Cytomegalovirus Induces Embryonic Mouse Tooth Defects

Background: Cytomegalovirus (CMV) is one of the most common causes of major birth defects in humans. Of the approximately 8400 children born each year in the U.S. with CMV-induced birth defects, more than 1/3 of these children exhibit hypoplasia and hypocalcification of tooth enamel which results in incisal and cuspal attrition, as well as rampant dental caries.

Purpose: Our objective was to initiate the investigation of the pathogenesis of CMV-induced tooth defects.

Methods: Mouse Cap stage (E15) mandibular first molars were infected with mouse CMV (mCMV) in vitro in a chemically-defined organ culture system and analyzed utilizing histological and immunolocalization methodologies. The antiviral, acyclovir, was used to inhibit mCMV replication and comparisons made between mCMV-infected and acyclovir-treated, mCMV-infected teeth.

Results: Active infection of Cap stage molars for up to 15 days in vitro results in smaller, developmentally-delayed and dysmorphic molars characterized by shallow, broad and misshapen cusps, infected and affected dental papilla mesenchyme, poorly differentiated odontoblasts and ameloblasts, and no dentin matrix. We also demonstrate that the severity of mCMV-induced tooth defects is dose-dependent, as well as being dependent on initial stage and duration of viral infection. Initial protein localization studies suggest that the pathogenesis is mediated through NF-kB signaling and that there appears to be an unusual interaction between abnormal mesenchymal cells and surrounding matrix. Rescue with acyclovir indicates that mCMV replication is necessary to initiate and sustain progressive tooth dysmorphogenesis.

Conclusions: Our results indicate that mCMV-induced changes in signaling pathways severely delays, but does not completely interrupt, tooth morphogenesis. Importantly, our results demonstrate that this well-defined embryonic mouse organ culture system can be utilized to delineate the molecular mechanism underlying the CMV-induced tooth defects that characterize the Amelogenesis Imperfecta phenocopy seen in many CMV-infected children.

This research was supported by NIH grant RO1 DE014535 (TJ/MM).