Nicotine Exposure During Pregnancy Results in Persistent Midline Epithelial Seam With Improper Palatal Fusion

Abstract

Introduction: Nonsyndromic cleft palate is a common birth defect (1:700) with a complex etiology involving both genetic and environmental risk factors. Nicotine, a major teratogen present in tobacco products, was shown to cause alterations and delays in the developing fetus. Methods: To demonstrate the postpartum effects of nicotine on palatal development, we delivered three different doses of nicotine (1.5, 3.0, and 4.5 mg/kg/d) and sterile saline (control) into pregnant BALB/c mice throughout their entire pregnancy using subcutaneous micro-osmotic pump. Dams were allowed to deliver (~day 21 of pregnancy) and neonatal assessments (weight, length, nicotine levels) were conducted, and palatal tissues were harvested for morphological and molecular analyses, as well as transcriptional profiling using microarrays. Results: Consistent administration of nicotine caused developmental retardation, still birth, low birth weight, and significant palatal size and shape abnormality and persistent midline epithelial seam in the pups. Through microarray analysis, we detected that 6232 genes were up-regulated and 6310 genes were down-regulated in nicotine-treated groups compared to the control. Moreover, 46% of the cleft palate-causing genes were found to be affected by nicotine exposure. Alterations of a subset of differentially expressed genes were illustrated with hierarchal clustering and a series of formal pathway analyses were performed using the bioinformatics tools. Conclusions: We concluded that nicotine exposure during pregnancy interferes with normal growth and development of the fetus, as well results in persistent midline epithelial seam with type B and C patterns of palatal fusion. Implications: Although there are several studies analyzing the genetic and environmental causes of palatal deformities, this study primarily shows the morphological and large-scale genomic outcomes of gestational nicotine exposure in neonatal mice palate.

α7 nAChR mediated Fas demethylation contributes to prenatal nicotine exposure-induced programmed thymocyte apoptosis in mice

“…The dose of 3 mg/kg/d of nicotine and the Balb/C strain were widely used to establish the PNE model for representing prenatal cigarette smoke exposure [ 30 – 32 ]. The 3 mg/kg/d dose of nicotine used in this study could equate to a moderate smoker during pregnancy (exposure to 6–8 cigarettes per day) [ 33 , 34 ].…”

Developmental toxicity of e‐cigarette aerosols

“…It readily crosses the placenta and is concentrated in the fetal compartment (Luck, Nau, Hansen, & Steldinger, 1985) where it binds to nicotinic acetylcholine receptors that are widely expressed throughout the fetal nervous system, lungs, and other fetal tissues (Hellström-Lindahl, Gorbounova, Seiger, Mousavi, & Nordberg, 1998;Wongtrakool, Wang, Hyde, et al, 2012). Both human and animal pregnancy exposure studies show nicotine to be a developmental toxicant (Lin, Yon, Jung, et al, 2012;Ozturk et al, 2016;Schneider, Bizarro, Asherson, & Stolerman, 2010;Wickström, 2007) that is capable of interfering with normal neurotransmitter function, resulting in apoptosis and mitotic abnormalities (Slotkin, 2008;Wickström, 2007;Zhao & Reece, 2005), inducing lung (Maritz & Harding, 2011) and neurodevelopmental abnormalities (Dwyer, Broide, & Leslie, 2008;Slotkin, Seidler, Qiao, et al, 2004), and causing genotoxic effects in human fetal cells in vitro (Demirhan et al, 2011). A recent review of extant human and animal research concerning the developmental toxicity of nicotine concluded that "….nicotine contributes critically to adverse effects of gestational tobacco exposure" (England et al, 2017).…”

Plausible Roles for RAGE in Conditions Exacerbated by Direct and Indirect (Secondhand) Smoke Exposure

“…As cigarettes are known to be one of the most common teratogens [112], a number of serious obstetric complications arise with cigarette smoke exposure during pregnancy [113]. Approximately 10% of pregnant women in the US smoke, thereby exposing nearly 400,000 fetuses yearly to tobacco specific toxins [114].…”

“…Approximately 10% of pregnant women in the US smoke, thereby exposing nearly 400,000 fetuses yearly to tobacco specific toxins [114]. Exposure to smoke during pregnancy has been demonstrated to increase the likelihood of congenital limb deficiencies [115], congenital heart defects [116], orofacial clefting [112], and many other developmental abnormalities. Active smoking has long been considered a teratogenic agent that increases the risk of premature birth, but recent data shows that 22%–30% of nonsmoking pregnant women exposed to SHS are also at risk [117].…”