Title: Inducible 70 kDa heat shock proteins protect embryos from teratogen-induced exencephaly: Analysis using Hspa1a/a1b knockout mice.

Authors: Barrier, Marianne; Dix, David J; Mirkes, Philip E

Published In Birth Defects Res A Clin Mol Teratol, (2009 Aug)

Abstract: BACKGROUND: It is well known that a variety of teratogens induce neural tube defects in animals; however, less is known about proteins that play a role in protecting embryos from teratogen-induced neural tube defects. Previously, our laboratory has shown that embryos overexpressing the 70-Da heat shock proteins (HSPs) Hspa1a and Hspa1b were partially protected from the deleterious effects of exposure to hyperthermia in vitro. METHODS: In the present studies, we have used a transgenic mouse in which both of the stress-inducible HSPs Hspa1a and Hspa1b were deleted by homologous recombination. Time-mated Hspa1a/a1b(-/-) (KO) and wildtype (WT) mice were exposed to hyperthermia in vivo on gestational day 8.5. RESULTS: Results show that 52% of the gestational day 15 fetuses from KO litters were exencephalic, whereas only 20% of WT fetuses were affected. In addition, 6% of treated KO fetuses also exhibited eye defects (microphthalmia and anopthalmia), defects not observed in WT fetuses exposed to hyperthermia. Lysotracker red staining and caspase-3 enzyme activity were examined within 10 hours after exposure to hyperthermia, and significantly greater levels of apoptosis and enzyme activity were observed in the KO embryos compared with WT embryos. CONCLUSIONS: These results show that embryos lacking the Hspa1a and Hspa1b genes are significantly more sensitive to hyperthermia-induced neural tube and eye defects, and this increased sensitivity is correlated with increased amounts of apoptosis. Thus, these results also suggest that Hspa1a and Hspa1b play an important role in protecting embryos from hyperthermia-induced congenital defects, possibly by reducing hyperthermia-induced apoptosis.

PubMed ID: 19639652

MeSH Terms: Animals; Disease Models, Animal; Embryonic Development/drug effects; Eye Abnormalities/chemically induced; Eye Abnormalities/embryology; Eye Abnormalities/prevention & control; Female; Fever/embryology*; Gene Expression Regulation, Developmental*; HSP70 Heat-Shock Proteins/genetics; HSP70 Heat-Shock Proteins/metabolism*; Heat-Shock Response; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural Tube Defects/embryology; Neural Tube Defects/etiology; Neural Tube Defects/prevention & control*; Pregnancy; Teratogens/toxicity*