Investigating the Links between Lower Iron Status in Pregnancy and Respiratory Disease in Offspring Using Murine Models

Abstract

Maternal iron deficiency occurs in 40-50% of all pregnancies and is associated with an increased risk of respiratory disease and asthma in children. We used murine models to examine the effects of lower iron status during pregnancy on lung function, inflammation and structure, as well as its contribution to increased severity of asthma in the offspring. A low iron diet during pregnancy impairs lung function, increases airway inflammation, and alters lung structure in the absence and presence of experimental asthma. A low iron diet during pregnancy further increases these major disease features in offspring with experimental asthma. Importantly, a low iron diet increases neutrophilic inflammation, which is indicative of more severe disease, in asthma. Together, our data demonstrate that lower dietary iron and systemic deficiency during pregnancy can lead to physiological, immunological and anatomical changes in the lungs and airways of offspring that predispose to greater susceptibility to respiratory disease. These findings suggest that correcting iron deficiency in pregnancy using iron supplements may play an important role in preventing or reducing the severity of respiratory disease in offspring. They also highlight the utility of experimental models for understanding how iron status in pregnancy affects disease outcomes in offspring and provide a means for testing the efficacy of different iron supplements for preventing disease.

Keywords: asthma; iron deficiency; offspring; pregnancy; respiratory disease.

Figure 1

Protocols. (A) Six to eight-week-old, female wild type BALB/c mice (F0) received control chow (CC) or low iron diet (LID) from week 0. Timed mating occurred at week five and offspring weaned at three weeks of age. (B) Eight-week-old female offspring (F1) treated with house dust mite (HDM; 25 μg/50 μL Saline) or saline (Sal; 50 μL) five days/week for five weeks.

Figure 2

Low iron diet (LID) during pregnancy increases airway hyperresponsiveness (AHR), indicative of impaired lung function, in male and female offspring. Baseline lung function was assessed in terms of (A) central airway resistance (Rn), (B) tissue damping, (C) tissue elastance, (D) transpulmonary resistance (Rrs), (E) elastance (Ers), and (F) compliance (Crs). The response to methacholine provocation was assessed in terms of (G) Rn, (H) tissue damping, (I) tissue elastance, (J) Rrs, (K) Ers, (L) Crs. (A–F) Analysed by unpaired student t-test, (G–L) analysed by 2-way ANOVA and statistics at maximal dose from AHR curves presented. n = 10–16 mice per group. Data are presented as mean ± SEM (* p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001).

Figure 3

Low iron diet (LID) during pregnancy increases airway inflammation and collagen deposition in male and female offspring. (A) Total leukocytes, (B) macrophages, (C) eosinophils (D) neutrophils and (E) lymphocytes were enumerated in bronchoalveolar lavage fluid (BALF) at five weeks. Histopathology was assessed in terms of (F) mean alveolar diameter, (G) mucus secreting cells (MSCs) per μm of basement membrane (BM), (H) small airway collagen deposition and (I) airway-associated eosinophils. n = 10–16 mice per group. Analysed by unpaired student t-test. Data are presented as mean ± SEM (* p < 0.05; ** p < 0.01).

Figure 4

Low iron diet (LID) during pregnancy impairs lung function and increases AHR in female offspring in the absence and presence of HDM. Baseline lung function was assessed in terms of (A) central airway resistance (Rn), (B) tissue damping, (C) tissue elastance, (D) transpulmonary resistance (Rrs), (E) elastance (Ers), (F) compliance (Crs). Response to methacholine provocation was assessed in terms of (G) Rn, (H) tissue damping, (I) tissue elastance, (J) Rrs, (K) Ers, (L) Crs. (A–F) Analysed by one-way ANOVA with Fishers LSD and unpaired student t-test, (G–L) analysed by 2-way ANOVA and statistics at maximal dose from AHR curves presented. n = 5–7 mice per group. Data are presented as mean ± SEM (* p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001).

Figure 5

Low iron diet (LID) during pregnancy increases airway inflammation and collagen deposition in female offspring in the absence and presence of HDM. (A) Total leukocytes, (B) macrophages, (C) eosinophils (D) neutrophils and (E) lymphocytes were enumerated in bronchoalveolar lavage fluid (BALF) at five weeks. Histopathology was assessed in terms of (F) mucus secreting cells (MSCs) per μm of basement membrane (BM), (G) small airway collagen deposition and (H) airway-associated eosinophils. n = 5–7 mice per group. Data analysed by one-way ANOVA with Fishers LSD and unpaired student t-test Data are presented as mean ± SEM (* p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001).