Maternal supplementation with citrulline or arginine during gestation impacts fetal amino acid availability in a model of intrauterine growth restriction (IUGR)

Clin Nutr. 2020 Dec;39(12):3736-3743. doi: 10.1016/j.clnu.2020.03.036. Epub 2020 Apr 10.


Background: Supplementing maternal diet with citrulline or arginine during gestation was shown to enhance fetal growth in a model of IUGR induced by maternal dietary protein restriction in the rat.

Objective: The aims of this study were to determine in the same model whether maternal supplementation with citrulline or arginine would increase 1) citrulline and arginine concentration in fetal circulation; 2) the expression of placental amino acid transporters, and 3) the fetal availability of essential amino acids.

Methods: Pregnant rats (n = 8 per group) were fed either an isocaloric control (20% protein, NP) or a low protein (LP, 4% protein) diet, either alone or supplemented with 2 g/kg/d of l-citrulline (LP + CIT) or isonitrogenous Arginine (LP + ARG) in drinking water throughout gestation. Fetuses were extracted by C-section on the 21st day of gestation. The gene expression of system A (Slc38a1, Slc38a2, and Slc38a4) and L (Slc7a2, Slc7a5, Slc7a8) amino acid transporters was measured in placenta and amino acid concentrations determined in maternal and fetal plasma.

Results: Maternal LP diet decreased fetal (4.01 ± 0.03 vs. 5.45 ± 0.07 g, p < 0.0001) and placental weight (0.617 ± 0.01 vs. 0.392 ± 0.04 g, p < 0.001), by 26 and 36% respectively, compared with NP diet. Supplementation with either CIT or ARG increased fetal birth weight by ≈ 5 or 11%, respectively (4.21 ± 0.05 and 4.48 ± 0.05 g vs. 4.01 ± 0.03 g, p < 0.05). CIT supplementation produced a 5- and 2-fold increase in fetal plasma citrulline and arginine, respectively, whereas ARG supplementation only increased fetal arginine concentration. LP diet led to lower placental SNAT 4 mRNA, and higher LAT2 and SNAT1 expression, compared with NP. SNAT4, 4hFC, LAT2 mRNA were up-regulated in LP + CIT and LP + ARG group compared with the un-supplemented LP group. Higher level of LAT1 mRNA was also observed in the LP + CIT group than in the LP group (p < 0.01). SNAT2 expression was unchanged in response to CIT or ARG supplementation. Fetal amino acid concentrations were decreased by LP diet, and were not restored by CIT or ARG supplementation.

Conclusions: The current findings confirm supplementation with citrulline or arginine enhances fetal growth in a rat model of IUGR. They further suggest that: 1) citrulline and arginine administered orally to the pregnant mother may reach fetal circulation; 2) citrulline effectively raises fetal arginine availability; and 3) although it failed to increase the concentrations of essential amino acids in fetal plasma, citrulline or arginine supplementation upregulates the gene expression of several placental amino acid transporters.

Keywords: Amino acids; Developmental origins of health and disease (DOHAD); Gestation; Placenta; Undernutrition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / drug effects*
  • Animals
  • Arginine / administration & dosage
  • Citrulline / administration & dosage*
  • Diet, Protein-Restricted
  • Dietary Supplements*
  • Disease Models, Animal
  • Female
  • Fetal Development / drug effects
  • Fetal Growth Retardation / etiology
  • Fetal Growth Retardation / prevention & control*
  • Fetus / drug effects*
  • Maternal Nutritional Physiological Phenomena
  • Pregnancy
  • Prenatal Care / methods
  • Rats


  • Amino Acids
  • Citrulline
  • Arginine