RESUMEN
Congenital Zika Syndrome (CZS) is caused by vertical transmission of Zika virus (ZIKV) to the gestating human fetus. A subset of CZS microcephalic infants present with reduced otoacoustic emissions; this test screens for hearing loss originating in the cochlea. This observation leads to the question of whether mammalian cochlear tissues are susceptible to infection by ZIKV during development. To address this question using a mouse model, the sensory cochlea was explanted at proliferative, newly post-mitotic or maturing stages. ZIKV was added for the first 24 h and organs cultured for up to 6 days to allow for cell differentiation. Results showed that ZIKV can robustly infect proliferating sensory progenitors, as well as post-mitotic hair cells and supporting cells. Virus neutralization using ZIKV-117 antibody blocked cochlear infection. AXL is a cell surface molecule known to enhance the attachment of flavivirus to host cells. While Axl mRNA is widely expressed in embryonic cochlear tissues susceptible to ZIKV infection, it is selectively downregulated in the post-mitotic sensory organ by E15.5, even though these cells remain infectible. These findings may offer insights into which target cells could potentially contribute to hearing loss resulting from fetal exposure to ZIKV in humans.
Asunto(s)
Cóclea/embriología , Cóclea/virología , Enfermedades Cocleares/embriología , Enfermedades Cocleares/virología , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Muerte Celular , Enfermedades Cocleares/genética , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Técnicas de Cultivo de Embriones , Ratones , Técnicas de Cultivo de Órganos , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Infección por el Virus Zika , Tirosina Quinasa del Receptor AxlRESUMEN
Molecular mechanisms governing the development of the mammalian cochlea, the hearing organ, remain largely unknown. Through genome sequencing in 3 subjects from 2 families with nonsyndromic cochlear aplasia, we identified homozygous 221-kb and 338-kb deletions in a noncoding region on chromosome 8 with an approximately 200-kb overlapping section. Genomic location of the overlapping deleted region started from approximately 350 kb downstream of GDF6, which codes for growth and differentiation factor 6. Otic lineage cells differentiated from induced pluripotent stem cells derived from an affected individual showed reduced expression of GDF6 compared with control cells. Knockout of Gdf6 in a mouse model resulted in cochlear aplasia, closely resembling the human phenotype. We conclude that GDF6 plays a necessary role in early cochlear development controlled by cis-regulatory elements located within an approximately 500-kb region of the genome in humans and that its disruption leads to deafness due to cochlear aplasia.
Asunto(s)
Cromosomas Humanos Par 8 , Cóclea , Enfermedades Cocleares , Factor 6 de Diferenciación de Crecimiento , Elementos de Respuesta , Animales , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 8/metabolismo , Cóclea/embriología , Cóclea/patología , Enfermedades Cocleares/embriología , Enfermedades Cocleares/genética , Enfermedades Cocleares/patología , Femenino , Factor 6 de Diferenciación de Crecimiento/biosíntesis , Factor 6 de Diferenciación de Crecimiento/genética , Humanos , Masculino , Ratones , Ratones TransgénicosRESUMEN
OBJECTIVE: This study aimed to determine the effect of radiofrequency radiation generated by 900 and 1800 MHz Global System for Mobile Communications sources on cochlear development in the rat model. METHODS: Eight pregnant albino Wistar rats were divided into three groups: control, 900 MHz and 1800 MHz. The latter two groups of pregnant rats were exposed to radiofrequency radiation for 1 hour per day starting on the 12th day of pregnancy until delivery. The rats in the control, 900 MHz and 1800 MHz groups gave birth to 24, 31 and 26 newborn rats respectively. Newborn rats in the 900 MHz and 1800 MHz groups were exposed to radiofrequency radiation for 1 hour per day for 21 days after delivery. Hearing evaluations of newborn rats were carried out using distortion product otoacoustic emissions testing. Eight newborn rats were randomly selected from each group for electron microscopic evaluation. RESULTS: Distortion product otoacoustic emission tests revealed no significant difference among the groups, but electron microscopic evaluation revealed significant differences among the groups with regard to the number of normal, apoptotic and necrotic cells. CONCLUSION: The findings indicated cellular structural damage in the cochlea caused by radiofrequency radiation exposure during cochlear development in the rat model.