Cigarette smoke exposure during pregnancy and its effect on the respiratory health of offspring

Cigarette smoking during pregnancy is particularly prevalent in Australia with as much as 8.8% of pregnant women reporting to have smoked cigarettes at some stage of their pregnancies. This is particularly alarming as the period of in utero development is a critical time for the fetus. Cigarette smoking during pregnancy has been linked to a host of morbidities in children including low birth weight, deficits in mental development, and abnormal lung development and function highlighting the need for models to investigate key mechanisms of smoking during pregnancy on lung development and function in offspring. This thesis reports on the development and characterisation of a novel murine model of cigarette smoke exposure and pregnancy. We aimed to use a murine model to recapitulate the clinical observations of a chronic smoker that becomes pregnant and continues to smoke throughout pregnancy and the breastfeeding period. We show that cigarette smoke exposure by a pregnant mother results in impaired lung function outcomes, inflammation of the airways, airway remodelling and increased markers of oxidative stress. We then demonstrated that in utero cigarette smoke exposure results in low birth weights, impaired lung function outcomes in early-life and altered transcriptional activity in the lungs. We then characterise our model’s use in investigating intergenerational and transgenerational inheritance of effects in the first, second and third generations of offspring. We demonstrated that while the first and second generation of offspring have deficits in lung development and function, the third generation does not. We further developed our model by exposing female mice to cigarette smoke only before or only after pregnancy. We showed that cigarette smoke exposure before or after pregnancy results in offspring that produce abnormal anti-viral responses when infected with influenza highlighting critical windows of influence for children not-yet-conceived, and in early life. In conclusion, cigarette smoking before, after and throughout pregnancy is detrimental to the mother, and affects her children and grandchildren.