ALTERED INTRACELLULAR PH AS A MECHANISM OF TERATOGENESIS

乙酰唑胺诱导一个独特的和特征性的肢体畸形， 怀孕啮齿动物的后代。 致畸作用机制是 被认为是碳酸酐酶的抑制。 一个后效应 碳酸酐酶抑制作用提高了动脉和组织二氧化碳 我们现在已经证明母体二氧化碳 吸入会导致同样独特的前肢畸形， 乙酰唑胺作用机制是抑制碳酸酐酶的观点 致畸作用 本申请描述了将试图揭示 CO2干扰发育的机制。 我们假设二氧化碳 降低细胞内pH值（pHi），随后导致细胞内 增殖速度加快，从而导致肢体缩小畸形。 我们 将测量致畸剂处理后发育中的肢芽中的pHi， 尝试将任何变化与畸形结局和增殖性 率 肢芽细胞对内部pH值变化的反应能力将 记录和操作此过程将与 畸胎结局。 我们认为，降低胚胎细胞的细胞内pH值可能是一种有效的方法。 致畸的一般机制，并打算研究一种人类致畸剂， 酒精，可以想象，它可以通过这种机制发挥作用。

Acetazolamide induces a unique and characteristic limb deformity in the offspring of pregnant rodents. The teratogenic mechanism of action is thought to be inhibition of carbonic anhydrase. One after effect of carbonic anhydrase inhibition is raised arterial and tissue carbon dioxide content and we have now demonstrated that maternal carbon dioxide inhalation leads to the same unique forelimb deformity substantiating the idea that carbonic anhydrase inhibition is the mechanism of acetazolamide teratogenesis. This application describes experiments which will attempt to uncover the mechanism by which C02 perturbs development. We hypothesize that C02 lowers intracellular pH (pHi) which subsequently leads to decreased proliferative rate thereby leading to the limb reduction deformity. We will measure pHi in the developing limb bud after teratogen treatment and attempt to correlate any changes with teratologic outcome and proliferative rate. The ability of limb bud cells to respond to internal pH changes will be documented and manipulation of this process will be correlated with teratologic outcome. We believe that reducing the intracellular pH of embryonic cells may be a general mechanism of teratogenesis and intend to study one human teratogen, alcohol, which could conceivably act through this mechanism.