Neuroepigenetics of prenatal nicotine exposure

Sci. Signal.  12 Jul 2016:
Vol. 9, Issue 436, pp. ec159
DOI: 10.1126/scisignal.aah5204

Nicotine intake through smoking and other forms of use while pregnant affects the health of the unborn child. Among other effects, exposure to nicotine during early development is associated with structural abnormalities in the cortex of the brain and with behavioral and mental disorders that occur in childhood and adulthood. In mice, nicotine exposure causes long-lasting changes in neuronal plasticity. Beyond the gestational (prenatal) period, the first three weeks of postnatal life of the mouse—a period roughly equivalent to the third trimester in humans—is a critical period of cortical development and maturation. Using a maternal transfer method that exposes pups to nicotine from conception to weaning, Jung et al. uncovered a molecular mechanism involving histone methylation that may mediate the persistent neuronal and behavioral effects of early nicotine exposure (see also Maldonado and Martin). Compared with those in control pups whose mother received saccharin in her drinking water, cortical neurons from pups whose mother had nicotine in her drinking water had increased spine density and branching complexity. Genomic analysis of cortical tissue dissected at 3 months of age, in which nicotine-exposed mice were nicotine-free since weaning at postnatal day 21 (P21), revealed nicotine-exposed mice had an increase in the expression of the gene encoding the methyltransferase Ash2l and a global increase in trimethylated histone 3 Lys4 (H3K4me3), a chromatin marker of transcriptional activity. Gene ontology and chromatin immunoprecipitation assays indicated that H3K4me3 was enriched at the promoters of genes associated with the regulation of synaptic function, including Mef2c. Mef2c has a role in dendritic remodeling and participates in a histone methylation complex with Ash2l. Exposure of cultured neural progenitor cells to nicotine increased the abundance of Ash2l and Mef2c, an effect that was blocked by either antagonists of heteromeric nicotinic acetylcholine receptors (nAchR) or an inhibitor of the nicotine-induced calcium-dependent depolarization. In utero electroporation-mediated knockdown of Ash2l or Mef2c prevented nicotine-induced increases in both cortical neuron remodeling (spine density and dendritic complexity) and passive avoidance behavior in P21 mice. The findings reveal an epigenetic mechanism and relevant target genes that mediate lasting physical and cognitive effects of early nicotine exposure.

Y. Jung, L. S. Hsieh, A. M. Lee, Z. Zhou, D. Coman, C. J. Heath, F. Hyder, Y. S. Mineur, Q. Yuan, D. Goldman, A. Bordey, M. R. Picciotto, An epigenetic mechanism mediates developmental nicotine effects on neuronal structure and behavior. Nat. Neurosci. 19, 905–914 (2016). [PubMed]

R. Maldonado, M. Martin, Epigenetics, behavior and early nicotine. Nat. Neurosci. 19, 863–864 (2016). [PubMed]