TOPLINE:

A mouse study found that paternal nicotine exposure was associated with sex-specific metabolic changes in offspring — female offspring had lower fasting glucose and insulin levels with enhanced adipose insulin signaling, whereas male offspring had lower insulin and glucagon levels along with altered liver transcriptional profiles, suggesting that paternal tobacco use could increase the risk for diabetes in descendants.

METHODOLOGY:

• Rising rates of metabolic diseases have spurred research that has shown that in addition to diet and activity, environmental toxicants — especially nicotine from cigarette smoking and e-cigarette use — act as endocrine disruptors that raise metabolic and cardiovascular risks and can have multigenerational effects. However, most studies have emphasized maternal exposure despite the higher prevalence of tobacco use among men.
• Researchers assessed the impact of paternal nicotine exposure on glucose metabolism, adipose tissue, and liver transcriptomes in male and female offspring by randomly assigning 3-week-old male mice to receive 200 μg/mL nicotine or 0.1% dimethyl sulfoxide (vehicle control) in drinking water for 6 weeks.
• After treatment, these exposed mice were mated with unexposed female mice to produce offspring for metabolic assessment.
• A total of 10 male and 10 female offspring per paternal exposure group were weaned at 3 weeks of age and placed on a synthetic diet for 5 weeks; five animals per group underwent a glucose tolerance test (GTT) at 6 weeks of age and an insulin tolerance test (ITT) at 7 weeks of age.
• The offspring were euthanized at 8 weeks after overnight fasting (about 16 hours); plasma was collected for measuring levels of metabolic hormones, and liver and gonadal white adipose tissue samples were collected and processed for RNA sequencing analyses.

TAKEAWAY:

• Female offspring of nicotine-exposed fathers had lower fasting glucose levels (measured after a 4-hour fast; GTT time 0) and lower glucose levels at 30 minutes during the GTT than female offspring of control mice; plasma insulin levels were also reduced at 8 weeks after overnight fasting.
• Transcriptomic analysis of gonadal white adipose tissues from female offspring of nicotine-exposed fathers revealed upregulation of genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) Insulin signaling pathway, suggesting enhanced insulin responsiveness and glucose uptake capacity in the adipose tissue.
• Male offspring had reduced plasma glucagon and insulin levels after overnight fasting, with liver transcriptomic analysis revealing downregulation of genes in the KEGG Glucagon signaling pathway and KEGG Insulin resistance pathway.
• Peroxisome proliferator-activated receptor (PPAR)-alpha and genes associated with the PPAR signaling pathway were underexpressed in the liver tissue of male offspring of nicotine-exposed fathers, indicating impaired fasting adaptation and reduced hepatic catabolic capacity; these transcriptomic patterns could plausibly increase long‑term susceptibility to metabolic disease, including insulin resistance and type 2 diabetes.

IN PRACTICE:

“Considering the evidence that male exposure can increase the likelihood of their children developing chronic diseases, it is crucial to incorporate male health into preconception care,” Raquel Chamorro-Garcia, the corresponding author of the study, said in a related press release.

SOURCE:

The study was led by Stephanie Aguiar, Department of Microbiology and Environmental Toxicology, University of California, Santa Cruz. It was published online in the Journal of the Endocrine Society.

LIMITATIONS:

According to the authors, limitations included the absence of information regarding other relevant tissues involved in glucose homeostasis such as the pancreas and muscles, the young age of animals at assessment (8 weeks), and lack of additional metabolomic data including liver lipidomics and insulin levels before and during GTT and ITT.

DISCLOSURES:

The study received support from the core center grant provided by the National Institute of Environmental Health Sciences, the University of California Office of the President Tobacco-Related Disease Research Program award, and University of California Santa Cruz Start-up Funds awarded to Chamorro-Garcia. The authors reported having no relevant conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.