Direct Effects of Nicotine on Cranial Growth and Development

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Here we seek to understand the direct effects of fetal and postnatal nicotine exposure on craniofacial growth and development. This area is significant as our knowledge of the concomitant effects of cigarettes have been well studied for birth defects, but little work has focused on the individual components such as nicotine. Electronic cigarettes have now entered the market without regulation and are being marketed as safe. As ~11% of pregnant women continue to smoke during pregnancy, electronic cigarettes or nicotine replacement therapies may be viewed as a safer alternative to cigarette smoking. However, our understanding of the effects of nicotine, the common component between cigarettes, electronic cigarettes, and nicotine replacement therapies, on the developing fetus, specifically the craniofacial skeleton, is poor. Smoking has been linked to an increased risk for the craniofacial birth defect, craniosynostosis. Craniosynostosis occurs in 1:1800-2500 live births and can present with a myriad of medical comorbidities including ocular proptoses, increased intracranial pressure, alter cranial volume, and mental retardation. Most diagnosed cases require neurosurgery to correct the deformity and restore normal growth trajectories. It is unknown if nicotine alone increases the risk for craniosynostosis, but nicotinic receptors have recently been identified within the growth sites of the calvaria (sutures). Here we aim to determine the effects of in utero and postnatal nicotine exposure in a dose by time of exposure manner to elucidate 1) if nicotine can alter craniofacial growth; 2) if there is a segregating effect by dose; and 3) if there is a window of susceptibility during which the fetus or infant would be most susceptible to these effects. The two areas of investigation of this project are: 1) Characterize the effect of in utero and postnatal (lactation) nicotine exposure on craniofacial growth. We will utilize our preclinical craniofacial growth model to determine the effects of nicotine in a dose by time manner. As we have previously identified nicotinic receptors within the growth sites of the skull we anticipate that increasing dose and time of exposure will result in measurable alterations in growth in our fetal and post-natal exposed animals. 2) Define the effects of nicotine on the cells of the cranial growth sites, the sutures. Nicotine is a potent stimulant drug known to have effects on cell metabolism. Here we will utilize cells garnered from the suture to determine the specific effect (proliferation, apoptosis, autophagy, osteogenesis, senescence) precipitated by nicotine exposure. In addition, we will determine the effect on nicotinic receptor expression a direct target of nicotine exposure.