Modeling the effects of nicotine and smoking exposures on the developing brain

Author(s): Daianna Gonzalez-Padilla,Leonardo Collado Torres,Keri Martinowich,Kristen R. Maynard,Andrew E. Jaffe

Affiliation(s): Lieber Institute for Brain Development

Social media: https://twitter.com/daianna_glez

Maternal smoking during pregnancy (MSDP) is a major health concern with significant implications for offspring health and well-being, including poor cognitive and behavioral outcomes that could be explained by the influence of prenatal tobacco exposure on brain development. Even when a lot has been investigated around prenatal smoking, very little is known about the nicotine-specific effects on the developing brain. This study performed a differential expression analysis (DEA) with RNA-seq data from frontal cortices of P0 pups born to mice that were either exposed to cigarette smoke or administered nicotine during pregnancy. This design enabled us to compare impacted genes across both conditions, finding 1010 differentially expressed genes (DEGs) in nicotine and 4165 DEGs in smoking (FDR<0.05, 19 nicotine-exposed vs 23 controls; 42 smoking-exposed vs 46 controls). Importantly, there were 496 DEGs upregulated in nicotine only, some of them involved in dopaminergic synapses and long-term depression. The analyses at the transcript and exon levels supported the results obtained at the gene level and revealed the existence of non-DE genes with DE transcripts and/or exons in nicotine that have to do with in utero embrionyc development and serotonin secretion. We also found that 4 out of 14 DEGs in human postmortem prefrontal cortices exposed to smoking (FDR<0.1), replicated in our exposed pups. Finally, this work identified novel exon-exon junctions, providing data for the discovery of potential new isoforms of the genes. This project involved writing novel code to compare gene and transcript-level results and is publicly available at https://github.com/LieberInstitute/smokingMouse_Indirects. These results highlight the importance of studying nicotine effects separately from smoking and the impact of nicotine alone on fetal brain development. The data is available through ExperimentHub under the package smokingMouse whose repository is https://github.com/LieberInstitute/smokingMouse. This project is my first ever first-author project and Bioconductor package as I’m a 3rd year LCG-UNAM undergrad. We aim to have a pre-print available on bioRxiv by the time Bioc2023 will be held.