In Utero Exposure to Maternal Electronic Nicotine Delivery System use Demonstrate Alterations to Craniofacial Development.

OBJECTIVE: Develop a model for the study of Electronic Nicotine Device (ENDS) exposure on craniofacial development. DESIGN: Experimental preclinical design followed as pregnant murine dams were randomized and exposed to filtered air exposure, carrier exposure consisting of 50% volume of propylene glycol and vegetable glycine (ENDS Carrier) respectively, or carrier exposure with 20 mg/ml of nicotine added to the liquid vaporizer (ENDS carrier with nicotine). SETTING: Preclinical murine model exposure using the SciReq exposure system. PARTICIPANTS: C57BL6 adult 8 week old female pregnant mice and exposed in utero litters. INTERVENTIONS: Exposure to control filtered air, ENDS carrier or ENDS carrier with nicotine added throughout gestation at 1 puff/minute, 4 h/day, five days a week. MAIN OUTCOME MEASURES: Cephalometric measures of post-natal day 15 pups born as exposed litters. RESULTS: Data suggests alterations to several facial morphology parameters in the developing offspring, suggesting electronic nicotine device systems may alter facial growth if used during pregnancy. CONCLUSIONS: Future research should concentrate on varied formulations and exposure regimens of ENDS to determine timing windows of exposures and ENDS formulations that may be harmful to craniofacial development.

In utero exposure to selective serotonin re-uptake inhibitor affects murine mandibular development.

OBJECTIVES: Antidepressants, specifically Selective Serotonin Re-uptake Inhibitors (SSRIs), that alter serotonin metabolism are currently the most commonly prescribed drugs for the treatment of depression. There is some evidence to suggest these drugs contribute to birth defects. As jaw development is often altered in craniofacial birth defects, the purpose of this study was to interrogate the effects of in utero SSRI exposure in a preclinical model of mandible development. MATERIALS AND METHODS: Wild-type C57BL6 mice were used to produce litters that were exposed in utero to an SSRI, Citalopram (500 µg/day). Murine mandibles from P15 pups were analysed for a change in shape and composition. RESULTS: Analysis indicated an overall shape change with total mandibular length and ramus height being shorter in exposed pups as compared to controls. Histomorphometric analysis revealed that first molar length was longer in exposed pups while third molar length was shorter in exposed as compared to control. Histological investigation of molars and surrounding periodontium revealed no change in collagen content of the molar in exposed pups, some alteration in collagen composition in the periodontium, increased alkaline phosphatase in molars and periodontium and decreased mesenchymal cell marker presence in exposed mandibles. CONCLUSION: The results of this study reveal SSRI exposure may interrupt mandible growth as well as overall dental maturation in a model of development giving insight into the expectation that children exposed to SSRIs may require orthodontic intervention.

rhBMP2 alone does not induce macrophage polarization towards an increased inflammatory response.

Once thought to have revolutionized therapeutic intervention in surgery, Recombinant Human Bone Morphogenic Protein 2 (rhBMP2) is now in its second decade of sustained controversy over the side effects associated with its use. Side effects associated with clinical use of rhBMP2 (Infuse, Medtronic Inc) include a marked inflammatory response, pain, therapeutic failures, ectopic bone, tissue degradation, and death. What is missing, despite the depth of literature on the subject, is a direct interrogation of rhBMP2, specifically for inflammation. Here we set out to determine if rhBMP2 alters traditional macrophage markers associated with pro-inflammatory responses, and pro-reparative responses to injury. Based on our previous work, we hypothesized there would be no direct effect of the peptide on macrophage polarization. Here we utilized commercially available murine macrophages, RAW 264.7, and treated these cells with rhBMP2 in standard growth media or macrophage polarizing media (M1 and M2) at several doses of the peptide. Our readouts were cell viability, apoptosis, gene expression of M1 and M2 markers, and ELISA for M1 marker iNOS, and M2 marker Arg1. Our data give very little evidence to support an alteration in macrophage phenotype by rhBMP2 alone, or alteration of the phenotype when cultured in enriched M1 or M2 media. These results further suggest that other factors associated with the clinical use of Infuse, likely supraphysiological rhBMP2 doses and off label usage, are more likely the culprit for poor outcomes. This further reinforces the utility of rhBMP2 and other peptides in tissue engineering therapies when conditions are tightly controlled.