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Nicotine exposure declines quality of early embryos and disrupts placental structure by destabilizing Notch signaling pathway

ABSTRACT: Nicotine is a common environmental pollution which is diffused into the air in the form of cigarette smoke fumes. Due to its lipophilic nature, nicotine can rapidly transport through membrane barriers and spread throughout the body which leads to abnormalities in the human brain, heart and even the fatal. However, the effects of nicotine on early embryonic development remains elusive. In this study, we found that nicotine significantly affected early embryonic development with decreased blastocyst formation. In addition, embryos treated with nicotine caused increased level of ROS, DNA damage and cell apoptosis. By RNA sequencing analysis, we demonstrated that nicotine affected the expression of placental development genes. Consistently, we found that the placental development at E17.5 was impaired by nicotine exposure, with increased placental weight and disrupted placental structure. This was due to excessive activation of the Notch signaling pathway, since blocking Notch signal by DAPT treatment recovered abnormal placental weight and structure induced by nicotine exposure. We also observed that nicotine exposure could specifically cause promoter hypermethylation of Phlda2 (a maternally expressed imprinted gene associated with placental development) and lead to its abnormal expression. Overall, this study provides evidence that nicotine causes the declining quality of early embryo and leads to placental abnormalities related with over-activation of the Notch signaling pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE186660 | GEO | 2023/10/17

REPOSITORIES: GEO

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Project description: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. To demonstrate the effect of nicotine on craniofacial development, particularly palatogenesis, we delivered three different doses of nicotine (1.5, 3.0 and 4.5 mg/kg/day) into pregnant BALB/c mice throughout their entire pregnancy using subcutaneous osmotic mini-pump. We assessed the pups for morphological anomalies, as well as genome-wide mRNA (transcriptome) microarray analysis. Consistent administration of nicotine caused developmental retardation, still birth, low birth weight, and significant palatal size and shape abnormality in the pups. However, it did not cause obvious cleft palate. The microarray data analysis using IPA identified differential expression of genes involved in various biological pathways, particularly cancer, genetic diseases, and tissue development in response to consistent nicotine exposure. 6232 up-regulated and 6310 down-regulated genes were detected in nicotine-treated groups compared to the control. Moreover, 45% of the genes associated with cleft palate were found to be affected by nicotine. Alterations of a subset of differentially expressed genes were illustrated with hierarchal clustering and RT-PCR. We concluded that consistent nicotine exposure during pregnancy interferes with normal growth and development of the fetus including palatogenesis; however, this interference does not result in cleft palate, rather smaller palate size with persistent MES. To our knowledge, this is the first experiment revealing the impact of nicotine on the fetal palate transcriptome in mice. Total 8 samples were analyzed. Using an osmotic minipump, duplicate samples from palates of either sterile physiological saline or nicotine (1.5 mg/kg/day, 3.0 mg/kg/day, or 4.5 mg/kg/day)-treated newborn pups.

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Nicotine exposure declines quality of early embryos and disrupts placental structure by destabilizing Notch signaling pathway

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