Narotsky M G, Francis E Z, Kavlock R J
ManTech Environmental Technology, Inc., Research Triangle Park, North Carolina 27709.
Fundam Appl Toxicol. 1994 Feb;22(2):251-65. doi: 10.1006/faat.1994.1029.
The anticonvulsant valproic acid (VPA), or 2-propylpentanoic acid, is a short-chain aliphatic acid that is teratogenic in humans and rodents. VPA and 14 related chemicals were screened for developmental toxicity using the Chernoff/Kavlock assay. Test agents, in corn oil, were administered by gavage to Sprague-Dawley rats once daily during organogenesis. The dams were allowed to deliver and the pups were examined postnatally. Segment II studies were also conducted using VPA and pentanoic acid in rats and with VPA in CD-1 mice. In both mice and rats, VPA caused transient maternal ataxia and developmental defects of the digits and, especially, the axial skeleton. Exencephaly, however, was seen only in mice. The screening protocol was effective in prioritizing agents within this class of compounds for more definitive developmental toxicity testing. All congeners tested induced maternal respiratory effects and six compounds caused motor depression. Only 2-ethylhexanoic (2EH) and 2-propylhexanoic (2PH) acid caused dramatic VPA-like effects on rat development (including mortality, extra presacral vertebrae, fused ribs, and delayed parturition), confirming the strict structural requirements for developmental toxicity previously reported for acute exposure in mice. The incorporation of skeletal examinations in the Chernoff/Kavlock assay enabled the detection of the sole developmental effect (increased incidence of lumbar ribs) of 2-butylhexanoic acid. VPA, 2EH, and 2PH were among the compounds that caused maternal motor depression. These data, consistent with previous reports, indicate a broader specificity for activity in the adult nervous system than that in the developing system and suggest differing mechanisms for the two effects.
抗惊厥药丙戊酸（VPA），即2-丙基戊酸，是一种短链脂肪酸，对人类和啮齿动物具有致畸性。使用切尔诺夫/卡夫洛克试验筛选了VPA和14种相关化学物质的发育毒性。将溶于玉米油中的受试物在器官形成期每天经口灌胃给予斯普拉格-道利大鼠一次。让母鼠分娩，并在产后检查幼崽。还使用VPA和戊酸对大鼠以及VPA对CD-1小鼠进行了第二阶段研究。在小鼠和大鼠中，VPA均导致母体短暂性共济失调以及指骨尤其是中轴骨骼的发育缺陷。然而，仅在小鼠中观察到了脑膨出。该筛选方案有效地对这类化合物中的药物进行了优先级排序，以便进行更明确的发育毒性测试。所有测试的同系物均引起母体呼吸效应，六种化合物导致运动抑制。只有2-乙基己酸（2EH）和2-丙基己酸（2PH）对大鼠发育产生了类似VPA的显著影响（包括死亡率、骶前椎骨增多、肋骨融合和分娩延迟），证实了先前报道的急性暴露于小鼠时发育毒性的严格结构要求。在切尔诺夫/卡夫洛克试验中纳入骨骼检查能够检测到2-丁基己酸的唯一发育效应（腰肋发生率增加）。VPA、2EH和2PH是导致母体运动抑制的化合物。这些数据与先前的报道一致，表明在成体神经系统中的活性特异性比在发育中的系统中更广泛，并提示这两种效应的机制不同。
