Finnell R H, Van Waes M, Bennett G D, Eberwine J H
Department of Veterinary Anatomy and Public Health, College of Veterinary Medicine, Texas A&M University, College Station 77843-4458.
Dev Genet. 1993;14(2):137-47. doi: 10.1002/dvg.1020140208.
The present study was undertaken to examine the role of heat shock response in the development of tolerance and cross-tolerance in an in vivo murine model of teratogen-induced neural tube defects. The experimental paradigm designed to address this question was to utilize inbred mouse strains that differed in their sensitivity to hyperthermia and valproic acid induced neural tube defects, subjecting the dams to subteratogenic pretreatments with either heat or valproic acid at two different timepoints during development prior to the administration of the teratogenic insult. A statistically significant reduction in the frequency of neural tube defects and/or embryolethality following a pretreatment in dams subsequently exposed to a teratogenic treatment was considered evidence for the induction of tolerance. This was observed in the SWV embryos exposed to the 38 degrees C pretreatment at 8:06 and to embryos exposed to either pretreatment temperature at 8:10 prior to a teratogenic heat shock at 8:12. In the LM/Bc embryos, only the 41 degrees C pretreatment at 8:06 induced thermotolerance. There was no evidence of tolerance induced in either mouse strain using valproic acid. On the other hand, cross-tolerance was clearly demonstrated in this study, with a low temperature (41 degrees C) pretreatment successfully protecting SWV fetuses from a subsequent teratogenic treatment with valproic acid, while valproic acid (200 mg/kg) was effective in reducing the risk of hyperthermia-induced neural tube defects in the LM/Bc fetuses. In all instances, tolerance was induced in the absence of significant induction of hsp synthesis. The lack of concordance between hsps and thermotolerance suggests that some other factor(s) is involved in conferring thermotolerance on developing murine embryos.
本研究旨在探讨热休克反应在致畸剂诱导神经管缺陷的体内小鼠模型中耐受性和交叉耐受性形成过程中的作用。为解决这一问题设计的实验范式是利用对热和丙戊酸诱导的神经管缺陷敏感性不同的近交系小鼠品系，在给予致畸性损伤之前，于发育过程中的两个不同时间点，对母鼠进行低于致畸剂量的热或丙戊酸预处理。在随后接受致畸性处理的母鼠中，预处理后神经管缺陷频率和/或胚胎致死率有统计学意义的降低被视为诱导耐受性的证据。这在8:06接受38摄氏度预处理的SWV胚胎以及8:10接受任一预处理温度、随后在8:12接受致畸性热休克的胚胎中观察到。在LM/Bc胚胎中，仅8:06的41摄氏度预处理诱导了热耐受性。使用丙戊酸在这两种小鼠品系中均未发现诱导耐受性的证据。另一方面，本研究清楚地证明了交叉耐受性，低温（41摄氏度）预处理成功保护SWV胎儿免受随后丙戊酸致畸性处理的影响，而丙戊酸（200mg/kg）有效降低了LM/Bc胎儿中热诱导神经管缺陷的风险。在所有情况下，耐受性的诱导均未伴随hsp合成的显著诱导。hsp与热耐受性之间缺乏一致性表明，一些其他因素参与了发育中小鼠胚胎热耐受性的赋予。
