Nicotine exposure of male mice produces behavioral impairment in F1 and F2 generations of offspring

Among cigarette-smoking pregnant mothers, studies have demonstrated an association with increased risk of behavioral disorders — not only in their children, but also in multiple generations of descendants [see Refs. 1–5 of the attached article]. Although maternal nicotine use is a considerable concern, more men smoke cigarettes than women. Some clinical studies have suggested that paternal cigarette smoking might adversely impact the child’s attention span, and might increase risk for attention deficit hyperactivity disorder (ADHD) in offspring.

However, human studies cannot fully separate the effects of paternal smoking from those of genetic and environmental factors. For example, ADHD and nicotine addiction are often seen together, and ADHD does tend to run in families — making it difficult to separate the genetics of paternal ADHD risk from the environment of paternal smoking, when studying behavioral changes in the offspring. Thus, experimental animal model systems can be valuable tools to “tease out” the (paternal) genetic, from the environmental, effect of nicotine on the developing baby while in the uterus, and then behavioral effects seen later in life.

Authors [see attached report] exposed male mice to nicotine (200 μg/mL in drinking water for 12 weeks) and then bred these male mice with “nicotine-naive” females — to produce the F1 generation; this was followed by breeding male and female F1 mice to produce the F2 generation. Both male and female mice in the F1 and F2 generations exhibited significant impairment in a number of behavioral traits, or phenotypes (such as significant increases in spontaneous locomotor activity and significant deficits in reversal learning).

The F1 generation was also found to have significant changes in monoamine neurotransmitter-signaling mechanisms in the brain (significant deficits in attention, brain monoamine content, and dopamine receptor mRNA expression). Analyzing spermatozoal DNA from the nicotine-exposed founder males, authors detected epigenetic modifications (significant changes in global DNA-methylation and DNA-methylation at promoter regions of the dopamine D2 receptor gene). Authors conclude that these alterations in DNA-methylation might be a plausible mechanism for the transgenerational transmission of the nicotine-induced behavioral and neurotransmitter phenotypes that were found.

PLoS Biol Oct 2o18; 16: e2006497

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