Preconceptional Lipid-Based Nutrient Supplementation in 2 Low-Resource Countries Results in Distinctly Different IGF-1/mTOR Placental Responses

Marisol Castillo-Castrejon, Ivana V Yang, Elizabeth J Davidson, Sarah J Borengasser, Purevsuren Jambal, Jamie Westcott, Jennifer F Kemp, Ana Garces, Sumera A Ali, Sarah Saleem, Robert L Goldenberg, Lester Figueroa, K Michael Hambidge, Nancy F Krebs, Theresa L Powell, Marisol Castillo-Castrejon, Ivana V Yang, Elizabeth J Davidson, Sarah J Borengasser, Purevsuren Jambal, Jamie Westcott, Jennifer F Kemp, Ana Garces, Sumera A Ali, Sarah Saleem, Robert L Goldenberg, Lester Figueroa, K Michael Hambidge, Nancy F Krebs, Theresa L Powell

Abstract

Background: Preconceptional maternal small-quantity lipid-based nutrient supplementation (SQLNS) improved intrauterine linear growth in low-resource countries as demonstrated by the Women First Preconception Maternal Nutrition Trial (WF). Fetal growth is dependent on nutrient availability and regulated by insulin-like growth factor 1 (IGF-1) through changes in placental transfer capacity, mediated by the mechanistic target of rapamycin (mTOR) pathway.

Objectives: Our objective was to evaluate the role of placental mTOR and IGF-1 signaling on fetal growth in women from 2 low-resource countries with high rates of stunting after they received preconceptional SQLNS.

Methods: We studied 48 women from preconception through delivery who were from Guatemala and Pakistan and received SQLNS or not, as part of the WF study. Placental samples were obtained at delivery (control, n = 24; SQLNS, n = 24). Placental protein or mRNA expression of eukaryotic translation initiation factor binding protein-1 (4E-BP1), ribosomal protein S6 (rpS6), AMP-activated protein kinase α (AMPKA), IGF-1, insulin-like growth factor receptor (IGF-1R), and pregnancy associated plasma protein (PAPP)-A, and DNA methylation of the IGF1 promoter were determined. Maternal serum IGF-1, insulin-like growth factor binding protein (IGFBP)-3, IGFBP-4, IGFBP-5, PAPP-A, PAPP-A2, and zinc were measured.

Results: Mean ± SEM maternal prepregnancy BMI differed between participants in Guatemala (26.5 ± 1.3) and Pakistan (19.8 ± 0.7) (P < 0.001). In Pakistani participants, SQLNS increased the placental rpS6(T37/46):rpS6 ratio (1.5-fold) and decreased the AMPKA(T172):AMPKA ratio. Placental IGF1 mRNA expression was positively correlated with birth length and birth weight z-scores. Placental PAPP-A (30-fold) and maternal serum zinc (1.2-fold) increased with SQLNS. In Guatemalan participants SQLNS did not influence placental mTOR signaling. Placental IGF-1R protein expression was positively associated with birth length and birth weight z-scores. SQLNS increased placental PAPP-A (40-fold) and maternal serum IGFBP-4 (1.6-fold).

Conclusions: In Pakistani pregnant women with poor nutritional status, preconceptional SQLNS activated placental mTOR and IGF-1 signaling and was associated with improved fetal growth. In contrast, in Guatemalan women SQLNS did not activate placental nutrient-sensing pathways. In populations experiencing childhood stunting, preconceptional SQLNS improves placental function and fetal growth only in the context of poor maternal nutrition. This trial was registered at clinicaltrials.gov as NCT01883193.

Keywords: maternal–fetal exchange; nutrition; pregnancy; stunting; zinc.

© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1
FIGURE 1
Effect of preconceptional SQLNS on placental AMPK and mechanistic target of rapamycin signaling in Pakistan (A–C) and Guatemala (D–F). The histogram shows the relative protein expression of the (A, D) AMPKA (T172):total AMPKA ratio, (B, E) rpS6 (S235/236):total rpS6 ratio, and (C, F) 4E-BP1 (T37/46):4E-BP1 ratio. Representative individual Protein Simple Western Blot capillaries are shown for total and phosphorylated proteins and vinculin as loading control. Data are presented as mean ± SEM, n = 12. *,**Different from control: *P < 0.05, **P < 0.005 (Student's unpaired t test). AMPKA, AMP-activated protein kinase α; rpS6, ribosomal protein S6; SQLNS, small-quantity lipid-based nutrient supplementation; 4E-BP1, eukaryotic translation initiation factor binding protein-1.
FIGURE 2
FIGURE 2
Effect of preconceptional SQLNS on, and the association of the IGF-1 axis with, birth length in Pakistani (A–D) and Guatemalan (E–H) study sites. (A, E) The histogram shows relative placental IGF1 mRNA expression by treatment arm (control, arm 3; SQLNS, arm 1) and site. Data are presented as mean ± SEM, n = 12. Pearson's correlation of (B, n = 19; F, n = 20) maternal serum concentration of IGF-1, (C, n = 19; G, n = 22) relative placental IGF1 mRNA expression, and (D, n = 19; H, n = 22) placental protein expression of IGF-1R with birth length z-score. AU, arbitrary units; IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor receptor; SQLNS, small-quantity lipid-based nutrient supplementation.
FIGURE 3
FIGURE 3
Associations between placental IGF1 gene promoter DNA methylation, placental IGF1 mRNA expression, and birth length z-score in Pakistan (A–D) and Guatemala (E–H). Pearson's correlation of placental DNA methylation of IGF1 gene promoter at the CpG 1132 site with (A, E, n = 24) relative placental mRNA expression of IGF1 and (C, n = 19; G, n = 22) birth length z-score. Pearson's correlation of placental DNA methylation of IGF1 gene promoter at the CpG 1077 site with (B, F, n = 24) relative placental mRNA expression of IGF1 and (D, n = 20; H, n = 22) birth length z-score. AU, arbitrary units; IGF-1, insulin-like growth factor-1.
FIGURE 4
FIGURE 4
Effect of preconceptional SQLNS on maternal serum concentration of IGFBP-3 and its association with fetal growth in Pakistan (A–C) and Guatemala (D–F). The histogram shows maternal serum concentrations of IGFBP-3 by treatment arm (control, arm 3; SQLNS, arm 1) and site. Data are presented as mean ± SEM (A, n = 10; D, n = 12). Pearson's correlation between maternal concentration of IGFBP-3 and (B, n = 19; E; n = 18) birth length z-score and (C, n = 19; F, n = 17) birth weight z-score by site. IGFBP-3, insulin-like growth factor binding protein-3; IGF-1, insulin-like growth factor-1; SQLNS, small-quantity lipid-based nutrient supplementation.
FIGURE 5
FIGURE 5
Effect of preconceptional SQLNS on maternal serum IGFBP-4 and its association with fetal growth in Pakistan (A–C) and Guatemala (D–F). The histogram shows maternal serum concentration of IGFBP-4 by treatment arm (control, arm 3; SQLNS, arm 1) and site. Data are presented as mean ± SEM (A, n = 11; D, n = 10). *Different from control, P < 0.05 (Student's unpaired t test). Pearson's correlation between maternal serum concentration of IGFBP-4 and (B, n = 18; E, n = 17) birth length z-score and (C, n = 19; F, n = 17) birth weight z-score by site. IGFBP-4, insulin-like growth factor binding protein-4; SQLNS, small-quantity lipid-based nutrient supplementation.
FIGURE 6
FIGURE 6
Effect of preconceptional SQLNS on maternal serum IGFBP-5 and its association with fetal growth in Pakistan (A–C) and Guatemala (D–F). The histogram shows maternal serum concentration of IGFBP-5 by treatment arm (control, arm 3; SQLNS, arm 1) and site. Data are presented as mean ± SEM (A, n = 11; D, n = 10). Pearson's correlation between maternal serum concentration of IGFBP-5 and (B, n = 18; E, n = 17) birth length z-score and (C, n = 19; F, n = 18) birth weight z-score by site. IGFBP-5, insulin-like growth factor binding protein-5; SQLNS, small-quantity lipid-based nutrient supplementation.
FIGURE 7
FIGURE 7
Effect of preconceptional SQLNS on placental protein expression of PAPP-A and its association with fetal growth in Pakistan (A–D) and Guatemala (E–H). The histogram shows relative placental protein expression of PAPP-A by treatment arm (control, arm 3; SQLNS, arm 1) and site (A, E). Data are presented as mean ± SEM, n = 12. Representative individual Protein Simple Western Blot capillaries are shown for PAPP-A and vinculin as loading control. **Different from control, P < 0.005 (Student's unpaired t test). Pearson's correlation between relative placental protein expression of PAPP-A and (B, n = 19; F, n = 22) birth length z-score, (C, n = 19; G, n = 22) birth weight z-score, and (D, n = 17; H, n = 19) placental area. AU, arbitrary units; PAPP-A, pregnancy associated plasma protein-A; SQLNS, small-quantity lipid-based nutrient supplementation.
FIGURE 8
FIGURE 8
Effect of preconceptional SQLNS on maternal serum concentration of zinc and its association with fetal growth in Pakistan (A–D) and Guatemala (E–H). The histogram shows maternal serum zinc concentration by treatment arm (control, arm 3; SQLNS, arm 1) and site. Data are presented as mean ± SEM (A, n = 12; E, n = 10). *Different from control, *P < 0.05 (Student's unpaired t test). Pearson's correlation between maternal zinc serum concentration and (B, n = 19; F, n = 17) birth length z-score, (C, n = 19; G, n = 17) birth weight z-score, and (D, n = 20; H, n = 19) relative placental protein expression of PAPP-A. AU, arbitrary units; PAPP-A, pregnancy associated plasma protein-A; SQLNS, small-quantity lipid-based nutrient supplementation.
FIGURE 9
FIGURE 9
Integrative model of examined variables in the maternal circulation and in the placenta. Representation of examined variables in the maternal circulation (left) associated with the regulation of the IGF-1 pathway: IGF-1; IGFBP-3, IGFBP-4, and IGFBP-5; PAPP-A and PAPP-A2; and zinc. Description of examined variables in the placenta (61) associated with the IGF-1/mechanistic target of rapamycin pathway and fetal growth: mRNA expression of IGF1; IGF-1R; AMPKA; rpS6; 4E-BP1; DNA methylation of IGF1 promoter at the CpG 1132 and 1077 sites; and SLC39A10. Study main findings are highlighted by circles. AMPKA, AMP-activated protein kinase α; Akt, protein kinase B; eIF4E, eukaryotic translation initiation factor 4E; IGFBP, insulin-like growth factor binding protein; IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor 1 receptor; mTORC1, mechanistic target of rapamycin complex 1; PAPP, pregnancy-associated plasma protein; rpS6, ribosomal protein S6; SLC39A10, zinc influx SLC39A transporter; S6K1, ribosomal protein S6 kinase β-1; 4E-BP1, eukaryotic translation initiation factor binding protein-1.

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