Newborn humans and rats malnourished in utero: free plasmal-tryptophan, neutral amino acids and brain serotonin synthesis

doi:10.1016/0006-8993(89)90687-2

Brain Research

Volume 488, Issues 1–2, 29 May 1989, Pages 1-13

https://doi.org/10.1016/0006-8993(89)90687-2 Get rights and content

Abstract

In the present study we report results concerning 5-hydroxytryptamine (5-HT) metabolism in two groups of small for date (SFD) human babies (gestational age 36 and 3 weeks), who suffered intrauterine nutritional restriction. A complementary study in the brain of rat fetuses with two types of intrauterine deprivation, in which brainl-tryptophan (l-Trp), tryptophan-5-hydroxylase (T5-H) activity and 5-HT content were determined on days 17, 19 and 21 of gestation. The same parameters studied prenatally were followed in both species during the immediate postnatal period. In the SFD babies the results were: (a) the free fraction of plasmal-Trp was significantly elevated; (b) plasma neutral amino acids were not substantially modified; (c) the bound fraction ofl-Trp and plasma proteins were significantly low, as compared to controls. In the fetal brain of intrauterine malnourished rats,l-Trp, activity of T5-H and 5-HT content, were significantly elevated, since day 17, as related to normal littermates. These alterations in 5-HT metabolism persisted during the early postnatal period in both species. Elevation of the free fraction of plasmal-Trp in early malnourished SFD human babies suggest an increased transport of this amino acid to the brain with a possible enhancement of serotonin synthesis, during a critical period of brain differentiation.

References (74)

AhmadG. et al.
Serotonin as a growth factor for chick embryo brain
Life Sci.
(1978)
BallardJ. et al.
A simplified score for assessment of fetal maturation of newly born infant
J. Pediatr.
(1979)
BermanJ.L. et al.
The metabolism of 5-hydroxytryptamine (serotonin) in the newborn
J. Pediatr.
(1965)
BloxamD.L. et al.
Error in determination of trptophan by the method of Denkla and Dewey. A revised procedure
Anal. Biochem.
(1974)
ChanezC. et al.
Long lasting effects of intrauterine growth retardation of 5-HT metabolism in the brain of developing rats
Brain Research
(1981)
CohenD.J. et al.
Central biogenic amine metabolism in children with the syndrome of chronic multiple tics of Gilles de la Tourette
Am. Acad. Child. Psychiatry
(1979)
GálE.M. et al.
Rapid nonisotopic assay of tryptophan-5-hydroxylase activity in tissues
Anal. Biochem.
(1973)
GromováH.A. et al.
Serotonin as a stimulator of hippocampal cell differentiation in tissue culture
Int. J. Dev. Neurosci.
(1983)
GuthrieH.A. et al.
Effect of severe under-nutrition in early life on growth, brain size and composition in adult rats
J. Nutr.
(1968)
HoshinoY. et al.
Plasma free tryptophan concentration in autistic children
Brain Dev.
(1986)

JequierE. et al.

Further studies on tryptophan hydroxylase in rat brainstem and beef pineal

Biochem. Pharmacol.

(1969)

KantakK.M. et al.

Effect of various periods of food deprivation on serotonin synthesis in the lateral hypothalamus

Pharmacol. Biochem. Behav.

(1978)

LauderJ.M.

Hormonal and humoral influences on brain development

Psychoneuroendocrinology

(1983)

LauderJ.M. et al.

In vivo and in vitro development of serotonergic neurons

Brain Res. Bull.

(1982)

LoscherW. et al.

l-5-Hydroxytryptophan. Correlation between anticonvulsant effect and increases in levels of 5-hydroxindoles in plasma and brain

Neuropharmacology

(1984)

LowryO.H. et al.

Protein measurement with the folin phenol reagent

J. Biol. Chem.

(1951)

McMenamyR.H. et al.

The specific binding ofl-tryptophan to serum albumin

J. Biol. Chem.

(1958)

MillerM. et al.

Tryptophan availability: relation to elevated brain serotonin in developmentally protein malnourished rats

Exp. Neurol.

(1977)

MillerM. et al.

Effects of developmental protein malnutrition on tryptophan utilization in brain and peripheral tissues

Brain Res. Bull.

(1977)

PardridgeW.M.

Tryptophan transport through the blood-brain barrier: in vivo measurement of free and albumin bound amino acid

Life Sci.

(1979)

Perez-CruetJ. et al.

Changes in brain serotonin metabolism associated with fasting and satiation in rats

Life Sci.

(1972)

SobotkaT.J. et al.

Neonatal malnutrition neurochemical, hormonal and behavioural manifestations

Brain Research

(1974)

SteinbuschH.W.M.

Distribution of serotonin immunoreactivity in the central nervous system of the rat cell bodies and terminals

Neuroscience

(1981)

SternW.C. et al.

Ontogeny of the levels of biogenic amines in various parts of the brain and in peripheral tissues in normal and protein malnourished rats

Exp. Neurol.

(1975)

TagliamonteA. et al.

Free tryptophan in serum controls brain tryptophan level and serotonin synthesis

Life Sci.

(1973)

TakahashiH. et al.

Distribution of serotonin-containing cell bodies in the brainstem of the human fetus determined with immunohistochemistry using antiserotonin serum

Brain Dev.

(1986)

TernauxJ.P. et al.

Peripheral and central 5-hydroxytryptamine in trisomy 21

Life Sci.

(1979)

Van PraagH.M. et al.

Central serotonin metabolism and frequency of depression

Psychiatry Res.

(1979)

Whitaker-AzmitiaP.M. et al.

Autoregulation of fetal serotonergic neuronal development: role of high affinity serotonin receptors

Neurosci. Lett.

(1986)

ApgarV.

A proposal for a new method of evaluation of the newborn infant

Curr. Res. Anesth. Analg.

(1953)

BourreJ.M. et al.

Influence of intrauterine malnutrition on brain development: alteration of myelination

Biol. Neonate

(1981)

ChaseH.P. et al.

The effect of malnutrition on the synthesis of myelin lipid

Pediatrics

(1967)

CurzonG. et al.

The effect of fatty acids on the binding of tryptophan to plasma protein

Nature (Lond.)

(1973)

CurzonG. et al.

Rapid method for the determination of 5-HT and 5-HIAA in small regions of rat brain

Br. J. Pharmacol.

(1970)

CurzonG. et al.

Drugs influencing plasma and brain tryptophan

Br. J. Pharmacol.

(1973)

DahlströmA. et al.

Evidence for the existence of monoamine containing neurons in the central nervous system

Acta Physiol. Scand.

(1964)

DenklaW.D. et al.

The determination of tryptophan in plasma, liver and urine

J. Lab. Clin. Med.

(1967)

Cited by (48)

Extreme enhancement or depletion of serotonin transporter function and serotonin availability in autism spectrum disorder
2019, Pharmacological Research
A variety of human and animal studies support the hypothesis that serotonin (5-hydroxytryptamine or 5-HT) system dysfunction is a contributing factor to the development of autism in some patients. However, many questions remain about how developmental manipulation of various components that influence 5-HT signaling (5-HT synthesis, transport, metabolism) persistently impair social behaviors. This review will summarize key aspects of central 5-HT function important for normal brain development, and review evidence implicating perinatal disruptions in 5-HT signaling in the pathophysiology of autism spectrum disorder. We discuss the importance, and relative dearth, of studies that explore the possible correlation to autism in the interactions between important intrinsic and extrinsic factors that may disrupt 5-HT homeostasis during development. In particular, we focus on exposure to 5-HT transport altering mechanisms such as selective serotonin-reuptake inhibitors or genetic polymorphisms in primary or auxiliary transporters of 5-HT, and how they relate to neurological stores of serotonin and its precursors. A deeper understanding of the many mechanisms by which 5-HT signaling can be disrupted, alone and in concert, may contribute to an improved understanding of the etiologies and heterogeneous nature of this disorder. We postulate that extreme bidirectional perturbations of these factors during development likely compound or synergize to facilitate enduring neurochemical changes resulting in insufficient or excessive 5-HT signaling, that could underlie the persistent behavioral characteristics of autism spectrum disorder.
Enteric and serological distribution of serotonin and its precursor tryptophan in perinatal low and normal weight piglets
2014, Animal
Perinatal mortality is high among small-for-gestational age (SGA) piglets and continues to be an economic burden and threat to animal welfare. As the physiological role of serotonin (5-hydroxytryptamine, 5-HT) in perinatal development and gastrointestinal function in the pig remains unknown, the aim of this study was to assess the enteric distribution of 5-HT cells and to determine 5-HT together with its precursor tryptophan in the serum of perinatal normal and SGA piglets. For this purpose, proximal and distal parts of the small intestine (SI) were processed for immunohistochemical analysis to assess the presence of 5-HT endocrine cells. Serum 5-HT was measured with ELISA, whereas its precursor, that is, the free fraction of tryptophan (FFT) together with albumin-bound tryptophan and total tryptophan, were analysed with HPLC in postnatal piglets. In addition, the morphological growth patterns of the different intestinal tissue layers of both normal and SGA piglets were stereologically analysed. The stereological volume density of 5-HT enteroendocrine cells showed a significant interaction effect between age and region. Indeed, the amount of 5-HT cells in both the proximal and distal part of the SI tended to decrease according to age, with the lowest values detected at day 3 postpartum. No differences could be observed related to BW. Interestingly, the serum concentration of 5-HT was higher in normal piglets compared with SGA piglets. Moreover, the ratio of FFT to total tryptophan was significantly affected by age and BW. Normal piglets had, on average, a lower FFT/total tryptophan ratio compared with SGA piglets. An approximate linear decrease was observed with increasing age. Finally, the immaturity of the intestinal system of the SGA piglets was not reflected in altered volume densities of the different intestinal layers. To conclude, although no BW effect could be detected in the distribution of enteric 5-HT cells, serum 5-HT and the ratio of FFT to total tryptophan ratio showed significant differences between normal piglets and their SGA littermates.
Increased expression of tryptophan-5-hydroxylase 1, but not 2, in brainstem as a result of intrauterine malnutrition
2012, International Journal of Developmental Neuroscience
Citation Excerpt :
The present results also corroborate what our group has previously reported. Malnourished offspring that were products of nutritional stress subjected to during pregnancy and lactation demonstrate an increase in 5-HT biosynthesis as a consequence of a chronic increase in the passage of free l-Trp to the brain and altered TPH activity (Hernández et al., 1989; Manjarrez et al., 1988, 1994, 1996, 1998). It is known that numerous metabolic, physical and psychological stressors produce a significant increase in the metabolism of serotonergic neurons and, consequently, cause an increase in the activity of TPH and release of 5-HT in distinct target regions of the brain (Boadle-Biber et al., 1989; Boadle-Biber, 1993; Chaouloff et al., 1999; Abumaria et al., 2006, 2007).
The aim of this study was to determine whether intrauterine malnutrition (IUM) produces a change in the expression of tryptophan-5-hydroxylase (TPH) 1 and/or 2 as the primary mechanism to explain the observed chronic cerebral acceleration of the synthesis of 5-hydroxytryptamine (5-HT). We used an IUM model and controls with ages of 1, 15 and 21 days. The brainstem was obtained to determine l-tryptophan, 5-HT and TPH activity. Expression of TPH1 and TPH2 via specific antibodies for each was also evaluated by immunocytochemistry and Western blot. Malnourished offspring had a significant elevation of l-Trp, TPH activity and 5-HT in the brainstem. Both isoforms (1 and 2) of TPH were expressed from birth in both groups; however, TPH1 expression was significantly higher in offspring with IUM in relation to the controls. Importantly, these malnourished offspring showed reduced expression of TPH2 compared to controls. It was confirmed that IUM produces an increase in 5-HT in the brainstem and also showed increased expression of TPH1 at birth, with decreased expression of TPH2. These findings together allow us to propose that chronic elevation of synthesis of 5-HT observed in the brain of the offspring with IUM is probably due to a change in the expression and activity of TPH1 induced from fetal life.
Malnutrition and brain development: An analysis of the effects of inadequate diet during different stages of life in rat
2012, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Moreover, serotonin depletion during synaptogenesis led to decreased synaptic density and deficits in spatial learning in the adult rat (Mazer et al., 1997). Others have reported increased 5-HT levels in the dorsal hippocampus as determined by in vivo microdialysis (Chen et al., 1992; Mokler et al., 2003, 1999) as well as in prefrontal cortex (Mokler et al., 2003) and in whole brain by biochemical assays (Alfaro-Rodrigez et al., 2006; Hernandez et al., 1989) after prenatal protein malnutrition. An elevated concentration of brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) was observed in prenatal malnourished animals at different ages from birth to day 30 (Mokler et al., 2003).
Protein malnutrition or undernutrition can result in abnormal development of the brain. Depending on type, age at onset and duration, different structural and functional deficits can be observed. In the present review, we discuss the neuroanatomical, behavioral, neurochemical and oxidative status changes associated with protein malnutrition or undernutrition at different ages during prenatal and immediately postnatal periods as well as in adult rat. Analysis of all data suggests that protein malnutrition as well as undernutrition induced impaired learning and retention when imposed during the immediately postnatal period and in adulthood, whereas hyperactivity including increased impulsiveness and greater reactivity to aversive stimuli occurred when malnutrition or undernutrition was imposed either pre or postnatally. This general state of hyperreactivity may be linked essentially to an alteration in dopaminergic system. Hence, the present review shows that in spite of the attention devoted in the literature to prenatal effects, cognitive deficits are more serious following malnutrition or undernutrition after birth. We thus clearly establish a special vulnerability to malnutrition after weaning in rats.
Dihydropteridine reductase activity in the brainstem of intrauterine growth-restricted rats
2010, International Journal of Developmental Neuroscience
Citation Excerpt :
BH4 is synthesized from two metabolic pathways (de novo pathway and recycling pathway) in which BH4 is regenerated after donating one electron for the corresponding hydroxylation (Kaufman, 1993; Thöny et al., 2000). On the other hand, there is experimental evidence in IUGR offspring that brain serotonin synthesis is accelerated during development, coincident with an elevation of both the concentration of brain l-Trp and the activity of Tph 2, which supports the activation of the serotonergic neuronal system (Miller et al., 1977; Hernandez et al., 1989; Manjarrez et al., 1988, 1994, 1996, 2001). Therefore, increased activity of Tph 2 in serotonergic neurons with increased hydroxylation needs suggests the hypothesis that an increased DHPR activity should also be present in the brain of IUGR rats.
The aim of this study was to determine whether intrauterine growth restriction produces an increase of dihydropteridine reductase activity as a compensatory mechanism that maintains the necessary concentration of cofactor, tetrahydrobiopterin, during accelerated brain serotonin biosynthesis. Intrauterine growth-restricted offspring and controls were used. On days 1, 10, 15 and 21 of life, the brainstem was dissected and l-tryptophan, serotonin, tryptophan-5-hydroxylase and dihydropteridine reductase activities were determined. Intrauterine growth-restricted pups showed a significant increase of l-tryptophan, 5-hydroxytryptamine, tryptophan-5-hydroxylase and also dihydropteridine activity in the brainstem in comparison to normal pups. These results confirm that intrauterine growth restriction produces an increase of serotonin biosynthesis in the brainstem. This is accompanied by an increase in dihydropteridine activity that appears to be a compensatory mechanism to maintain sufficient tetrahydrobiopterin for the donation of electrons during the accelerated synthesis of brain serotonin in intrauterine growth-restricted rats.
Changes in the metabolic footprint of placental explant-conditioned medium cultured in different oxygen tensions from placentas of small for gestational age and normal pregnancies
2010, Placenta
Being born small for gestational age (SGA) confers significantly increased risks of perinatal morbidity and mortality. Accumulating evidence suggests that an SGA fetus results from a poorly perfused and abnormally developed placenta. Some of the placental features seen in SGA, such as abnormal cell turnover and impaired nutrient transport, can be reproduced by culture of placental explants in hypoxic conditions. Metabolic footprinting offers a hypothesis-generating strategy to investigate factors absorbed by and released from this tissue in vitro. Previously, metabolic footprinting of the conditioned culture media has identified differences in placental explants cultured under normoxic and hypoxic conditions and between normal pregnancies and those complicated by pre-eclampsia. In this study we aimed to examine the differences in the metabolic footprint of placental villous explants cultured at different oxygen (O₂) tensions between women who deliver an SGA baby (n = 9) and those from normal controls (n = 8). Placental villous explants from cases and controls were cultured for 96 h in 1% (hypoxic), 6% (normoxic) and 20% (hyperoxic) O₂. Metabolic footprints were analysed by Ultra Performance Liquid Chromatography coupled to an electrospray hybrid LTQ-Orbitrap Mass Spectrometry (UPLC-MS). 574 metabolite features showed significant difference between SGA and normal at one or more of the oxygen tensions. SGA explant media cultured under hypoxic conditions was observed, on a univariate level, to exhibit the same metabolic signature as controls cultured under normoxic conditions in 49% of the metabolites of interest, suggesting that SGA tissue is acclimatised to hypoxic conditions in vivo. No such behaviour was observed under hyperoxic culture conditions. Glycerophospholipid and tryptophan metabolism were highlighted as areas of particular interest.

View all citing articles on Scopus

View full text

Newborn humans and rats malnourished in utero: free plasmal-tryptophan, neutral amino acids and brain serotonin synthesis

Abstract

Life Sci.

J. Pediatr.

J. Pediatr.

Anal. Biochem.

Brain Research

Am. Acad. Child. Psychiatry

Anal. Biochem.

Int. J. Dev. Neurosci.

J. Nutr.

Brain Dev.

Biochem. Pharmacol.

Pharmacol. Biochem. Behav.

Psychoneuroendocrinology

Brain Res. Bull.

Neuropharmacology

J. Biol. Chem.

J. Biol. Chem.

Exp. Neurol.

Brain Res. Bull.

Life Sci.

Life Sci.

Brain Research

Neuroscience

Exp. Neurol.

Life Sci.

Brain Dev.

Life Sci.

Psychiatry Res.

Neurosci. Lett.

A proposal for a new method of evaluation of the newborn infant

Curr. Res. Anesth. Analg.

Influence of intrauterine malnutrition on brain development: alteration of myelination

Biol. Neonate

The effect of malnutrition on the synthesis of myelin lipid

Pediatrics

The effect of fatty acids on the binding of tryptophan to plasma protein

Nature (Lond.)

Rapid method for the determination of 5-HT and 5-HIAA in small regions of rat brain

Br. J. Pharmacol.

Drugs influencing plasma and brain tryptophan

Br. J. Pharmacol.

Evidence for the existence of monoamine containing neurons in the central nervous system

Acta Physiol. Scand.

The determination of tryptophan in plasma, liver and urine

J. Lab. Clin. Med.