Down-Regulation of Placental Transport of Amino Acids Precedes the Development of Intrauterine Growth Restriction in Maternal Nutrient Restricted Baboons

Pantham, Priyadarshini; Rosario, Fredrick J.; Weintraub, Susan T.; Nathanielsz, Peter W.; Powell, Theresa L.; Li, Cun; Jansson, Thomas

doi:10.1095/biolreprod.116.141085

Cited by 55 publications

(53 citation statements)

References 47 publications

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“…Furthermore, the AA transporter systems L and ASCT2 in the placenta of women with preeclampsia and intrauterine growth restriction (IUGR) are quite different from normal [22], suggesting that AAs may play an important role in the disease mechanism. Lower fetal concentrations of most AAs are observed in the umbilical cord and muscle of IUGR fetuses, compared with normal birth weight fetuses [12,23,24], demonstrating the impaired transport of AAs from the maternal to the fetal circulation in IUGR pregnancies. In our study, we first discovered that most of the AAs decreased in the CHD group, and strong associations were detected between AAs and CHD.…”

Section: Discussionmentioning

confidence: 97%

Decreased Amino Acid Concentrations are Involved in Congenital Heart Disease

Lai

Zhang

et al. 2019

Ann Nutr Metab

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Objective: Congenital heart disease (CHD) is the most common malformation in China. In this study, we determined whether amino acids (AAs) in the amniotic fluid (AF) of patients with CHD changed and clarified whether AAs would affect the insulin-like growth factor type 1 receptor (IGF1R). Method: Fifty-seven AF samples from pregnant women carrying CHD-aﬀected (n = 17) or normal (n = 40) fetuses were collected. The AA concentrations were measured in AF by liquid chromatography-tandem mass spectrometry. The IGF axis-related and epigenetic marker proteins in AF after serial treatments were quantified using a multiple reaction monitoring approach. IGF1R and P300 were also confirmed by Western blot in AF without any treatment. Results: Most AAs decreased in the AF of patients with CHD. P300 and IGF1R decreased significantly in the CHD group. When H9C2 cells were cultured in one-half AA concentrations, the expression of P300 and IGF1R was reduced. Histone acetylation of the IGF1R promoter also decreased. Conclusion: Our data suggest that AAs decreased in the AF of patients with CHD. AAs may partly regulate the IGF1R through P300, which may be involved in heart development.

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Section: Discussionmentioning

confidence: 97%

Decreased Amino Acid Concentrations are Involved in Congenital Heart Disease

Lai

Zhang

et al. 2019

Ann Nutr Metab

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“…However, also direct fetal responses to hypoglycemia and reduced amino acids were shown to result in a reduction in mTOR signaling in fetal livers leading to reduced IGF-1 bioavailability and fetal growth restriction [13]. Interestingly, previous animal studies described undernutrition-mediated fetal and placental growth restriction to appear late in gestation after IGF-1/insulin and mTOR placental signaling changed due to early pregnancy undernutrition, showing a clear causality [14]. Similarly, in our present study fetal growth declined most prominently in the third trimester of pregnancy, resulting in smaller newborns and placentas in GB patients.…”

Section: Discussionmentioning

confidence: 99%

Intrauterine Fetal Growth Delay During Late Pregnancy After Maternal Gastric Bypass Surgery

et al. 2018

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Purpose To investigate intrauterine fetal growth development and birth anthropometry of fetuses conceived after maternal gastric bypass surgery. Materials and Methods Longitudinal cohort study describing longitudinal growth estimated by ultrasound on 43 singleton pregnancies after gastric bypass compared to 43 BMI-matched controls. Results In fetuses after maternal gastric bypass surgery, growth percentiles decreased markedly from the beginning of the second trimester until the end of the third trimester (decrease of 3.1 fetal abdomen circumference percentiles (95 %CI 0.9–5.3, p = 0.007) per four gestational weeks). While in the second trimester, fetal anthropometric measures did not differ between the groups, the mean abdomen circumference percentiles appeared significantly smaller during the third trimester in offspring of mothers after gastric bypass (mean difference 25.1 percentiles, p < 0.001). Similar tendencies have been observed in estimated fetal weight resulting in significantly more SGA offspring at delivery in the gastric bypass group. In children born after maternal gastric bypass surgery, weight percentiles (32.12th vs. 55.86th percentile, p < 0.001) as well as placental weight (525.2 g vs. 635.7 g, p < 0.001) were significantly reduced compared to controls. Conclusion In fetuses conceived after maternal gastric bypass, intrauterine fetal growth distinctively declined in the second and third trimester, most prominently observed in fetal abdomen circumferences. Birth weight and placental weight at birth was significantly lower compared to BMI-matched controls, possibly due to altered maternal metabolic factors and comparable to mothers experiencing chronic hunger episodes.

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“…This has been evidenced by studies in women demonstrating that the activity of key amino acid transport systems A and L is reduced in FGR (Glazier et al 1997;Jansson et al 1998). In addition, animal studies have shown that reductions in placental system A activity precede FGR (Jansson et al 2006;Pantham et al 2016) and that blockade of system A by substrate inhibition results in reduced fetal growth (Cramer et al 2002). Collectively, these studies illustrate the importance of placental amino acid transport for appropriate growth of the fetus and suggest that reductions in amino acid transport may result in FGR.…”

Section: Introductionmentioning

confidence: 96%

Evidence of adaptation of maternofetal transport of glutamine relative to placental size in normal mice, and in those with fetal growth restriction

McIntyre

Hayward

Sibley

et al. 2019

The Journal of Physiology

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Key points Fetal growth restriction (FGR) is a major risk factor for stillbirth and has significant impact upon lifelong health. A small, poorly functioning placenta, as evidenced by reduced transport of nutrients to the baby, underpins FGR. It remains unclear how a small but normal placenta differs from the small FGR placenta in terms of ability to transfer nutrients to the fetus. Placental transport of glutamine and glutamate, key amino acids for fetal growth, was assessed in normal mice and those with FGR. Glutamine and glutamate transport was greater in the lightest versus heaviest placenta in a litter of normally grown mice. Placentas of mice with FGR had increased transport capacity in mid‐pregnancy, but this adaptation was insufficient in late pregnancy. Placental adaptations, in terms of increased nutrient transport (per gram) to compensate for small size, appear to achieve appropriate fetal growth in normal pregnancy. Failure of this adaptation might contribute to FGR. Abstract Fetal growth restriction (FGR), a major risk factor for stillbirth, and neonatal and adulthood morbidity, is associated with reduced placental size and decreased placental nutrient transport. In mice, a small, normal placenta increases its nutrient transport, thus compensating for its reduced size and maintaining normal fetal growth. Whether this adaptation occurs for glutamine and glutamate, two key amino acids for placental metabolism and fetal growth, is unknown. Additionally, an assessment of placental transport of glutamine and glutamate between FGR and normal pregnancy is currently lacking. We thus tested the hypothesis that the transport of glutamine and glutamate would be increased (per gram of tissue) in a small normal placenta [C57BL6/J (wild‐type, WT) mice], but that this adaptation fails in the small dysfunctional placenta in FGR [insulin‐like growth factor 2 knockout (P0) mouse model of FGR]. In WT mice, comparing the lightest versus heaviest placenta in a litter, unidirectional maternofetal clearance (Kmf) of 14C‐glutamine and 14C‐glutamate (glutamineKmf and glutamateKmf) was significantly higher at embryonic day (E) 18.5, in line with increased expression of LAT1, a glutamine transporter protein. In P0 mice, glutamineKmf and glutamateKmf were higher (P0 versus wild‐type littermates, WTL) at E15.5. At E18.5, glutamineKmf remained elevated whereas glutamateKmf was similar between groups. In summary, we provide evidence that glutamineKmf and glutamateKmf adapt according to placental size in WT mice. The placenta of the growth‐restricted P0 fetus also elevates transport capacity to compensate for size at E15.5, but this adaptation is insufficient at E18.5; this may contribute to decreased fetal growth.

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Down-Regulation of Placental Transport of Amino Acids Precedes the Development of Intrauterine Growth Restriction in Maternal Nutrient Restricted Baboons

Cited by 55 publications

References 47 publications

Decreased Amino Acid Concentrations are Involved in Congenital Heart Disease

Decreased Amino Acid Concentrations are Involved in Congenital Heart Disease

Intrauterine Fetal Growth Delay During Late Pregnancy After Maternal Gastric Bypass Surgery

Evidence of adaptation of maternofetal transport of glutamine relative to placental size in normal mice, and in those with fetal growth restriction

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