NEURAL TUBE DEFECTS INDUCED BY ANIONS VIA INCREASED PHI

具体的有机脂族单羧酸（或其阴离子）， 如抗惊厥药丙戊酸或其代谢物 环境污染物，2-甲氧基乙酸和2- 乙基己酸在不止一个物种中具有致畸性。 这些代理人造成各种类型的畸形 取决于药剂被施用的妊娠时间， 管理。 在确定胚胎细胞内 在施用致畸剂后，pH（pHi）增加， 2-乙基己酸或丙戊酸的剂量，但在 较高但无致畸性剂量的2-乙基己酸或丙戊酸 酸，但在较高但非致畸剂量的 天然存在的脂肪酸，1-辛酸，一个假设是 制定了 假设胚胎中pHi的增加 是单羧酸盐的作用机制 导致先天畸形 这项研究将具体 分析神经管缺陷与神经细胞增殖的关系， 因为已知这些试剂产生菌株特异性 在体内神经管缺陷，神经管闭合失败， 在整个胚胎培养中容易检测到，丙戊酸是 一种疑似人类神经管致畸剂 基本假设将从三个角度进行分析。 第一，神经管之间的关联强度 致畸性和增加的胚胎pHi将通过 评价致畸和非致畸的这些参数 一元羧酸 该协会还将通过评估 使用近交系小鼠，其中一种已被发现 对丙戊酸诱导的神经管致畸作用敏感 (SWV)而另一个已被证明是抗性的（C57 BL/6）。 第二，有机酸引起和 将探索胚胎pHi增加。 这些研究将 重点抑制三种膜转运过程 其可能参与胚胎pHi的调节， 特别是Na+/H+反向转运蛋白， 单羧酸/转运蛋白和C1-/HCO 3-交换剂。 第三，这个建议将探讨几个假设的生化 胚胎pHi升高可能导致 缺陷 对其中一种途径的分析表明， 糖酵解通量的增加导致乳酸盐的增加， 致畸的 对第二种途径的分析表明， 糖酵解通量的增加导致乳酸盐的增加， 致畸的 对第二种途径的分析表明， Na ~+/K ~+ ATP酶的激活取代了胚胎的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.