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Maternal cigarette smoke exposure (CSE) continues to be a common prenatal exposure with approximately 10% of babies exposed in uteroduring the third trimester in the U.S. and is the predominant risk factor for having an infant that is small for gestational age (SGA). Cigarette smoke is a complex mixture of thousands of chemical compounds that may directly affect the developing fetus or indirectly affect growth by disrupting placenta development and function. The individual components of maternal cigarette smoke and the biological pathways which they perturb to adversely affect the developing fetus and placenta have not been fully explained. We investigated changes in the transcriptome and methylome using RNA sequencing (RNA-Seq, n=35) and whole genome bisulfite sequencing (WGBS, n=10) on early pregnancy placenta samples with or without maternal CSE. Overall, 204 transcripts (100 up-regulated, 104 down-regulated) were differentially expressed with maternal CSE (nominal p-value <0.01). As expected, CYP1A1 expression was induced in samples with maternal CSE. Other differentially expressed genes included CGB (p<10-3) which encodes the β subunit of human chorionic gonadotropin (hCG), important for the establishment and maintenance of pregnancy. WGBS identified 458 differentially methylated regions (each containing CpGs) enriched for binding sites of transcription factors with known function in trophoblast development and response to CSE including Oct1 and AhR. Regulatory networks of the methylation signatures were obtained by applying weighted correlation matrices which identified three modules (R=0.8, p<10-3) that associated with CSE. Targeted genes mapping to these modules were identified by GREAT and pathway analysis by DAVID was applied. Strikingly, Tobacco Use Disorder (N=69 genes, p=1.16x10-5) was the top associated disease. Among the genes with altered methylation was NRG1, which promotes extravillous trophoblast formation in placental explants. In conclusion, maternal CSE alters the transcriptome and the methylome of the placenta that provides insights into the mechanisms that may lead to the increased risk of SGA of infants exposed to maternal CSE in utero. This project was funded by the Cross Foundation, Center for Pediatric Genomic Medicine Pilot Program.

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Maternal Cigarette Smoke Exposure Induces Alterations in the Transcriptome and Methylome of Human Placenta