Sex-specific lung functional changes in adult mice exposed only to second-hand smoke in utero

Abstract

BackgroundAn increasing number of epidemiological and experimental studies have associated exposure to second-hand smoke (SHS) during pregnancy with adverse outcomes in newborns. As we have previously shown in mice, in utero exposure to SHS at critical stages of fetal development, results in altered lung responses and increased disease susceptibility upon re-exposure to irritants (SHS or ovalbumin) in adulthood. In this study, we asked whether the in utero SHS exposure alone is sufficient to alter lung structure and function in adult mice.MethodsPregnant BALB/c mice were exposed from days 6 to 19 of pregnancy to 10 mg/m3 of SHS or HEPA-filtered air. Male and female offspring (n = 13–15/group) were sacrificed at 15 weeks of age. We measured lung function with non-invasive and invasive methods, performed lung morphometric analysis on trichrome-stained lung tissue samples, and assessed lung gene expression via RNA sequencing and protein assays.Results In utero SHS exposure significantly increased mean linear intercept and decreased the surface area per unit volume of the lungs in both males and females, indicating perturbation in alveolar developmental processes. Tidal volume, minute volume and inspiratory capacity were significantly decreased compared with the controls only in male mice exposed in utero to SHS, suggesting that males are more sensitive than females to an SHS insult during lung development. This also suggests that in our model, lung structure changes may be necessary but are not sufficient to impair lung function. SERPINA1A, the mouse ortholog of human α1-antitrypsin, deficiency of which is a known genetic risk factor for emphysema, was down-regulated at the protein level in the in utero SHS-exposed mice. Additionally, DNMT3A protein expression was dysregulated, indicating that DNA methylation occurred in the lungs.ConclusionsOur results indicate that in utero SHS exposure alone alters both lung function and structure well into adulthood (15 weeks) in male mice. Furthermore, lung function alterations in this model are sex-specific, with males being more susceptible to in utero SHS effects. Overall, our data suggest that in utero SHS exposure alone can predispose to adult lung diseases.

Female vulnerability to the effects of smoking on health outcomes in older people

“…In HRS, men exposed to passive smoke had a higher risk of heart disease and stroke than women. In a mouse model of prenatal exposure to passive smoke, males had greater alteration in adult lung tidal volume [35].…”

“…Further studies of sex differences in response to cigarette smoke should consider physiologically distinct stages of the lifespan: development (0-18), young adulthood (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), middleage including post-menopause , and older ages when chronic diseases increase exponentially (60+). For example, a mouse model of air pollution toxicity had attenuated responses of lung and brain by middle-age (18 months) [46,47].…”

In utero exposure to cigarette smoke and effects across generations: A conference of animals on asthma

“…The observed pulmonary morphological changes could further indicate a higher susceptibility for COPD . This contention is supported by a study showing that in utero ETS exposure alone can be sufficient to induce lung structural changes …”

Perinatal nicotine with or without early life influenza infection leads to lung dysfunction with age.

“…Nicotine-induced alterations in alveolar size and abnormal lung function were most prominent in males. This is intriguing considering previous evidence of greater deleterious effects of nicotine or second-hand smoke on lung function in males (135,168). Other studies have shown similar differences in lung function, but did not examine the role of sex within their groups (114).…”

“…This suggests that the weight loss due to infection was not the factor driving lung functional abnormalities. Lastly, publications have shown that in animal models, males have been highly implicated to have decreased lung function compared to females, but only when an extrinsic factor (such as nicotine or smoke exposure) is involved (135,168,(241)(242)(243).…”