α-Lipoic acid eliminates dioxin-induced offspring sexual immaturity by improving abnormalities in folic acid metabolism.

Maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes developmental and reproductive disorders in pups due to the attenuated luteinizing hormone (LH) production during the perinatal stage; however, the administration of α-lipoic acid (LA) to TCDD-exposed pregnant rats reversed the attenuated LH production. Therefore, reproductive disorders in pups are expected to be ameliorated with LA supplementation. To address this issue, pregnant rats orally received low dose TCDD at gestational day 15 (GD15) and proceeded to parturition. The control received a corn oil vehicle. To examine the preventive effects of LA, supplementation with LA was provided until postnatal day 21. In this study, we demonstrated that maternal administration of LA restored the sexually dimorphic behavior of male and female offspring. TCDD-induced LA insufficiency is likely a direct cause of TCDD reproductive toxicity. In the analysis to clarify the mechanism of the decrease in LA, we found evidence suggesting that TCDD inhibits the synthesis and increases the utilization of S-adenosylmethionine (SAM), a cofactor for LA synthesis, resulting in a decrease in the SAM level. Furthermore, folate metabolism, which is involved in SAM synthesis, is disrupted by TCDD, which may adversely affect infant growth. Maternal supplementation of LA restored SAM to its original level in the fetal hypothalamus; in turn, SAM ameliorated abnormal folate consumption and suppressed aryl hydrocarbon receptor activation induced by TCDD. The study demonstrates that the application of LA could prevent and recover next-generation dioxin reproductive toxicity, which provides the potential to establish effective protective measures against dioxin toxicity.

Amelioration potential of Moringa oleifera extracts against sodium arsenate induced embryotoxicity and genotoxicity in mouse (Mus musculus) / Potencial de melhoria de extratos de Moringa oleifera contra embriotoxicidade e genotoxicidade induzida por arseniato de sódio em camundongos (Mus musculus)

Previous studies have suggested that arsenic crosses the placenta and affects the fetus development. The study under consideration aims to show comparative ameliorative effect of Moringa oleifera leaf and flower extracts against sodium arsenate induced fetus toxicity of mice. Pregnant mice (N=44) were kept in lab and divided into eleven group from (A to K) and were orally administered the doses 6 mg/kg, 12 mg/kg for sodium arsenate, 150 mg/kg and 300 mg/kg for Moringa oleifera leaf extracts (MOLE) and 150 mg/kg and 300 mg/kg for Moringa oleifera flower extracts (MOFE) comparing with control. The investigation revealed evident reduction in the fetuses weight, hind limb, fore limb, tail and snout length, crown rump and head circumferences well as malformations in tail, feet, arms, legs, skin and eyes in the negative control group (only administered with sodium arsenate). Co-administration of sodium arsenate with MOLE and MOFE ameliorate the reversed effect of sodium arsenate on the shape, length, body weight and DNA damage of fetus significantly at 95% confidence interval. However, Moringa oleifera leaf extract showed more significant results in comparison to Moringa oleifera flower extract. Hence concluded that Moringa oleifera leaf extract ameliorated the embryo toxic effects of sodium arsenate and can be used against environmental teratogens.

Estudos anteriores sugeriram que o arsênio atravessa a placenta e afeta o desenvolvimento do feto. O estudo em consideração visa mostrar o efeito melhorador comparativo de extratos de folhas e flores de Moringa oleifera contra a toxicidade fetal induzida por arseniato de sódio em camundongos. Camundongos grávidas (N = 44) foram mantidos em laboratório e divididos em 11 grupos (de A a K) e foram administrados por via oral nas doses de 6 mg/kg, 12 mg/kg para arseniato de sódio, 150 mg/kg e 300 mg/kg para extratos de folhas de Moringa oleifera (MOLE) e 150 mg/kg e 300 mg/kg para extratos de flores de Moringa oleifera (MOFE) em comparação com o controle. A investigação revelou redução evidente no peso do feto, membro posterior, membro anterior, comprimento da cauda e focinho, coroa, nádega e circunferência da cabeça, bem como malformações na cauda, pés, braços, pernas, pele e olhos no grupo de controle negativo (apenas administrado com arseniato de sódio). A coadministração de arseniato de sódio com MOLE e MOFE melhora significativamente o efeito reverso do arseniato de sódio na forma, comprimento, peso corporal e dano ao DNA do feto, com intervalo de confiança de 95%. No entanto, o extrato da folha da Moringa oleifera apresentou resultados mais significativos em comparação ao extrato da flor da Moringa oleifera. Portanto, concluiu que o extrato da folha de Moringa oleifera melhorou os efeitos tóxicos do arseniato de sódio para o embrião e pode ser usado contra teratógenos ambientais.

Current activities between the DevTox Berlin workshops and the Japanese Teratology Society Terminology Committee in harmonizing the terminology for classifying anomalies in laboratory animals in developmental toxicity studies: Report from the Satellite Workshop of the 60th Annual Meeting of the Japanese Teratology Society.

In recent years, the Japanese Teratology Society has worked with the DevTox Berlin Workshops project to provide internationally consistent terminology for teratogenic effects. This paper summarizes a satellite workshop of the 60th Annual Meeting of the Japanese Teratology Society, which was entitled "Current activities between DevTox Berlin Workshops to develop a harmonized terminology for classifying anomalies in laboratory animals in developmental toxicity studies." The Japanese Teratology Society - Laboratory Animal Terminology Project (JTS-LATP) reviewed "gray zone" anomalies and focused on developing criteria for reclassifying a large number of gray zone anomalies to clarify them and to make it easier to judge fetal categories. This effort will lead to international agreement, based on shared conceptions. The present article aimed to provide the reader with a summary of the issues discussed at the 2020 satellite meeting, which included discussions on open issues from the DevTox Berlin Workshops, ongoing work by the JTS-LATP on gray zone (GZ) anomalies, current industrial concerns, and future challenges.

Developmental toxicity studies on triclopyr acid, triclopyr butoxyethyl ester and triclopyr triethylamine salt in the rabbit.

Developmental toxicity studies have been conducted in the rabbit on triclopyr acid and its active-ingredient variants, triclopyr triethylamine salt (T-TEA) and triclopyr butoxyethyl ester (T-BEE), which are dissociated or hydrolysed in vivo to triclopyr acid. In this paper, the available developmental toxicity studies on triclopyr acid, T-TEA and T-BEE are summarised and evaluated. For triclopyr acid and T-TEA, there was no evidence of impaired reproductive performance, fetotoxicity, or teratogenicity, even at maternally toxic doses. The no-observed-adverse-effect levels (NOAELs) for developmental toxicity were 75 mg/kg bw per day for triclopyr acid and 100 mg/kg bw per day for T-TEA, equivalent to 72 mg/kg bw per day expressed as triclopyr acid. A study on T-BEE showed increased post-implantation loss and slight increases in skeletal anomalies and variants at the highest dose tested of 100 mg/kg bw per day, a maternally toxic dose. In a follow-up study on T-BEE, focusing on post-implantation loss, no general increase in post-implantation loss was observed, but one animal at 100 mg/kg bw per day with maternal toxicity had complete resorption of implants. The NOAEL for post-implantation loss was 60 mg/kg bw per day, equivalent to 44 mg/kg bw per day expressed as triclopyr acid. It cannot be excluded that T-BEE may be associated with increased post-implantation loss, but it was only seen in association with maternal toxicity. It is concluded that triclopyr acid and its variants are not specifically toxic to the rabbit embryo and fetus, since post-implantation loss only occurred at doses causing maternal toxicity.

Adult pancreatic islet endocrine cells emerge as fetal hormone-expressing cells.

The precise developmental dynamics of the pancreatic islet endocrine cell types, and their interrelation, are unknown. Some authors claim the persistence of islet cell differentiation from precursor cells after birth ("neogenesis"). Here, using four conditional cell lineage tracing ("pulse-and-chase") murine models, we describe the natural history of pancreatic islet cells, once they express a hormone gene, until late in life. Concerning the contribution of early-appearing embryonic hormone-expressing cells to the formation of islets, we report that adult islet cells emerge from embryonic hormone-expressing cells arising at different time points during development, without any evidence of postnatal neogenesis. We observe specific patterns of hormone gene activation and switching during islet morphogenesis, revealing that, within each cell type, cells have heterogeneous developmental trajectories. This likely applies to most maturating cells in the body, and explains the observed phenotypic variability within differentiated cell types. Such knowledge should help devising novel regenerative therapies.

Prenatal cyanuric acid exposure depresses hippocampal synaptic plasticity and induces spatial learning and memory deficits.

The infant and fetus may be exposed to cyanuric acid (CA) via several different routes into the diet or milk product as well as deliberate contamination. Previous findings indicated chronic CA treatment caused neurotransmission and synaptic impairment in the early developing hippocampus. This study was designed to characterize the effects of different doses (10 mg/kg, 20 mg/kg and 40 mg/kg) of CA exposure on the developing fetus. Pregnant rats were intraperitoneally exposed to CA during the entire period of gestation and male offspring were selected for water maze task, neural recording and N-methyl-d-aspartate (NMDA) receptor detection around the eighth postnatal week. We found that CA exposure impaired the learning and memory function in a dose-dependent manner. The paired-pulse ratio (PPR) and GluN2A-dependent long-term potentiation (LTP) at the Schaffer collateral-CA1 pathway were affected in CA-exposed rats. Remarkably, hippocampal levels of NMDA-GluN2A, but not NMDA-GluN2B, were significantly decreased. Meanwhile, the spine density of hippocampal CA1 neurons was not altered by the CA exposure. Our findings are consistent with the hypothesis that CA treatment during the prenatal period produces deficits in spatial cognition by disrupting hippocampal synaptic function.

Duration of Exposure to General Endotracheal Anesthesia during Cesarean Deliveries at Term and Perinatal Complications.

OBJECTIVE: To examine whether the duration of time from initiation of general endotracheal anesthesia (GETA) to delivery for cesarean deliveries (CDs) performed is related to perinatal outcomes. STUDY DESIGN: This is a retrospective study of patients with singleton nonanomalous gestations undergoing CD ≥37 weeks of gestation under GETA with reassuring fetal status at a single tertiary care center from 2000 to 2016. Duration from GETA initiation until delivery was calculated as the time interval from GETA induction to delivery (I-D), categorized into tertiles. Outcomes for those in the tertile with the shortest I-D were compared with those in the other two tertiles. The primary perinatal outcome was a composite of complications (continuous positive airway pressure or high-flow nasal cannula for ≥2 consecutive hours, inspired oxygen ≥30% for ≥4 consecutive hours, mechanical ventilation, stillbirth, or neonatal death ≤72 hours after birth). Secondary outcomes were 5-minute Apgar score <7 and a composite of maternal morbidity (bladder injury, bowel injury, and extension of hysterotomy). Bivariable and multivariable analyses were used to compare outcomes. RESULTS: Two hundred eighteen maternal-perinatal dyads were analyzed. They were dichotomized based on I-D ≤4 minutes (those in the tertile with the shortest duration) or >4 minutes. Women with I-D >4 minutes were more likely to have prior abdominal surgery and less likely to have labored prior to CD. I-D >4 minutes was associated with significantly increased frequency of the primary perinatal outcome. This persisted after multivariable adjustment. In bivariable analysis, 5-minute Apgar <7 was more common in the group with I-D >4 minutes, but this did not persist in multivariable analysis. Frequency of maternal morbidity did not differ. CONCLUSION: When CD is performed at term using GETA without evidence of nonreassuring fetal status prior to delivery, I-D interval >4 minutes is associated with increased frequency of perinatal complications. KEY POINTS: · Cesarean delivery under general anesthesia is associated with increased perinatal complications.. · Perinatal complications are increased with increasing duration of exposure to general anesthetics.. · Maternal complications were not increased with shorter duration of exposure to general anesthesia..

COVID-19: can we treat the mother without harming her baby?

Medical care is predicated on 'do no harm', yet the urgency to find drugs and vaccines to treat or prevent COVID-19 has led to an extraordinary effort to develop and test new therapies. Whilst this is an essential cornerstone of a united global response to the COVID-19 pandemic, the absolute requirements for meticulous efficacy and safety data remain. This is especially pertinent to the needs of pregnant women; a group traditionally poorly represented in drug trials, yet a group at heightened risk of unintended adverse materno-fetal consequences due to the unique physiology of pregnancy and the life course implications of fetal or neonatal drug exposure. However, due to the complexities of drug trial participation when pregnant (be they vaccines or therapeutics for acute disease), many clinical drug trials will exclude them. Clinicians must determine the best course of drug treatment with a dearth of evidence from either clinical or preclinical studies, where at least in the short term they may be more focused on the outcome of the mother than of her offspring.

Antenatal Dexamethasone Treatment Induces Sex-dependent Upregulation of NTPDase1/CD39 and Ecto-5'-nucleotidase/CD73 in the Rat Fetal Brain.

Dexamethasone (DEX) is frequently used to treat women at risk of preterm delivery, but although indispensable for the completion of organ maturation in the fetus, antenatal DEX treatment may exert adverse sex-dimorphic neurodevelopmental effects. Literature findings implicated oxidative stress in adverse effects of DEX treatment. Purinergic signaling is involved in neurodevelopment and controlled by ectonucleotidases, among which in the brain the most abundant are ectonucleoside triphosphate diphosphohydrolase 1 (NTPDase1/CD39) and ecto-5'-nucleotidase (e5'NT/CD73), which jointly dephosphorylate ATP to adenosine. They are also involved in cell adhesion and migration, processes integral to brain development. Upregulation of CD39 and CD73 after DEX treatment was reported in adult rat hippocampus. We investigated the effects of maternal DEX treatment on CD39 and CD73 expression and enzymatic activity in the rat fetal brain of both sexes, in the context of oxidative status of the brain tissue. Fetuses were obtained at embryonic day (ED) 21, from Wistar rat dams treated with 0.5 mg DEX/kg/day, at ED 16, 17, and 18, and brains were processed and used for further analysis. Sex-specific increase in CD39 and CD73 expression and in the corresponding enzyme activities was induced in the brain of antenatally DEX-treated fetuses, more prominently in males. The oxidative stress induction after antenatal DEX treatment was confirmed in both sexes, although showing a slight bias in males. Due to the involvement of purinergic system in crucial neurodevelopmental processes, future investigations are needed to determine the role of these observed changes in the adverse effects of antenatal DEX treatment.

Maternal, Decidual, and Neonatal Lymphocyte Composition Is Affected in Pregnant Kidney Transplant Recipients.

Pregnancy after renal transplantation is associated with an increased risk of complications. While a delicately balanced uterine immune system is essential for a successful pregnancy, little is known about the uterine immune environment of pregnant kidney transplant recipients. Moreover, children born to kidney transplant recipients are exposed in utero to immunosuppressive drugs, with possible consequences for neonatal outcomes. Here, we defined the effects of kidney transplantation on the immune cell composition during pregnancy with a cohort of kidney transplant recipients as well as healthy controls with uncomplicated pregnancies. Maternal immune cells from peripheral blood were collected during pregnancy as well as from decidua and cord blood obtained after delivery. Multiparameter flow cytometry was used to identify and characterize populations of cells. While systemic immune cell frequencies were altered in kidney transplant patients, immune cell dynamics over the course of pregnancy were largely similar to healthy women. In the decidua of women with a kidney transplant, we observed a decreased frequency of HLA-DR+ Treg, particularly in those treated with tacrolimus versus those that were treated with azathioprine next to tacrolimus, or with azathioprine alone. In addition, both the innate and adaptive neonatal immune system of children born to kidney transplant recipients was significantly altered compared to neonates born from uncomplicated pregnancies. Overall, our findings indicate a significant and distinct impact on the maternal systemic, uterine, and neonatal immune cell composition in pregnant kidney transplant recipients, which could have important consequences for the incidence of pregnancy complications, treatment decisions, and the offspring's health.

Choline metabolome response to prenatal choline supplementation across pregnancy: A randomized controlled trial.

Pregnancy places a unique stress upon choline metabolism, requiring adaptations to support both maternal and fetal requirements. The impact of pregnancy and prenatal choline supplementation on choline and its metabolome in free-living, healthy adults is relatively uncharacterized. This study investigated the effect of prenatal choline supplementation on maternal and fetal biomarkers of choline metabolism among free-living pregnant persons consuming self-selected diets. Participants were randomized to supplemental choline (as choline chloride) intakes of 550 mg/d (500 mg/d d0-choline + 50 mg/d methyl-d9-choline; intervention) or 25 mg/d d9-choline (control) from gestational week (GW) 12-16 until Delivery. Fasting blood and 24-h urine samples were obtained at study Visit 1 (GW 12-16), Visit 2 (GW 20-24), and Visit 3 (GW 28-32). At Delivery, maternal and cord blood and placental tissue samples were collected. Participants randomized to 550 (vs. 25) mg supplemental choline/d achieved higher (p < .05) plasma concentrations of free choline, betaine, dimethylglycine, phosphatidylcholine (PC), and sphingomyelin at one or more study timepoint. Betaine was most responsive to prenatal choline supplementation with increases (p ≤ .001) in maternal plasma observed at Visit 2-Delivery (relative to Visit 1 and control), as well as in the placenta and cord plasma. Notably, greater plasma enrichments of d3-PC and LDL-C were observed in the intervention (vs. control) group, indicating enhanced PC synthesis through the de novo phosphatidylethanolamine N-methyltransferase pathway and lipid export. Overall, these data show that prenatal choline supplementation profoundly alters the choline metabolome, supporting pregnancy-related metabolic adaptations and revealing biomarkers for use in nutritional assessment and monitoring during pregnancy.

The exposure levels of phthalates in pregnant women and impact factors of fetal malformation.

METHODS: Urine samples were collected from 157 women with fetal malformations (case group) and 147 women with normal fetuses (control group). High-performance liquid chromatography-mass spectrometry (HPLC-MS) was used to detect the content of eight metabolites of phthalate compounds in urine, including monoethyl phthalate (MEP), mononbutyl phthalate (MBP), monoisobutyl phthalate (MiBP), mono-(2-ethylhexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-benzyl phthalate (MBzP). Demographic data were collected from questionnaires administered in specimen collection. RESULTS: The exposure level of MEOHP and MEHP in the case group was higher than the others. And there were significant differences between structural malformations and chromosomal malformations in the levels of MEHHP and MEOHP. Pregnant women with low income, high body mass index (BMI), frequent plastic contact, and low nutrients intake were at risk of suffering from fetal malformation. CONCLUSION: This study provides evidence for the correlation between the concentration of phthalates and fetal malformation. In addition, decreasing plastic exposure and supplementing nutrients may reduce the incidence of fetal malformations.

Polystyrene microplastics disturb maternal-fetal immune balance and cause reproductive toxicity in pregnant mice.

Microplastics (MPs), which are emerging as a new type of environmental pollutants, have raised great concerns regarding their threats to human health. A successful pregnancy depends on the sophisticated regulation of the maternal-fetal immune balance, but the risks of polystyrene MP (PS-MP) exposure in early pregnancy remain unclear. In this study, we exposed the C57BL/6-mated BALB/c mice to PS-MP particles and used the flow cytometry to explore threats towards the immune system. Herein, the allogeneic mating murine model showed an elevated embryo resorption rate with a 10 µm PS-MP particle exposure during the peri-implantation period. Both the number and diameter of uterine arterioles decreased, which might reduce the uterine blood supply. Moreover, the percentage of decidual natural killer cells was reduced, whereas the helper T cells in the placenta increased. In addition, the M1/M2 ratio in macrophages reversed significantly to a dominant M2-subtype. Lastly, the cytokine secretion shifted towards an immunosuppressive state. Overall, our results demonstrated that PS-MPs have the potential to cause adverse effects on pregnancy outcomes via immune disturbance, providing new insights into the study of reproductive toxicity of MP particles in the human body.

Placental transport of parabens studied using an ex-vivo human perfusion model.

INTRODUCTION: Parabens are a group of chemicals widely used as preservatives in daily consumer products such as cosmetics, food items, pharmaceuticals and household commodities. They have been broadly detected in human samples indicating a general human exposure, and concerns arose from their potential endocrine disrupting effect. Especially the exposure to parabens during pregnancy is concerning, as the time of fetal development is a particularly vulnerable period. The aim of this study was to investigate the transport and metabolism of four commonly used parabens: methyl-, ethyl-, propyl- and butylparaben (MeP, EtP, PrP and BuP) and the metabolite para-hydroxybenzoic acid (PHBA) across the human placenta. METHODS: An ex-vivo human placental perfusion model was used. The test compounds were added in the maternal compartment (with initial concentrations of 1 mM or 0.1 mM). Placental transport was evaluated by fetal-maternal concentration ratios (FM-ratio), transport index (TI) and indicative permeability (IP). RESULTS: Information about parabens kinetics was taken from 10 perfusions and PHBA from 7 perfusions. Paraben metabolism was not detected. The placental transport of MeP, EtP, PrP, BuP and PHBA revealed a transfer from maternal to fetal circulations with FM120 of 0.86 ± 0.27 (MeP), 0.98 ± 0.28 (EtP), 1.00 ± 0.28 (PrP), 1.12 ± 0.59 (BuP) and 0.82 ± 0.37 (PHBA). The test substances accumulated in the perfused tissue in some degree. The average kinetic parameters FM-ratio, TI and IP were not different between chemicals. DISCUSSION: The present study shows that the placenta barrier is permeable to all four parabens and the metabolite, which implies potential fetal exposure.

Benzo[a]pyrene impairs the migratory pattern of human gonadotropin-releasing-hormone-secreting neuroblasts.

Benzo[a]pyrene (BaP) is a widespread pollutant that can act as an endocrine disrupting compound (EDC) and interferes with reproductive function. The central regulatory network of the reproductive system is mediated by gonadotropin-releasing hormone (GnRH) neurons, which originate in the olfactory placode and, during ontogenesis, migrate into the hypothalamus. Given the importance of the migratory process for GnRH neuron maturation, we investigated the effect of BaP (10 µM for 24 h) on GnRH neuroblasts isolated from the human fetal olfactory epithelium (FNCB4). BaP exposure significantly reduced the mRNA level of genes implicated in FNCB4 cell migration and affected their migratory ability. Our findings demonstrate that BaP may interfere with the central neuronal network controlling human reproduction affecting GnRH neuron maturation.

Successful Prediction of Human Fetal Exposure to P-Glycoprotein Substrate Drugs Using the Proteomics-Informed Relative Expression Factor Approach and PBPK Modeling and Simulation.

Many women take drugs during their pregnancy to treat a variety of clinical conditions. To optimize drug efficacy and reduce fetal toxicity, it is important to determine or predict fetal drug exposure throughout pregnancy. Previously, we developed and verified a maternal-fetal physiologically based pharmacokinetic (m-f PBPK) model to predict fetal Kp,uu (unbound fetal plasma AUC/unbound maternal plasma AUC) of drugs that passively cross the placenta. Here, we used in vitro transport studies in Transwell, in combination with our m-f PBPK model, to predict fetal Kp,uu of drugs that are effluxed by placental P-glycoprotein (P-gp)-namely, dexamethasone, betamethasone, darunavir, and lopinavir. Using Transwell, we determined the efflux ratio of these drugs in hMDR1-MDCKcP-gpKO cells, in which human P-gp was overexpressed and the endogenous P-gp was knocked out. Then, using the proteomics-informed efflux ratio-relative expressive factor approach, we predicted the fetal Kp,uu of these drugs at term. Finally, to verify our predictions, we compared them with the observed in vivo fetal Kp,uu at term. The latter was estimated using our m-f PBPK model and published fetal [umbilical vein (UV)]/maternal plasma drug concentrations obtained at term (UV/maternal plasma). Fetal Kp,uu predictions for dexamethasone (0.63), betamethasone (0.59), darunavir (0.17), and lopinavir (0.08) were successful, as they fell within the 90% confidence interval of the corresponding in vivo fetal Kp,uu (0.30-0.66, 0.29-0.71, 0.11-0.22, 0.04-0.19, respectively). This is the first demonstration of successful prediction of fetal Kp,uu of P-gp drug substrates from in vitro studies. SIGNIFICANCE STATEMENT: For the first time, using in vitro studies in cells, this study successfully predicted human fetal Kp,uu of P-gp substrate drugs. This success confirms that the m-f PBPK model, combined with the ER-REF approach, can successfully predict fetal drug exposure to P-gp substrates. This success provides increased confidence in the use of the ER-REF approach, combined with the m-f PBPK model, to predict fetal Kp,uu of drugs (transported by P-gp or other transporters), both at term and at earlier gestational ages.

The Effects of Early Prenatal Alcohol Exposure on Epigenome and Embryonic Development.

Prenatal alcohol exposure is one of the most significant causes of developmental disability in the Western world. Maternal alcohol consumption during pregnancy leads to an increased risk of neurological deficits and developmental abnormalities in the fetus. Over the past decade, several human and animal studies have demonstrated that alcohol causes alterations in epigenetic marks, including DNA methylation, histone modifications, and non-coding RNAs. There is an increasing amount of evidence that early pregnancy is a sensitive period for environmental-induced epigenetic changes. It is a dynamic period of epigenetic reprogramming, cell divisions, and DNA replication and, therefore, a particularly interesting period to study the molecular changes caused by alcohol exposure as well as the etiology of alcohol-induced developmental disorders. This article will review the current knowledge about the in vivo and in vitro effects of alcohol exposure on the epigenome, gene regulation, and the phenotype during the first weeks of pregnancy.

Differential Serotonin Uptake Mechanisms at the Human Maternal-Fetal Interface.

Serotonin (5-HT) plays an extensive role during pregnancy in regulating both the placental physiology and embryonic/fetal development. The uptake of 5-HT into cells is central to the control of local concentrations of 5-HT near its molecular targets. Here, we investigated the mechanisms of 5-HT uptake into human primary placental cells and cord blood platelets, all isolated immediately after birth. Trophoblasts and cord blood platelets showed 5-HT uptake with similar Michaelis constant (Km) values (~0.6 µM), typical of the high-affinity serotonin transporter (SERT). The uptake of 5-HT into trophoblasts was efficiently inhibited by various SERT-targeting drugs. In contrast, the uptake of 5-HT into feto-placental endothelial cells was not inhibited by a SERT blocker and showed a Km value (~782 µM) in the low-affinity range. Consistent with this, SERT mRNAs were abundant in term trophoblasts but sparse in feto-placental endothelial cells, whereas the opposite was found for the low-affinity plasma membrane monoamine transporter (PMAT) mRNAs. Organic cation transporter (OCT) 1, 2, and 3 mRNAs were absent or sparse in both cell types. In summary, the results demonstrate, for the first time, the presence of functional 5-HT uptake systems in feto-placental endothelial cells and fetal platelets, cells that are in direct contact with fetal blood plasma. The data also highlight the sensitivity to various psychotropic drugs of 5-HT transport into trophoblasts facing the maternal blood. The multiple, high-, and low-affinity systems present for the cellular uptake of 5-HT underscore the importance of 5-HT homeostasis at the maternal-fetal interface.

Characterizing the effects of in utero valproic acid exposure on murine fetoplacental development.

INTRODUCTION: Valproic acid (VPA) is an effective anti-epileptic drug clinically used to treat seizures, bipolar disorders and neuropathic pain in women of reproductive age. Current approval of VPA for psychiatric conditions and migraine has increased the number of VPA exposed pregnancies. VPA crosses the placental barrier and induces birth defects in about 10% of exposed pregnancies. In addition, VPA exposure results in neurodevelopmental disorders in children without any overt birth defects. The current study was designed to investigate the effects of in utero VPA exposure on fetoplacental growth in a mouse model. METHODS: Pregnant CD-1 dams were exposed to a single teratogenic dose of 400 mg/kg VPA or saline via subcutaneous injection on gestational day (GD) 9 and fetuses were harvested on GD 13, 15, 17 and 19, respectively. Resorptions, gross malformations, fetal weight, fetal head weight, fetal crown-rump length, fetal head transverse and anteroposterior diameters, placental weight and placental diameter were noted. RESULTS: VPA exposure led to multiple external deformities including exencephaly, open eye defect, subcutaneous hemorrhage and underdevelopment of tail. All fetoplacental growth parameters fetal weight, fetal head weight, fetal crown-rump length, placental weight and placental diameter were significantly reduced in VPA-exposed fetuses with and without congenital malformations such as exencephaly, compared to control fetuses. DISCUSSION: In conclusion, the effects of in utero VPA exposure on fetal and placental growth persisted throughout pregnancy and our results suggest that the effects of VPA on placental growth may play a role in VPA-induced toxicity.