Impaired Placental Transport Research Articles

Gestational exposure to BDE-209 induces placental injury via the endoplasmic reticulum stress-mediated PERK/ATF4/CHOP signaling pathway

Several epidemiological studies have reported significant associations between prenatal polybrominated diphenyl ethers (PBDEs) exposure and adverse birth outcomes. Placental injury is thought to mediate these associations. However, few study has investigated the adverse effects of PBDEs exposure on placental growth and development. We examined the impacts of gestational exposure to BDE-209, the most abundant PBDE conger detected in human samples, on placental structure and function, and its model of action in vivo and in vitro. Pregnant mice were exposed to 0, 2, 20, 200 mg/kg/day of BDE-209 by gavages from gestational day (GD) 0 to GD18. Results showed that gestational BDE-209 exposure significantly reduced placental weight, impaired placental vascular development and induced placental cell apoptosis. In addition, gestational BDE-209 exposure impaired placental transport and endocrine function as demonstrated by markedly downregulated expression of Glut1, Znt1, Pgf and Igf2 in BDE-209-treated placentas. Mechanistically, gestational exposure to BDE-209 upregulated the expression of GRP78, and 3 downstream proteins (p-eIF2α, ATF4 and CHOP) of the PERK signaling, suggesting the activation of endoplasmic reticulum (ER) stress and PERK signaling pathway in mouse placentas. Further in vitro study showed that PERK siRNA pretreatment markedly reversed BDE-209-induced cell apoptosis in human JEG-3 cells. Collectively, our results suggest that the activation of the ER stress-mediated PERK/ATF4/CHOP signaling pathway played a role in BDE-209-induced placental injury. Our findings provide new insight into the mechanisms of BDE-209 induced reproductive and developmental toxicity.

Fetal Sex Does Not Impact Placental Blood Flow or Placental Amino Acid Transfer in Late Gestation Pregnant Sheep With or Without Placental Insufficiency.

Pregnant sheep have been used to model complications of human pregnancies including placental insufficiency and intrauterine growth restriction. Some of the hallmarks of placental insufficiency are slower uterine and umbilical blood flow rates, impaired placental transport of oxygen and amino acids, and lower fetal arterial concentrations of anabolic growth factors. An impact of fetal sex on these outcomes has not been identified in either human or sheep pregnancies. This is likely because most studies measuring these outcomes have used small numbers of subjects or animals. We undertook a secondary analysis of previously published data generated by our laboratory in late-gestation (gestational age of 133 ± 0days gestational age) control sheep (n = 29 male fetuses; n = 26 female fetuses; n = 3 sex not recorded) and sheep exposed to elevated ambient temperatures to cause experimental placental insufficiency (n = 23 male fetuses; n = 17 female fetuses; n = 1 sex not recorded). The primary goal was to determine how fetal sex modifies the effect of the experimental insult on outcomes related to placental blood flow, amino acid and oxygen transport, and fetal hormones. Of the 112 outcomes measured, we only found an interaction between fetal sex and experimental insult for the uterine uptake rates of isoleucine, phenylalanine, and arginine. Additionally, most outcomes measured did not show a difference based on fetal sex when adjusting for the impact of placental insufficiency. Exceptions included fetal norepinephrine and cortisol concentrations, which were higher in female compared to male fetuses. For the parameters measured in the current analysis, the impact of fetal sex was not widespread.

Cloned pig fetuses exhibit fatty acid deficiency from impaired placental transport.

Cloned pig fetuses produced by somatic cell nuclear transfer show a high incidence of erroneous development in the uteri of surrogate mothers. The mechanisms underlying the abnormal intrauterine development of cloned pig fetuses are poorly understood. This study aimed to explore the potential causes of the aberrant development of cloned pig fetuses. The levels of numerous fatty acids in allantoic fluid and muscle tissue were lower in cloned pig fetuses than in artificial insemination-generated pig fetuses, thereby suggesting that cloned pig fetuses underwent fatty acid deficiency. Cloned pig fetuses also displayed trophoblast hypoplasia and a reduced expression of placental fatty acid transport protein 4 (FATP4), which is the predominant FATP family member expressed in porcine placentas. This result suggested that the placental fatty acid transport functions were impaired in cloned pig fetuses, possibly causing fatty acid deficiency in cloned pig fetuses. The present study provides useful information in elucidating the mechanisms underlying the abnormal development of cloned pig fetuses.

Placental transport rather than maternal concentration of amino acids regulates fetal growth in monochorionic twins: Implications for fetal origin hypothesis

Objective: The cause of discordant growth in monochorionic twins is not clear. We hypothesize that growth restriction of 1 monochorionic twin is due to fetal under-nutrition. Study Design: We measured plasma amino acid concentrations by high performance liquid chromatography in maternal venous and fetal umbilical cord venous blood samples that were collected at birth from gestational age–matched monochorionic twins (n = 14) with a birth weight discordance of ≥20%. The concordant monochorionic twins with birth weight differences of ≤10% constitute a control group. Results: In the intrauterine growth-restricted twins, fetal concentrations of essential amino acids valine (P <.01), leucine (P <.01), isoleucine (P <.01), phenylalanine (P <.01), and L-arginine (P <.05) were lower than the co-twins and concordant monochorionic twin pairs. Fetal concentrations of the nonessential amino acids taurine (P <.001), serine (P <.01), glycine (P <.01), tyrosine (P <.01), and aspartic acid (P <.01) were lower in the intrauterine growth-restricted twin than the co-twin or concordant monochorionic twins. No such differences were found between concordant monochorionic twin pairs. Maternal amino acid concentrations were similar between discordant and concordant groups. Conclusion: Concentrations of certain essential and nonessential amino acids in the intrauterine growth-restricted twins were lower than the co-twins. These differences support the hypothesis that intrauterine growth-restriction that affects 1 of the monochorionic twins is due to the impaired placental transport of amino acids rather than intertwin transfusion of blood. (Am J Obstet Gynecol 2001;185:1239-46.)

Placental transport of leucine and lysine is reduced in intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is characterized by a reduction in fetal plasma concentrations of a number of essential amino acids. Whether this is caused by impaired placental transport is unknown. We studied transport of leucine and lysine in syncytiotrophoblast microvillous (MVM) and basal membrane (BM) vesicles isolated from uncomplicated (control) and IUGR pregnancies. In addition, we investigated the possibility that leucine uptake is stimulated by an outwardly directed glycine gradient. Uptake of 3H-L-lysine (0.1 microM) and 3H-L-leucine (0.25 microM) was studied at 37 degrees C using rapid filtration techniques. In IUGR, mediated uptake of lysine was reduced by 44% (p < 0.05) in BM and uptake of leucine was lower in both MVM (-46%, p < 0.05) and BM (-38%, p < 0.05) compared with control vesicles. Intravesicular glycine (2 mM) increased the uptake of leucine by 98% in MVM (p < 0.05). These data suggest that the activity of placental transporters for cationic and neutral amino acids is reduced in IUGR. We speculate that a reduced glycine gradient in the placenta in IUGR, due to reduction in system A activity, will impair leucine transport to the fetus, providing an additional mechanism for reduced placental transport of leucine in IUGR.

Ethanol induced teratogenesis: Characterization, mechanisms and diagnositic approaches

Extensive research has been aimed at characterising FAS and FAE. Whereas the symptomology for FAS has been established, that of FAE remains to be fully characterized. Various mechanisms of ethanol induced teratogenesis have been proposed however it remains to be defined how these mechanisms combine to produce the entire constellation of teratogenic characteristics observed. At present, impaired placental transport, abnormal muscle organogenesis and fetal hypoxia have limitations in explaining the entire spectrum of defects in FAS. The role of prostaglandins and hormones requires further research. Also, other as yet unidentified mechanisms may exist. Even if the composite mechanism can be established, ethanol effects in utrro will likely not be preventable by any approach other than consumption modification. In light of this notion, future research into identifying high-risk pregnant drinkers for clinical intervention is emphasized. Intervention leading to abstinence or, if this is not possible, removing the infant as early as possible from an intrauterine environment that is causing growth retardation and fetal distress, are the only solutions available at present.