Molecular impact of nicotine and smoking exposure on the developing and adult mouse brain

Maternal smoking during pregnancy (MSDP) is associated with cognitive and behavioral effects on offspring. Although neurodevelopmental effects of prenatal nicotine exposure (PNE) have been described, the extent to which the molecular impacts of MSDP are attributable to nicotine remains unclear. In addition, the molecular responses to cigarette smoke in the developing and mature brain have not been contrasted. Distinguishing nicotine-specific effects from broader consequences of tobacco exposure is required to inform therapies for affected newborns and cessation strategies for pregnant women. In this study, pregnant mice received nicotine or were exposed to chronic cigarette smoke, and RNA sequencing was performed on frontal cortices of postnatal day 0 pups and adult dams. A total of 1010 and 4165 differentially expressed genes (DEGs) were identified in the nicotine and smoking-exposed pup brain, respectively (19 nicotine-exposed vs 23 vehicle-exposed; 42 smoking-exposed vs 46 controls). PNE was related to dopaminergic synapses and long-term synaptic depression and MSDP to functions of the SNARE complex and vesicle transport. No DEGs at FDR<0.05 were found in adult mouse brain for any exposure (11 nicotine-administered vs 7 vehicle-administered; 10 smoking-exposed vs 11 controls), nor in whole blood of adult dams-analyzed as proxy for brain effects (12 smoking-exposed vs 11 controls). Nonetheless, 29% and 43% of DEGs in smoking-exposed pup brain replicated in blood and human prenatal brain, respectively. Results demonstrate shared and unique effects of PNE and MSDP on the developing brain, attenuated impacts on adult brain, and convergent gene targets in human brain.