Research ArticleReproductive Biology

Temperature-activated ion channels in neural crest cells confer maternal fever–associated birth defects

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Sci. Signal.  10 Oct 2017:
Vol. 10, Issue 500, eaal4055
DOI: 10.1126/scisignal.aal4055

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Fevers, TRPV channels, and birth defects

Cardiac and craniofacial birth defects are common, but many cannot be attributed to specific mutations. An environmental trigger associated with these birth defects is fever during the first trimester. Using chick or zebrafish embryos, Hutson et al. found that hyperthermia activated temperature-sensitive TRPV1 and TRPV4 ion channels in neural crest cells, which give rise to the tissues affected by the birth defects. The authors developed a noninvasive method of transiently activating TRPV1 or TRPV4 in neural crest cells in chick embryos to mimic fever-induced stimulation of these channels. TRPV1 or TRPV4 activation resulted in cardiac and craniofacial birth defects similar to those induced by fever. These results suggest that preventing TRPV1 and TRPV4 activation during first trimester febrile episodes may reduce the incidence of common forms of birth defects.

Abstract

Birth defects of the heart and face are common, and most have no known genetic cause, suggesting a role for environmental factors. Maternal fever during the first trimester is an environmental risk factor linked to these defects. Neural crest cells are precursor populations essential to the development of both at-risk tissues. We report that two heat-activated transient receptor potential (TRP) ion channels, TRPV1 and TRPV4, were present in neural crest cells during critical windows of heart and face development. TRPV1 antagonists protected against the development of hyperthermia-induced defects in chick embryos. Treatment with chemical agonists of TRPV1 or TRPV4 replicated hyperthermia-induced birth defects in chick and zebrafish embryos. To test whether transient TRPV channel permeability in neural crest cells was sufficient to induce these defects, we engineered iron-binding modifications to TRPV1 and TRPV4 that enabled remote and noninvasive activation of these channels in specific cellular locations and at specific developmental times in chick embryos with radio-frequency electromagnetic fields. Transient stimulation of radio frequency–controlled TRP channels in neural crest cells replicated fever-associated defects in developing chick embryos. Our data provide a previously undescribed mechanism for congenital defects, whereby hyperthermia activates ion channels that negatively affect fetal development.

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