scholarly journals Restraint Stress during Pregnancy Rapidly Raises Kynurenic Acid Levels in Mouse Placenta and Fetal Brain

2016 ◽  
Vol 38 (6) ◽  
pp. 458-468 ◽  
Author(s):  
Francesca M. Notarangelo ◽  
Robert Schwarcz
Keyword(s):  
Brain Development ◽  
Restraint Stress ◽  
Kynurenic Acid ◽  
Acute Stress ◽  
Fetal Brain ◽  
Maternal Plasma ◽  
Stressful Events ◽  
Fetal Plasma ◽  
Maternal Liver

Stressful events during pregnancy adversely affect brain development and may increase the risk of psychiatric disorders later in life. Early changes in the kynurenine (KYN) pathway (KP) of tryptophan (TRP) degradation, which contains several neuroactive metabolites, including kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and quinolinic acid (QUIN), may constitute a molecular link between prenatal stress and delayed pathological consequences. To begin testing this hypothesis experimentally, we examined the effects of a 2-h restraint stress on KP metabolism in pregnant FVB/N mice on gestational day 17. TRP, KYN, KYNA, 3-HK, and QUIN levels were measured in maternal and fetal plasma and brain, as well as in the placenta, immediately after stress termination and 2 h later. In the same animals, we determined the activity of TRP 2,3-dioxygenase (TDO) in the maternal liver and in the placenta. Compared to unstressed controls, mostly transient changes in KP metabolism were observed in all of the tissues examined. Specifically, stress caused significant elevations of KYNA levels in the maternal plasma, placenta, and fetal brain, and also resulted in increased levels of TRP and KYN in the placenta, fetal plasma, and fetal brain. In contrast, 3-HK and QUIN levels remained unchanged from control values in all tissues at any time point. In the maternal liver, TDO activity was increased 2 h after stress cessation. Taken together, these findings indicate that an acute stress during the late gestational period preferentially affects the KYNA branch of KP metabolism in the fetal brain. Possible long-term consequences for postnatal brain development and pathology remain to be examined.

The effect of thyroxine, 3,5-dimethyl-3'-isopropyl-L-thyronine and iodized oil on fetal brain development in the iodine-deficient sheep

1989 ◽  
Vol 121 (1) ◽  
pp. 7-15 ◽  
Author(s):  
M. T. Mano ◽  
B.J. Potter ◽  
G. B. Belling ◽  
D. M. Martin ◽  
B. G. Gragg ◽  
...  
Keyword(s):  
Brain Development ◽  
Thyroid Function ◽  
Iodine Deficiency ◽  
Fetal Brain ◽  
Maternal Plasma ◽  
Iodized Oil ◽  
Irreversible Damage ◽  
Fetal Plasma ◽  
Fetal Brain Development ◽  
Fetal Thyroid

Abstract. Studies have been carried out to investigate the role of maternal and fetal thyroid function in the effects of iodine deficiency on fetal brain development in sheep. Iodine deficiency was established with an especially prepared low-iodine diet of maize and pea pollard. The iodine-deficient sheep were mated and at the end of the second trimester of pregnancy (100 days gestation) were divided into groups which received either a sc injection of T4 or 3,5-dimethyl-3'-isopropyl-L-thyronine or an im injection of iodized oil. At 140 days gestation (10 days prior to parturition) comparison of the fetuses delivered by hysterotomy revealed that the retarded fetal brain development observed in iodine deficiency was greatly improved by T4 and by iodized oil. However, T4 and iodized oil failed to correct the reduction in the number and the increase in the length of synaptic appositions which were observed in the fetal cerebral cortex after iodine deficiency. In addition, the histological appearance of the fetal thyroid gland and the levels of plasma thyroid hormones were restored to normal. The administration of 3,5-dimethyl-3'-isopropyl-L-thyronine had no effect on the retarded fetal brain and body development of the iodine-deficient fetuses. The lack of response may be due to the inability of 3,5-dimethyl-3'-isopropyl-L-thyronine to cross the ovine placenta as no reduction in the abnormally elevated fetal plasma TSH was observed in spite of a fall in maternal plasma TSH and apparent restoration of maternal thyroid function. It is concluded that the retarded fetal brain development observed during iodine deficiency in sheep can be substantially improved by iodized oil or to a lesser extent by T4 administration at 100 days gestation and that this is dependent on the restoration of both maternal and fetal thyroid function which supports previous observations from this laboratory following fetal and maternal thyroidectomy. The persistence of some effects of iodine deficiency on the fetal brain suggests that irreversible damage may have occurred.

scholarly journals Prenatal Dynamics of Kynurenine Pathway Metabolism in Mice: Focus on Kynurenic Acid

2017 ◽  
Vol 39 (6) ◽  
pp. 519-528 ◽  
Author(s):  
Nick Goeden ◽  
Francesca M. Notarangelo ◽  
Ana Pocivavsek ◽  
Sarah Beggiato ◽  
Alexandre Bonnin ◽  
...  
Keyword(s):  
Kynurenic Acid ◽  
Ex Vivo ◽  
Fetal Brain ◽  
Maternal Plasma ◽  
Kynurenine Pathway ◽  
Special Focus ◽  
Maternal Circulation ◽  
Placental Perfusion ◽  
Fetal Plasma

The kynurenine pathway (KP), the major catabolic route of tryptophan in mammals, contains several neuroactive metabolites, including kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK). KP metabolism, and especially the fate of KYNA, during pregnancy is poorly understood, yet it may play a significant role in the development of psychiatric disorders later in life. The present study was designed to investigate the prenatal features of KP metabolism in vivo, with special focus on KYNA. To this end, pregnant CD-1 mice were treated systemically with kynurenine (100 mg/kg), KYNA (10 mg/kg), or saline on embryonic day 18. As expected, administration of either kynurenine or KYNA increased KYNA levels in the maternal plasma and placenta. Maternal kynurenine treatment also raised kynurenine levels in the fetal plasma and brain, demonstrating the ability of this pivotal KP metabolite to cross the placenta and increase the levels of both KYNA and 3-HK in the fetal brain. In contrast, maternal administration of KYNA caused only a small, nonsignificant elevation in KYNA levels in fetal plasma and brain. Complementary experiments using an ex vivo placental perfusion procedure confirmed the significant transplacental transfer of kynurenine and demonstrated that only a very small fraction of maternal kynurenine is converted to KYNA in the placenta and released into the fetal compartment under physiological conditions. Jointly, these results help to clarify the contributions of the maternal circulation and the placenta to fetal KYNA in the late prenatal period.

Effect of long-term infusion of ovine corticotrophin-releasing factor in the immature ovine fetus

1986 ◽  
Vol 111 (3) ◽  
pp. 469-475 ◽  
Author(s):  
E. M. Wintour ◽  
R. J. Bell ◽  
R. S. Carson ◽  
R. J. MacIsaac ◽  
G. W. Tregear ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Maternal Plasma ◽  
In Utero ◽  
Premature Delivery ◽  
Jugular Veins ◽  
Plasma Progesterone ◽  
Fetal Plasma ◽  
Corticotrophin Releasing Factor ◽  
Ovine Fetus

ABSTRACT Synthetic ovine corticotrophin-releasing factor (oCRF) was infused continuously into the jugular veins of six ovine fetuses for 5–11 days. Two fetuses receiving 0·1 and 1·0 μg oCRF/h from gestational days 134 and 135 respectively, lambed prematurely on days 141 and 140 respectively. Three out of four fetuses receiving oCRF at 2·4 μg/h, from 125 days of gestation, delivered spontaneously at 131, 131 and 136 days, whilst one died in utero at 132 days. Two fetuses receiving vehicle only or oCRF intra-amniotically, were born at 148 and 145 days respectively, whilst six fetuses chronically cannulated but not infused were born at 149·8 ±2·1 (s.d.) days. In ewes lambing at term, maternal plasma progesterone concentrations were 41·4±11·4 (s.e.m.; n = 5), 28·8±7·8 (n = 6), 17·1 ±4·8 (n = 5) and 7·9± 1·1 (n = 4) nmol/l on 3, 2, 1 and 0 days respectively before the lambs were born. No such decrease in maternal plasma progesterone concentrations was seen in the oCRF-infused fetuses. Fetal plasma concentrations of immunoreactive ACTH were maintained above normal in oCRF-infused fetuses, but some desensitization to bolus oCRF injections occurred in these fetuses. Four of the five fetuses born prematurely were sufficiently mature to survive, being able to stand, breathe and suckle. It is concluded that continuous oCRF infusions into immature fetuses can accelerate maturation of a number of organs and systems culminating in the premature delivery of viable lambs. J. Endocr. (1986) 111, 469–475

scholarly journals Protein restriction during pregnancy affects maternal liver lipid metabolism and fetal brain lipid composition in the rat

2010 ◽  
Vol 298 (2) ◽  
pp. E270-E277 ◽  
Author(s):  
Nimbe Torres ◽  
Claudia J. Bautista ◽  
Armando R. Tovar ◽  
Guillermo Ordáz ◽  
Maricela Rodríguez-Cruz ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Brain Development ◽  
Liver Lipid ◽  
Fetal Brain ◽  
Protein Restriction ◽  
Brain Lipid ◽  
Maternal Liver ◽  
Fetal Brain Development ◽  
Liver Lipid Metabolism ◽  
The Impact

Suboptimal developmental environments program offspring to lifelong metabolic problems. The aim of this study was to determine the impact of protein restriction in pregnancy on maternal liver lipid metabolism at 19 days of gestation (dG) and its effect on fetal brain development. Control (C) and restricted (R) mothers were fed with isocaloric diets containing 20 and 10% of casein. At 19 dG, maternal blood and livers and fetal livers and brains were collected. Serum insulin and leptin levels were determinate in mothers. Maternal and fetal liver lipid and fetal brain lipid quantification were performed. Maternal liver and fetal brain fatty acids were quantified by gas chromatography. In mothers, liver desaturase and elongase mRNAs were measured by RT-PCR. Maternal body and liver weights were similar in both groups. However, fat body composition, including liver lipids, was lower in R mothers. A higher fasting insulin at 19 dG in the R group was observed (C = 0.2 ± 0.04 vs. R = 0.9 ± 0.16 ng/ml, P < 0.01) and was inversely related to early growth retardation. Serum leptin in R mothers was significantly higher than that observed in C rats (C = 5 ± 0.1 vs. R = 7 ± 0.7 ng/ml, P < 0.05). In addition, protein restriction significantly reduced gene expression in maternal liver of desaturases and elongases and the concentration of arachidonic (AA) and docosahexanoic (DHA) acids. In fetus from R mothers, a low body weight (C = 3 ± 0.3 vs. R = 2 ± 0.1 g, P < 0.05), as well as liver and brain lipids, including the content of DHA in the brain, was reduced. This study showed that protein restriction during pregnancy may negatively impact normal fetal brain development by changes in maternal lipid metabolism.

Regulation of placental metabolism by glucose supply

1995 ◽  
Vol 7 (3) ◽  
pp. 365 ◽  
Author(s):  
WW Hay
Keyword(s):  
Plasma Glucose ◽  
Glucose Concentration ◽  
Glucose Consumption ◽  
Maternal Plasma ◽  
Plasma Glucose Concentration ◽  
Transporter Proteins ◽  
Fetal Plasma ◽  
Carbon Substrates ◽  
Glucose Supply

Glucose is supplied to the placenta and fetus from the maternal plasma according to concentration-dependent mechanisms exhibiting saturation kinetics that are mediated by facilitative transporter proteins on both the maternal-facing microvillus and fetal-facing basal trophoblast membranes. Placental glucose transport to the fetus requires a net maternal-to-fetal plasma glucose concentration gradient that is determined by placental as well as fetal glucose consumption. Fetal plasma glucose concentration, independent of maternal glucose concentration, regulates the partition of placental glucose uptake into transfer to the fetus and consumption by the placenta. Placental transport capacity increases with advancing gestation, probably by an increased number of transporter proteins as surface area increases. Placental glucose consumption contributes to most or all of placental lactate and fructose production and other less well defined non-oxidative pathways of carbon metabolism. Placental glucose consumption accounts for at least 50% of placental oxygen consumption which remains independent of short-term or long-term changes in placental glucose supply, thus requiring varying amounts of other carbon substrates. Placental glucose supply, therefore, plays a key role in regulating placental glucose metabolism and placental carbon balance, and interacts reciprocally with other carbon substrates to maintain placental oxidative metabolism.

scholarly journals Voluntary wheel running initially increases adrenal sensitivity to adrenocorticotrophic hormone, which is attenuated with long-term training

2009 ◽  
Vol 106 (1) ◽  
pp. 66-72 ◽  
Author(s):  
Jonathan E. Campbell ◽  
Nasimeh Rakhshani ◽  
Sergiu Fediuc ◽  
Silvio Bruni ◽  
Michael C. Riddell
Keyword(s):  
Stress Response ◽  
Hpa Axis ◽  
Restraint Stress ◽  
Acute Stress ◽  
Wheel Running ◽  
Male Rats ◽  
Voluntary Wheel Running ◽  
Acute Stress Response ◽  
Voluntary Wheel

Although exercise is a common and potent activator of the hypothalamic-pituitary adrenal (HPA) axis, the effects of exercise on the acute stress response are not well understood. Here, we investigated the effects of short- (2 wk) and long-term (8 wk) voluntary wheel running on adrenal sensitivity to ACTH stimulation and the acute stress response to restraint in male rats. Diurnal glucocorticoid patterns were measured on days 7 (all groups) and 35 (8-wk groups). Rats were subjected to 20 min of restraint stress on either week 1 or on week 7 of treatment to assess HPA activation. One week later, exogenous ACTH (75 ng/kg) was administered to assess adrenal sensitivity to ACTH. Following this, adrenals were collected and analyzed for key proteins involved in corticosterone (CORT) synthesis. By the end of week 1, exercising (E) animals had twofold higher peak diurnal CORT levels compared with sedentary (S) animals ( P < 0.01). CORT values were not different between groups at week 8. In response to restraint stress at week 2, CORT values in E were approximately threefold greater than in S ( P < 0.05). No difference was found between E and S rats in the response to, or recovery from, restraint at week 8. During the ACTH challenge at week 2, E demonstrated a ∼2.5-fold increase in adrenal sensitivity compared with S, while no difference was found between E and S at week 8. The expression of steroidogenic acute regulatory protein was found to be ∼50% higher in the adrenals in E compared with S at week 2 ( P < 0.05), but no difference existed between groups at week 8. These results show that volitional wheel running initially causes hyperactivation of the HPA axis, due to enhanced adrenal sensitivity to ACTH, but that these alterations in HPA activity are completely restored by 8 wk of training.

Comparison of maternal to fetal transfer of 3,5,3 ′-triiodothyronine versus thyroxine in rats, as assessed from 3,5,3′-triiodothyronine levels in fetal tissues

1989 ◽  
Vol 120 (1) ◽  
pp. 20-30 ◽  
Author(s):  
Gabriella Morreale de Escobar ◽  
María Jesís Obregón ◽  
Carmen Ruiz de Oña ◽  
Francisco Escobar del Rey
Keyword(s):  
Fetal Brain ◽  
Maternal Plasma ◽  
Constant Infusion ◽  
Rat Fetus ◽  
Fetal Plasma ◽  
Fetal Tissues ◽  
Thyroid Hormone Action ◽  
Fetal Thyroid ◽  
The Brain ◽  
Tsh Levels

Abstract. Thyroxine (T4) is transferred from the mother to the hypothyroid rat fetus late in gestation, mitigating T4 and T3 deficiency in fetal tissues, the brain included. We have now compared the effects of maternal infusion with T3. Normal and thyroidectomized rats were started on methimazole (MMI) on the 14th day of gestation, given alone, or together with a constant infusion of 0.45 μg (0.69 nmol) T3 or of 1.8 μg (2.3 nmol) T4/100 g per day. Maternal and fetal samples were obtained at the 21st day of gestation. The doses of T3 and T4 were biologically equivalent for the dams, as assessed from maternal plasma and tissue T3, and plasma TSH levels. MMI blocked the fetal thyroid; T4 and T3 levels were low in all fetal tissues, and fetal plasma TSH was high. Maternal infusion with T4 mitigated both T4 and T3 deficiency in all fetal tissues, the brain included, and decreased fetal plasma TSH. In contrast, infusion of T3 normalized fetal plasma T3 and increased the T3 levels in several tissues, but not in the brain. Neither did it decrease the high fetal plasma TSH levels. The results show that when the fetus is hypothyroid, T3 crosses the rat placenta at the end of gestation, but does not affect all tissues to the same degree. In contrast to the effects of maternal T4, maternal T3 does not alleviate the T3 deficiency of the brain or, presumably, of the thyrotrope. Thus, end-points of thyroid hormone action related to TSH release should not be used to measure transfer of maternal T3 to the fetal compartment. Moreover, T4 should be given, and not T3, to protect the hypothyroid fetal brain.

scholarly journals LASMA AMINO ACID CONCENTRATIONS AND 35S-DISTRIBUTION IN THE SOW AND FETUS FOLLOWING INJECTION OF 35S-METHIONINE

1975 ◽  
Vol 55 (4) ◽  
pp. 627-632 ◽  
Author(s):  
J. E. KNIPFEL ◽  
R. F. WILLES ◽  
J. I. ELLIOT
Keyword(s):  
Amino Acid ◽  
Fetal Liver ◽  
Maternal Plasma ◽  
Liver Uptake ◽  
Isoleucine Leucine ◽  
Fetal Circulation ◽  
Fetal Plasma ◽  
Maternal Liver ◽  
Methionine Concentration ◽  
Amino Acid Concentrations

Following maternal intravenous injection of 1.6 mg/kg body weight 35S-methionine, only a small proportion of the administered 35S reached fetal circulation. Fetal liver uptake of 35S was much less than that of maternal liver. A transient minor increase in the maternal plasma methionine concentration was not reflected in fetal plasma. Isoleucine, leucine, valine and phenylalanine were at lower concentrations in fetal plasma than in maternal plasma, with threonine, glutamic acid, proline, glycine, alanine and tyrosine generally higher in fetal blood. The proportion of 35S reaching the fetal circulation appeared to be cleared at a slower rate than the 35S from maternal plasma. The placenta appeared to function as an effective buffer against transient minor changes in the maternal plasma methionine concentration. The extent of the buffering capacity of the placenta against maternal plasma amino acid fluctuations requires further investigation.

scholarly journals Male and Female, Prenatal Brain Development Differs in Response to the Maternal Omega 3 and 6 Nutritional Status

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 734-734
Author(s):  
Michael Crawford ◽  
Mark Johnson ◽  
Yiqun Wang ◽  
David Edwards ◽  
Nora Tusor ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Corpus Callosum ◽  
Brain Development ◽  
Grey Matter ◽  
Fetal Brain ◽  
Maternal Plasma ◽  
Magnetic Resonance Images ◽  
Brain Growth ◽  
Omega 3 ◽  
The Brain

Abstract Objectives To establish why prenatal brain growth in male fetuses responded to an omega-3-rich supplement but the females did not. Methods In a study of maternal lipid status during pregnancy in relation to regional fetal brain development a supplement containing long chain polyenoic fatty acids (300 mg of docosahexaenoic acid DHA, 42 mg eicosapentaenoic (EPA), 8.4 mg arachidonic and placebo 721 mg of oleic acid). Magnetic resonance images were obtained of newborn brains. Quantitative analysis of regions of the brain showed the supplement enhanced brain volume, with and without CSF, cortex, whole grey matter, and corpus callosum but only boys. Results We wish to report correlations for arachidonic and stearic acids with several regions of brain growth in girls but not boys: for example, maternal RBC stearic acid at recruitment correlated with whole cortex (0.85 p &lt; 0.0002), grey matter (0.847 p &lt; 0.0002), corpus callosum (0.699 p &lt; 0.008), whole brain (0.792 p &lt; 0.001), brain plus CSF (0.733 p &lt; 0.004, n = 13). Correlations with arachidonic acid at delivery reflected its index of arachidonic biomagnification and linoleic bioreduction. This measure of placental efficiency for arachidonic was for cortex (0.748 p &lt; 0. 0034), deep grey matter (0.659 p &lt; 0.014), whole grey matter (0.753 p &lt; 0.003), hippocampus (0.611 p &lt; 0.03), lentiform (0.774 p &lt; 0.002), thalami (0.654 p &lt; 0.015), corpus callosum (0.640 p &lt; 0.018), brain (0.685 p &lt; 0.0098), brain with CSF (0.774 p &lt; 0.0019 n = 12). None were seen with the placebo boys (n = 22). Following embryogenesis, the placenta develops ahead of the demands of fetal growth. The fetal cardiovascular system is required to develop to support organogenesis and the brain growth thrust. The fetal immune system is required to help maintain pregnancy and for birth. All these systems are rich in arachidonic acid with little omega 3. The placenta biomagnifies arachidonic acid for the fetus: (typically maternal plasma lecithin 8.76% ± 1.49 CFD fetal cord 17.5% ± 3.22 p &lt; 0.0001 (n = 44), whereas DHA in the same mothers was 4.13% ± 0.98 vs 5.79% ± 1.69 p &lt; 0.0001. Conclusions We conclude that arachidonic acid is playing an as yet, unseen role, and female physiology is more focused on arachidonic acid to serve the basics of reproduction. Funding Sources The Mother and Child Foundation, Waterloo Foundation and the BORNE Charity.

scholarly journals Hypoxemia Near Mid-Gestation Has Long-term Effects on Fetal Brain Development

1999 ◽  
Vol 58 (9) ◽  
pp. 932-945 ◽  
Author(s):  
S. Rees ◽  
S. Breen ◽  
M. Loeliger ◽  
G. McCrabb ◽  
R. Harding
Keyword(s):  
Brain Development ◽  
Fetal Brain ◽  
Long Term Effects ◽  
Fetal Brain Development
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