Consequences of early gestational ozone exposure and fetal growth restriction on lung morphological changes in peri-adolescent rats: Influence of offspring sex
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Ambient air pollution exposure in pregnancy may affect fetal growth restriction (FGR). In turn, FGR is associated with impaired lung function in children that can persist into adulthood. Lung diseases linked to FGR include asthma, pulmonary hypertension, and chronic obstructive pulmonary disease (COPD). In the U.S., COPD prevalence is increasing, especially within the female population; and prevalence for both men and women is highest in urbanized areas. Hypothesis. We hypothesized that offspring from our ozone (O3)-induced model of FGR would be at risk for impaired lung functional growth and development. Methods. Timed-pregnant Long Evans rats were exposed for 2-days (4h/day) to air or 0.8 ppm O3 during implantation [gestation day 5-6]. After weaning, one female (F) and male (M) per litter were selected for this study. At 7 weeks-of-age, left lung lobes were inflated at 25 cm H2O pressure with 10% formalin for lung displacement volumes (n = 9-12/group). Transverse lung sections at @ airway (AW) 5, 8 and 15 were stained with H&E for airspace morphometry (AW8; n = 7-9/group) and trichrome for vascular morphometry (AW5, 8 and 15; n = 6/group). Student’s t tests were used to assess differences in F and M offspring separately to explore potential differences that may contribute to the COPD associations noted above. Results. Compared to corresponding Air-dam offspring by sex (F-A or M-A), no differences in body weight, length, or BMI were observed in O3-dam offspring (F-O3 or M-O3); however, M-A were @30% “heavier” and 10% “longer” than F-A offspring. F-O3 but not M-O3 offspring had significantly smaller lung displacement volumes (10%) and AW8 transverse lung sectional areas (15%). At AW8, the pulmonary artery appeared significantly thicker (medial layer by 30%; adventitial layer by 28%) in F-O3 but not in M-O3 offspring. Conversely, the number of alveoli and corresponding alveolar area within the AW8 lung section was significantly reduced (by 21% and 23%, respectively) in F-O3 but not M-O3 offspring. The number of ductal spaces and corresponding ductal area (at AW8) were not different; however, the mean ductal width was larger (by 12%) in F-O3 but not in M-O3 offspring. Hence, the % space occupied by alveoli in F-O3 offspring appeared to be significantly reduced (22% by area and 37% by volume estimation). Conclusion. These changes are consistent with impaired angiogenesis and decreased alveolarization in F-O3 offspring. Such alterations during early lung development may be important regarding long-term respiratory morbidity. Results further reveal the utility of this FGR model to provide biologic plausibility and insights into the consequences of early life exposure to ozone, a ubiquitous urban air pollutant. (Abstract does not reflect USEPA policy).