Lack of concordance between heat shock proteins and the development of tolerance to teratogen‐induced neural tube defects

Abstract

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.

Strain-dependent alterations in the expression of folate pathway genes following teratogenic exposure to valproic acid in a mouse model

“…In the more resistant LM/Bc strain, FBP-1 expression at gestational day 8:18 actually increases following the valproic acid treatment (Table II) to levels which were similar to those observed in the SWV embryos. Previously, our laboratory has shown that the SWV embryos lag behind the LM/Bc in their progression through neural tube closure [Finnell et al, 1993;Wlodarczyk et al, 1996;Finnell and Bennett, unpublished]. Therefore, it is quite possible that by gestational day 8:18, the LM/ Bc embryos had progressed to a stage of neural tube development which was immune to the slight perturbations in folate transport gene expression induced by valproic acid treatment.…”

Hyperthermia: malformations to chaperones

“…Likewise, it was shown that both resistant and susceptible strains to valproic acid-induced neural tube defects were protected by a prior 10-min 411C hyperthermia pretreatment (Finnell et al, 1993). However, in these two latter studies correlation between the induction of the heat-shock response and the thermoprotection to either cadmium or valproic acid was not specifically determined (Kapron-Bras and Hales, 1992;Finnell et al, 1993). Therefore, it appears that the heatshock response is a protective cellular mechanism that can be induced by numerous stresses.…”

“…Expanding this study to include both a susceptible (BALB/c) and resistant (SWV) mouse strain, it was demonstrated that the heat-pretreatment failed to significantly reduce the effects of cadmium on BALB/c embryos but did protect SWV embryos (Kapron-Bras and Hales, 1992). Likewise, it was shown that both resistant and susceptible strains to valproic acid-induced neural tube defects were protected by a prior 10-min 411C hyperthermia pretreatment (Finnell et al, 1993). However, in these two latter studies correlation between the induction of the heat-shock response and the thermoprotection to either cadmium or valproic acid was not specifically determined (Kapron-Bras and Hales, 1992;Finnell et al, 1993).…”

“…More specifically, studies demonstrated a protective or tolerant effect could be induced if embryos were exposed to a lower non-teratogenic temperature prior to the teratogenic insult. In embryos, thermotolerance was found to be acquired within 30-60 min and could last at least 6-8 h after the mild heat pretreatment (Mirkes, 1987;Walsh et al, 1987;Kapron-Bras and Hales, 1991;Finnell et al, 1993). Evidence implicated HSP70, in cell culture studies as well as those using embryos, as being a mediator of this phenomenon since its induction and degradation reflected the induction and decay of thermotolerance (Landry et al, 1982;Li, 1985).…”

Identification of a growth arrest specific (gas 5) gene by differential display as a candidate gene for determining susceptibility to hyperthermia-induced exencephaly in mice

“…Although the association between maternal hyperthermia exposure and NTDs in humans remains controversial, the wealth of literature supporting its teratogenicity in animals suggests that humans would, in all likelihood, respond similarly [Finnell et al, 1993]. In fact, a number of prospective and retrospective studies support a teratogenic association in humans [Miller et al, 1978;Milunsky et al, 1992;McDonald, 1958McDonald, , 1961Coffey and Jessop, 1959;Erickson, 1991;Fraser and Skeleton, 1978;Spragett and Fraser, 1982].…”