During pregnancy, excess levels of the glucocorticoid stress hormone, cortisol, is known to significantly alter fetal brain networks and result in long-term cognitive and behavioral problems. As of 2019, the World Health Organization recognizes 10-20% of children and adolescents experience mental health disorders worldwide. Without proper diagnosis and treatment, these conditions dramatically impact the child?s development and impairs their potential to live a productive life. A significant advance for the field would be the discovery of a biosensor that produces biomarkers of prenatal cortisol exposure, which may aid in the prospective identification of individuals with a higher risk of mental health disorders. Coincidentally, fetal ameloblasts in primary teeth lay down and mineralize the enamel matrix during the same developmental window in which critical fetal brain networks are established during gestation, making ameloblasts attractive candidates for biosensors. Once the enamel matrix is produced, it remains a stable structure for the duration of development, eruption, and after shedding of the primary tooth, making the primary tooth matrix a promising source of biomarkers. In support of this possibility, our lab previously found that primary teeth collected from kindergarten children with high salivary cortisol reactivity have reduced tooth enamel thickness and density. Cortisol reactivity in children is associated with increased levels of prenatal cortisol. In this proposal, I aim to determine a panel of tooth matrix biomarkers related to elevated prenatal cortisol exposure, and to identify the mechanisms by which ameloblasts are natural biosensors of alterations in the prenatal environment. Therefore, I will test my central hypothesis that teeth store permanent, measurable records of cortisol exposure as a result of altered ameloblast proliferation and maturation during tooth formation. I will use the following specific aims for these studies.
Aim 1 : Determine a panel of physical tooth measurements associated with increased cortisol reactivity.
Aim 2 : Identify the cellular mechanisms by which cortisol affects tooth morphology and enamel mineralization. These proposed studies will allow me to identify tooth matrix biomarkers that, collectively, produce a signature for increased prenatal cortisol exposure. In addition, results from this study will provide the foundation for future studies to investigate how ameloblasts can biologically detect and record other prenatal environmental stressors known to impact fetal development. This proposed research plan, combined with my dental clinical training, will provide me with the skills and experience I need to become an independent investigator.
Elevated levels of the stress hormone, cortisol, during pregnancy permanently alters fetal physiology and raises the child?s vulnerability to develop mental health disorders in the future. Primary teeth formed during increased cortisol exposure, contain biomarkers that could be used to direct early interventions for children at risk of developing behavioral disorders. In this proposal, we will define a set of tooth matrix biomarkers associated with increased cortisol levels during pregnancy, and investigate the mechanisms that make developing tooth cells natural biosensors of our prenatal environment. ! !
