Early gestational ozone exposure impairs lung vascular and alveolar development in peri-adolescent female rats: Potential linkage to later life lung disease.

RATIONALE Air pollution exposure in pregnancy may affect fetal growth, and fetal growth restriction (FGR) is associ­ated with lung im­pairment that can persist into adulthood. Associated diseases include asthma, pulmonary hypertension (PH), and chronic obstructive pulmo­nary disease (COPD). METHODS Using our ozone (O3)-induced model of FGR, we hypothesized that offspring may have impaired lung development. Long Evans dams were exposed for 2-days (4h/day) to air or 0.8 ppm O3 during im­plan­tation [gestation day 5-6]. One female (F) and male (M) per litter were then necropsied 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 and used for airspace morphometry (AW8; n=7-9/group) or with trichrome for vascular morphometry (n=6/group). Differences in F and M offspring were assessed separately using Student’s t tests. RESULTS Compared to 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); but males were larger. F-O3 but not M-O3 offspring had significantly smaller lung displacement volumes (10%) and lung AW8 transverse areas (15%). In F-O3 but not in M-O3, the pulmonary artery (intimal + medial) layer was significantly thicker (38% and 29%) at AW5 and AW8, respectively; and the % medial wall thickness (MWT) of small (<125 µm) and medium (125-250 µm) vessels were significantly greater (53% and 44%) in F-O3 but not M-O3 offspring. Conversely, at AW8, alveoli number and area were significantly reduced (21% and 23%) in F-O3 but not M-O3. Alveoli number and %MWT were negatively correlated. Ductal space number and area were not different; however, the mean ductal width was larger (12%) in F-O3 but not in M-O3 offspring. Hence, the % space occupied by alveoli in F-O3 offspring was significantly reduced (22% by area and 37% by volume estimation). CONCLUSIONS The morphometric changes observed in F-O3 offspring are indicative of impaired angiogenesis and decreased alveolarization. Such changes during early lung de­velop­ment may predispose offspring to diseases such as PH or COPD. PH disproportionately affects women. In the U.S., COPD prev­a­lence is increasing, espe­cially in women. COPD prevalence for men and women is highest in urbanized areas. This FGR model provid­es biologic plausibility for potential con­se­quences of gestational exposure to ozone, a ubiqui­tous urban air pollutant. (USEPA funding; abstract does not reflect USEPA policy).  

Impact/Purpose

Air pollution exposure in pregnancy may affect fetal growth.  We have previously demonstrated that early gestational ozone exposure in rats resulted in fetal growth restriction.  For this investigation, we hypothesized that offspring from dams exposed to ozone early in gestation may have impaired lung development. Herein we showed that such exposure  impaired lung vascular and alveolar development in peri-adolescent female rats; and we discuss potential linkage to later life lung disease.

Citation

Dye, J., H. Nguyen, E. Stewart, Mette C. Schladweiler, A. Ledbetter, AND C. Miller. Early gestational ozone exposure impairs lung vascular and alveolar development in peri-adolescent female rats: Potential linkage to later life lung disease. American Thoracic Society (ATS) Annual conference, Washington DC, DC, May 19 - 24, 2023.