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Dads' Exercise and Nicotine Exposure Affect Children’s Cognitive and Metabolic Health

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The results of studies by researchers at Florida State University College of Medicine suggest that nicotine exposure in men could lead to cognitive deficits in their children and grandchildren. The research found that adding nicotine to the drinking water of male mice led to epigenetic changes in sperm cell genes that might impact on key neurodevelopmental pathways. The immediate offspring of these nicotine-exposed male mice exhibited hyperactivity, attention deficit, and cognitive issues that are typical of those found in attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder in humans. The grandchildren of the nicotine-exposed fathers also demonstrated learning deficits, suggesting that at least some of the detrimental nicotine-related effects can be passed down through generations.

“Our data raise the possibility that some of the cognitive disabilities found in today’s generation of children and adults may be attributable to adverse environmental insults suffered a generation or two ago,” suggests Pradeep Bhide, Ph.D., the Jim and Betty Ann Rodgers eminent scholar chair of developmental neuroscience at Florida State University College of Medicine. “Cigarette smoking was more common and more readily accepted by the population in the 1940s, ’50s, and ’60s compared to today. Could that exposure be revealing itself as a marked rise in the diagnoses of neurodevelopmental disorders such as ADHD and autism?”

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The Florida State University team and colleagues at Harvard Medical School published their findings in PLOS Biology, in a paper titled, “Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants.”

Studies have shown that nicotine use by pregnant women is associated with an increased risk of behavioral disorders in their children and in subsequent generations, the authors write. But in reality smoking is more prevalent in men than in women, and while studies in humans have suggested that paternal cigarette smoking can increase the risk of ADHD in their children, “human studies cannot fully separate the effects of paternal smoking from those of genetic and environmental factors.” ADHD and nicotine addiction often go hand-in-hand, and ADHD tends to run in families, so it can be difficult separating the role of paternal ADHD from paternal smoking on behavioral changes observed in offspring.

To investigate the effects of paternal nicotine on offspring the team exposed male mice to nicotine in their drinking water for 12 weeks, and then bred the mice with drug-naïve females. Both male and female offspring (F1) were then bred with drug-naïve partners to produce a second (F2) generation of animals originating from the nicotine-exposed fathers.

Tests in the resulting litters showed that both male and female F1 offspring of the nicotine-exposed fathers displayed increased spontaneous locomotor activity and deficits in reversal learning. The male offspring also exhibited “significant deficits in attention, brain monoamine content, and dopamine receptor mRNA expression,” the team comments. And while the hyperactivity and attention deficit phenotypes evident in the F1 mice weren’t transmitted to second-generation offspring, the male F2 mice did display deficits in reversal learning.

An examination of the nicotine-exposed fathers’ sperm cells showed changes to global DNA methylation, and in particular, there were changes to DNA methylation at promotors of the dopamine D2 receptor gene. Dopamine receptors play a key role in neurodevelopmental processes. “Nicotine-induced spermatozoal DNA methylation at dopamine receptor promoter regions may be a plausible epigenetic mechanism for transgenerational transmission of the effects of the paternal nicotine exposure,” the authors suggest.

“In analyzing spermatozoa from the father we found multiple genes with epigenetic changes,” comments co-author Deirdre MCarthy, Ph.D., research faculty at Florida State University College of Medicine. “This includes the dopamine D2 gene, which has an important role in brain development and learning. This is the likely source for the cognitive deficits found in their descendants.”

The fact that only some of the deficits evident in F1 offspring were also found in F2 male offspring suggests that “at least some of the deleterious effects of the nicotine exposure may be transient,” they continue, although the team acknowledges that more research will be needed. “These findings underscore the need to enlarge the current focus of research and public policy targeting nicotine exposure of pregnant mothers by a more equitable focus on nicotine exposure of the mother and the father.”

“I believe the findings from our study can be extrapolated to humans,” Dr. Bhide adds. “Doctors may not warn men that their smoking could be harming their unborn child even if the mother never smoked. I believe our study brings this to the fore.”

Within the last couple of weeks, researchers at Ohio State University Wexner Medical Center independently reported studies in mice, which showed that a father’s level of exercise prior to conception may have long-lasting effects on their childrens’ metabolic health. A team headed by Kristin Stanford, Ph.D., assistant professor at Ohio State University, bred high fat diet-fed obese male mice that were either sedentary or that had free access to running wheels, with female mice that were fed on a normal diet. They found that while the offspring of the sedentary obese fathers had more fat and demonstrated increased glucose intolerance than offspring of fathers fed a normal, chow diet, paternal exercise suppressed the effects of the paternal high-fat diet, and their offspring demonstrated better glucose metabolism, lower body weight, and decreased fat mass.

In the field of metabolic diseases, we are proud of our portfolio of stable and effective animal models, especially those for Non-alcoholic Fatty Liver Disease (NAFLD). Though popular recently, they still lack effective drug treatment.

“Here’s what’s really interesting, Dr. Stanford comments. “Offspring from the dads fed a high-fat diet fared worse, so they were more glucose intolerant. But exercise negated that effect. When the dad exercised, even on a high-fat diet, we saw improved metabolic health in their adult offspring.”

An examination of the fathers’ sperm cells showed that the high-fat diet was associated with decreased sperm motility and multiple changes to sperm small RNA, which could be reversed by exercise training. … We saw a strong change in their small-RNA profile,” Dr. Stanford adds. Now we want to see exactly which small-RNAs are responsible for these metabolic improvements, where it’s happening in the offspring and why.”

The studies were reported in Diabetes (“Paternal Exercise Improves Glucose Metabolism in Adult Offspring”). The Ohio State University researchers believe that their mouse studies may have direct relevance to humans. “There’s potential for this to translate to humans,” Dr. Stanford comments. “We know that in adult men obesity impairs testosterone levels, sperm number, and motility, and it decreases the number of live births … If we ask someone who’s getting ready to have a child to exercise moderately, even for a month before conception, that could have a strong effect on the health of their sperm and the long-term metabolic health of their children.”

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