ALTERED INTRACELLULAR PH AS A MECHANISM OF TERATOGENESIS

细胞内相位改变是致畸机制

• 批准号: 3316499
• 负责人: WILLIAM J SCOTT
• 金额: $ 7.69万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-04-01 至 1989-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3316499
• 关键词: acetazolamide; acid base balance; alcohols; autoradiography; carbon dioxide; carbonate dehydratase; carbonic anhydrase inhibitors; congenital skeletal disorder; gestational age; histogenesis; hypercapnia; prenatal growth disorder; radiotracer; teratogens

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.

乙酰唑胺诱发一种独特的和特征性的肢体畸形