LACK OF CONCORDANCE BETWEEN HEAT-SHOCK PROTEINS AND THE DEVELOPMENT OF TOLERANCE TO TERATOGEN-INDUCED NEURAL-TUBE DEFECTS

The present study was undertaken to examine the role of heat shock res ponse in the development of tolerance and cross-tolerance in an in viv o murine model of teratogen-induced neural tube defects. The experimen tal paradigm designed to address this question was to utilize inbred m ouse strains that differed in their sensitivity to hyperthermia and va lproic acid induced neural tube defects, subjecting the dams to subter atogenic pretreatments with either heat or valproic acid at two differ ent timepoints during development prior to the administration of the t eratogenic insult. A statistically significant reduction in the freque ncy of neural tube defects and/or embryolethality following a pretreat ment in dams subsequently exposed to a teratogenic treatment was consi dered evidence for the induction of tolerance. This was observed in th e 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-degr ees-C pretreatment at 8:06 induced thermotolerance. There was no evide nce of tolerance induced in either mouse strain using valproic acid. O n the other hand, cross-tolerance was clearly demonstrated in this stu dy, with a low temperature (41-degrees-C) pretreatment successfully pr otecting SWV fetuses from a subsequent teratogenic treatment with valp roic acid, while valproic acid (200 mg/kg) was effective in reducing t he risk of hyperthermia-induced neural tube defects in the LM/Bc fetus es. In all instances, tolerance was induced in the absence of signific ant induction of hsp synthesis. The lack of concordance between hsps a nd thermotolerance suggests that some other factor(s) is involved in c onferring thermotolerance on developing murine embryos.