Protein Deficiency and Intestinal Nematode Infection in Pregnant Mice Differentially Impact Fetal Growth through Specific Stress Hormones, Growth Factors, and Cytokines>1–3

Abstract

Background: Protein deficiency (PD) and intestinal nematode infections commonly co-occur during pregnancy and impair fetal growth, but the complex network of signals has not been explored.Objective: Our objective was to assess those stress hormones, growth factors, and cytokines affected by maternal PD and nematode infection and associated with fetal growth.Methods: Using a 2 × 2 factorial design, CD-1 mice, fed protein-sufficient (PS; 24%) or protein-deficient (PD; 6%) isoenergetic diets, were either uninfected or infected every 5 d with Heligmosomoides bakeri, beginning on gestational day (GD) 5. Biomarker concentrations were measured on GD 18 in maternal serum (m), fetal serum (f), and amniotic fluid (af) by using Luminex.Results: Maternal PD lowered fetal body mass (PS/uninfected 1.25 ± 0.02 g, PS/infected 1.19 ± 0.02 g vs. PD/uninfected 1.11 ± 0.02 g, PD/infected 0.97 ± 0.02 g; P = 0.02), fetal lung (P = 0.005), and liver (P = 0.003) but not brain mass, whereas maternal infection lowered fetal length (PS/uninfected 2.28 ± 0.02 cm, PD/uninfected 2.27 ± 0.03 cm vs. PS/infected 2.21 ± 0.03 cm, PD/infected 2.11 ± 0.02 cm; P = 0.05) and kidney mass (P = 0.04). PD elevated stress hormones (m–adrenocortiotropic hormone, f-corticosterone, af-corticosterone) and reduced insulin-like growth factor 1 in all compartments (P ≤ 0.01), but these were unassociated with fetal mass or length. Fetal mass was positively associated with f-leptin (R2 = 0.71, P = 0.0001) and negatively with fetal cytokines [tumor necrosis factor-α: R2 = 0.62, P = 0.001; interleukin-4 (IL-4): R2 = 0.63, P = 0.0004]. In contrast, maternal infection lowered f-prolactin (P = 0.02) that was positively associated with fetal length (R2 = 0.43; P = 0.03); no other biomarker was affected by infection. Regression analyses showed associations between organ growth, cytokines, and growth factors: 1) thymus, spleen, heart, and brain with m–IL-10; 2) brain and kidney with f–vascular endothelial growth factor, af–monocyte chemotactic protein 1, af–interferon-γ, and af-eotaxin; and 3) liver and lung with f-leptin and af-corticosterone (all P ≤ 0.02).Conclusions: PD and nematode infection impaired fetal mass and linear growth, respectively. Fetal mass, length, and individual organ masses were regulated by different hormones, growth factors, and cytokines.