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Maternal effects of smoking continue long after birth

According to a new Yale-led study, early exposure to nicotine can trigger widespread genetic changes that affect brain cell synapses long after birth. The findings help explain why maternal smoking links to behavior changes such as attention deficit-hyperactivity disorder and addiction.


Nicotine affects a master regulator of how DNA is packaged, and goes on to influence the activity of genes crucial in forming and stabilizing synapses between brain cells. The study was published online May 30 in the journal Nature Neuroscience.

"When this regulator is induced in mice, they pay attention to a stimulus they should ignore,'' said Marina Picciotto, the Charles B.G. Murphy Professor of Psychiatry, professor in the Child Study Center and the Departments of Neuroscience and Pharmacology, and senior author of the paper.

An inability to focus is the hallmark of attention deficit hyperactivity disorder and other behavioral disorders, which have been linked to maternal smoking and exposure to second-hand smoke. However, scientists did not understand how early environmental exposure to smoking could create behavioral problems years later.


Picciotto's lab found that mice exposed to nicotine during early development did indeed develop behavioral problems that mimic symptoms of attention deficit disorder in humans.


After extensive genomic screening of those mice exposed to nicotine, they found higher levels of a key regulator of histone methylation. Methylation is a key process controlling gene expression — which means the ability of that gene to be turned off or on. Methylation changes how tightly or loosely DNA is wrapped within the chromosome. The researchers found that genes essential to the creation of brain synapses were heavily affected.

Furthermore, the scientists found that these genetic changes were maintained even in adult mice. However, when researchers inhibited that master regulator of histone methylation, the adult mice were calmer and no longer reacted to a stimulus they should ignore.

In a final test, they triggered expression of this regulator in mice never exposed to nicotine, and the mice exhibited behavior that mimicked attention deficit disorder.


"It is exciting to find a signal that could explain the long-lasting effects of nicotine on brain cell structure and behavior. It was even more intriguing to find a regulator of gene expression that responds to a stimulus like nicotine — which may change synapse and brain activity during development."

Marina Picciotto PhD, the Charles B.G. Murphy Professor of Psychiatry, Professor in the Child Study Center, Departments of Neuroscience and Pharmacology, and senior author of the paper.


Abstract
Developmental nicotine exposure causes persistent changes in cortical neuron morphology and in behavior. We used microarray screening to identify master transcriptional or epigenetic regulators mediating these effects of nicotine and discovered increases in Ash2l mRNA, encoding a component of a histone methyltransferase complex. We therefore examined genome-wide changes in trimethylation of histone H3 on Lys4 (H3K4me3), a mark induced by the Ash2l complex associated with increased gene transcription. A large proportion of regulated promoter sites were involved in synapse maintenance. We found that Mef2c interacts with Ash2l and mediates changes in H3K4me3. Knockdown of Ash2l or Mef2c abolished nicotine-mediated alterations of dendritic complexity in vitro and in vivo, and attenuated nicotine-dependent changes in passive avoidance behavior. In contrast, overexpression mimicked nicotine-mediated alterations of neuronal structure and passive avoidance behavior. These studies identify Ash2l as a target induced by nicotinic stimulation that couples developmental nicotine exposure to changes in brain epigenetic marks, neuronal structure and behavior.
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Jun 9, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   



Nicotine is a potent parasympathomimetic alkaloid found in nightshade plants (Solanaceae).
It's stimulant is also found in the leaves of Nicotiana rustica as well as in the tobacco plant —
Nicotiana tabacum (above). But it is also present, to a smaller extent. in various edible plants.
Image Credit: Public Domain


 


 

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