+/K+ATPase激活侵占胚胎ATP供应 导致畸形。

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 C1-/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.