Introduction: Chronic obstructive pulmonary disease (COPD) is Canada’s fifth leading cause of death and is primarily caused by smoking. However, only <20% of smokers develop COPD, suggesting that other factors are important. Early-life exposures may also increase COPD risk by impairing lung development and altering response to cigarette smoke (CS). Maternal diabetes (MD) increases the risk for premature birth and childhood asthma, which are risk factors for COPD. However, the direct impact of MD on offspring susceptibility towards CS and COPD remains unexplored. I hypothesize that exposure to MD worsens CS induced lung damage in offspring.

Methods: Six-week-old C57BL/6NJ female mice were fed with a high-fat diet (HFD-45% kcal) to induce diabetes-like features or low-fat (LFD-10% kcal) control-diet for 6-weeks, and throughout pregnancy and weaning. Weaned offspring were fed standard research chow-diet until 8-weeks of age, at which point they were exposed to CS/Room air for 50 mins, twice/day, for four days. Lung function and inflammation were assessed on day five. Lung tissues were collected for DNA methylation and gene expression analysis. Data were analyzed in Prism GraphPad using two-way ANOVA, significance set at p<0.05.

Results: Offspring from diabetic pregnancy were significantly heavier at 3-weeks than controls. At 8-weeks the body weight difference maintained only in males. CS exposure significantly increased total lung resistance (14%) and airway resistance (18%) in HFD male offspring compared to control. HFD influenced CS induced immune cell infiltration in a sex-specific manner. Female HFD-CS offspring had significantly decreased neutrophils, CD4+ T-cells and NK cells compared to control-smokers. Male HFD-CS offspring had significantly elevated B-cells and NKT cells compared to HFD-control. At baseline, HFD female offspring had elevated Eotaxin and MIG but reduced IL-1α. CS induced cytokine changes in control animals, which were sex specific, were blunted in HFD exposed offspring. Additionally, I observed changes in gene abundance (Igf, Igfbp3 and Ephx1), but without specific changes in DNA methylation in smoking individuals from diabetic pregnancy.

Conclusion: MD alters offspring susceptibility towards CS-induced lung dysfunction and inflammation, in a sex-specific manner. MD may modulate response to cigarettes in early adulthood, suggesting a propensity to future COPD.