Fetal Nervous System Research Articles

Perinatal injuries of the fetal nervous system and contributory factors

The issue of perinatal injury of the central nervous system and birth trauma draws close attention of various specialists. The objective: to identify the effect of extragenital pathology of the pregnant woman and obstetric factors on the formation of perinatal CNS injuries and traumatic injuries of the newborn. Materials and methods. The authors studied ante- and intranatal risk factors for perinatal CNS damage and birth trauma in 183 babies in severe or moderately severe condition (main group) born in the City Clinical Perinatal Center in 2011–2017. There were assessed the clinical manifestations and results of instrumental studies. The control group was formed by the case – control type of 183 women in labor and their children without birth injuries. The results. There were revealed the most significant risk factors for the formation of perinatal CNS injury and birth trauma of the newborn: a high frequency of pregnancy complications (100%), extragenital diseases (90.2%), urogenital infections (33.3%), umbilical cord pathology (33.3%) and other complications of labor (42.1%). The conclusion. The complications of pregnancy and childbirth, extragenital diseases, urogenital infections contribute to the frequency of perinatal CNS damage and development of birth trauma.

769: Fetal autonomic nervous system response to acidosis

The Autonomic Nervous System (ANS) is a major component of fetal adaptation to hypoxia. Different methods have been developed to study Heart Rate Variability (HRV), which reflects fluctuation of ANS. The aim of this study was to evaluate the different methods of ANS analysis on their abilities to reflect fetal acidosis during labor in an experimental model. Experimental study on a sheep model based on repetitive umbilical cord occlusions (UCOs) with mild (1/5 minutes), moderate (1/3 minutes) and severe (1/2 minutes) rhythm of UCOs until arterial pH reached 7.10. Hemodynamic, blood gas analysis, morphological analysis of decelerations and HRV parameters were recorded throughout the experimentation. Morphological analysis relied on depth, slope and the sum of total area of decelerations. HRV analysis included temporal analysis (RMSSD, SDNN, STV), spectral analysis (LF, HF, HF n.u.) and a new index developed by our team (Fetal Stress Index, FSI). We defined and compared 3 groups of pH: >7.20, 7.10-7.20 and <7.10. 11 experiments were performed, resulted in gradually fetal acidemia. FSI was correlated to arterial pH and lactates (p<0.05). FSI increased when fetal acidemia occurred. There was no significant relationship between RMSSD, STV LF, HF, HFn.u., total area of decelerations and pH or lactates. SDNN, baseline of fetal heart rate and slopes during decelerations increased while pH decreased, but not in a significative way. FSI seems a good HRV method to evaluate acidosis. It would be interesting to test the accuracy of a multiparametric model to predict fetal acidosis including FSI, SDNN, variation of the baseline of fetal heart rate and deceleration slopes.

Association between Brain-Derived Neurotrophic Factor (BDNF) Levels in 2nd Trimester Amniotic Fluid and Fetal Development.

The development of the fetal nervous system mirrors general fetal development, comprising a combination of genetic resources and effects of the intrauterine environment. Our aim was to assess the 2nd trimester amniotic fluid levels of brain-derived neurotrophic factor (BDNF) and to investigate its association with fetal growth. In accordance with our study design, samples of amniotic fluid were collected from women who had undergone amniocentesis early in the 2nd trimester. All pregnancies were followed up until delivery and fetal growth patterns and birth weights were recorded, following which pregnancies were divided into three groups based on fetal weight: (1) AGA (appropriate for gestational age), (2) SGA (small for gestational age), and (3) LGA (large for gestational age). We focused on these three groups representing a reflection of the intrauterine growth spectrum. Our results revealed the presence of notably higher BDNF levels in the amniotic fluid of impaired growth fetuses by comparison with those of normal growth. Both SGA and macrosomic fetuses are characterized by notably higher amniotic fluid levels of BDNF (mean values of 36,300 pg/ml and 35,700 pg/ml, respectively) compared to normal-growth fetuses (mean value of 32,700 pg/ml). Though apparently small, this difference is, nevertheless, statistically significant (p value < 0.05) in SGA fetuses in the extremes of the distribution, i.e., below the 3rd centile. In conclusion, there is clear evidence that severe impairment of fetal growth induces the increased production of fetal brain growth factor as an adaptive mechanism in reaction to a hostile intrauterine environment, thereby accelerating fetal brain development and maturation.

THE ROLE OF MAGNETIC RESONANCE IMAGING IN THE PERINATAL ASSESSMENT OF THE CONDITION FETAL CNS WITH HEMOLYTIC DISEASE, WHO RECEIVED TREATMENT BY INTRAUTERINE INTRAVASCULAR BLOOD TRANSFUSION

Objective: to determine the role of magnetic resonance imaging (MRI) in the pathomorphological evaluation of focal changes in the central nervous system (CNS) of fetuses with hemolytic disease before and after treatment, by intrauterine intravascular blood transfusion, and to compare the MRI data of fetuses with ultrasound neurosonography (NSH) newborns. The study included 45 pregnant women and their 45 newborns. Patients are divided into 2 groups. The main group: 30 pregnant women (mean gestation period 32,1 weeks) with hemolytic disease of the fetus who underwent intrauterine intravascular blood transfusion and their 30 newborns with hemolytic disease of the newborn. In this group, comparative MRI examinations of the central nervous system were performed using a protocol including fast MP sequences based on T1 and T2-weighted images, as well as the DWI pulse sequence, both before treatment (intrauterine intravascular blood transfusion of the fetus), and after treatment (regardless of the multiplicity of intrauterine intravascular transfusion — before delivery). The comparison group comprised 15 pregnant women (mean gestation period of 38,6 weeks) with no signs of hemolytic disease, examined by MRI for other indications (concomitant pathology of pregnancy) and their 15 newborns, comparable in gestational age to the main group. The obstetric anamnesis, the MRI data of the central nervous system of fetuses before the treatment (the first intrauterine intravascular transfusion) and after the treatment (before the delivery) and the results of ultrasound for the first day of life were analyzed. When comparing the MRI data of changes in the central nervous system, in the main group (in fetuses with bladder) in relation to the comparison group before treatment (the first intrauterine, intravascular transfusion), a high incidence of focal changes in the brain substance in the main group was revealed. The use of MRIdiagnostics demonstrates a decrease in the risk of development of PCNC in ischemic type, in dynamics before and after treatment. Based on the MRI diagnostic data of the fetal CNS, it is possible to judge the prognosis of the outcomes of hemolytic disease of the fetus, in comparison with the neonatal neurosonography data for the first day.

Nervous System Embriology

This study briefly reviews the main events and processes that lead to the formation of the nervous system in mammals. At the end of gastrulation, they begin a series of fundamental morphogenetic processes with the formation of the neural plate (start of neurulation) culminating in the attainment of a normal nervous system. Embryological ectodermal primordia involved in the formation of the nervous system are the neuroectoblast, the neural crest cells and placodes that will evolve based on inductive phenomena, mainly from the notochord, prechordal plate and ectoderm. During the embryonic period consolidates the final development plan of the nervous system: 1) it comes complete neural tube formation when closing the rostral and caudal neuropores, 2) the different placodes invaginate to help form the organs of senses and sensory ganglia of the head, 3) the neural crest cells migrate to give rise to sensory and autonomic constituents of the peripheral nervous system and 4) developing brain vesicles, which will derive all the constituents of the brain. In the fetal period nervous system increases its mass and ultimately strengthens their functional organization.

Injections to pregnant mice produce prenatal stress that affects aggressive behavior in their adult male offspring

Maternal stress could reprogram the developing fetal nervous system. A common target of maternal glucocorticoids is fetal neuro-endocrine axis. In the present study, pregnant mice were exposed to stress by injection and their male offspring were tested for sexual and aggressive behaviors in adult life. Three groups of pregnant mice were exposed to stress by sham syringe injection. The first group was injected on days 13, 14, and 15 p.c., the second group was injected on days 17 and 18 p.c., and the third group was injected daily from days 13 to 18 p.c. while control mice were not injected. Male offspring that were exposed to stress on days 13–18 p.c. and 17–18 p.c. were less aggressive and had lower blood testosterone levels in comparison to the control group. In male sexual behavior, there were no statistically significant differences between the groups. Body weight differed significantly with groups injected on days 13–18 p.c. and 13–15 p.c. having significantly higher body weight in adult life than the other two groups. After behavioral testing, brains were processed for immunohistochemical staining with antibodies against vasopressin (AVP) and calbindin (CALB). The expression of AVP and CALB in the lateral septum and in the preoptic area, respectively, did not differ between groups, suggesting that these two masculinization markers were not affected by prenatal stress. Present study therefore shows that even presumably mild and short prenatal stress weakens aggressive behavior of adult male mice, possibly due to reduced testosterone levels in blood.

Is there any association between fetal nervous system anomalies and heavy metal-trace element levels in amniotic fluid?

Aim: In this study the authors aimed to evaluate whether there are any causal relationship between heavy metals-trace elements and fetal malformations of central nervous system (CNS). Materials and Methods: The study group consisted of pregnancies with fetal congenital nervous system anomaly (anencephaly, acrania, neural tube defects, etc.) in 16-22 weeks (n=36). Pregnancies with the same weeks of pregnancy who underwent amniocentesis due to high risk in triple test with the result of normal karyotype constituted the control group (n=30). In the both groups the authors analyzed the heavy metals and trace elements in amniotic fluid. Metals and elements were measured by using atomic absorption spectrophotometer technique with a UNICAM-929 spectrophotometer. Results: When compared, the groups were similar in terms of age, parity, BMI, and gestational week (p > 0.05). In fetal congenital anomaly group the authors detected low levels of copper (Cu) and zinc (Zn) rather than control groups (p p p > 0.05). Conclusion: This study can contribute benefits to the literature in terms of clarifying the pathogenesis of fetal congenital nervous system anomalies.

Prenatal CRH: An integrating signal of fetal distress.

Corticotropin-releasing hormone (CRH) is distributed throughout the brain and in peripheral sites but primarily is localized in the paraventricular nucleus of the hypothalamus. It is a "master" stress hormone that is responsible for the synthesis of proopiomelanocortin (POMC) in the anterior pituitary gland. Behaviorally active peptide hormones, including adrenocorticotropin hormone (ACTH) and B-endorphin, are liberated from POMC by enzymes to activate critical processes during stress. CRH is not detectable in the circulation even during extreme stress. However, during human pregnancy, the human placenta expresses the gene for CRH (pCRH) resulting in detectable levels in maternal plasma that increases 20- to 40-fold over the course of gestation. Placental CRH is identical to CRH of hypothalamic origin in size, structure, immunoreactivity, and bioactivity. However, unlike the negative feedback between adrenal cortisol and hypothalamic CRH, cortisol stimulates the synthesis and release of pCRH. The bidirectional release of pCRH into maternal and fetal compartments is associated with regulating the timing of delivery, remodeling the fetal nervous system, and influencing developmental trajectories. Fetal exposure to pCRH during early and late gestation is associated with unique patterns of cortical thinning in school-age children. Placental CRH is elevated in response to physical and behavioral stress and may be an integrative marker of early adversity.

The Critical Role of the Central Autonomic Nervous System in Fetal-Neonatal Transition

The objective of this article is to understand the complex role of the central autonomic nervous system in normal and complicated fetal-neonatal transition and how autonomic nervous system dysfunction can lead to brain injury. The central autonomic nervous system supports coordinated fetal transitional cardiovascular, respiratory, and endocrine responses to provide safe transition of the fetus at delivery. Fetal and maternal medical and environmental exposures can disrupt normal maturation of the autonomic nervous system in utero, cause dysfunction, and complicate fetal-neonatal transition. Brain injury may both be caused by autonomic nervous system failure and contribute directly to autonomic nervous system dysfunction in the fetus and newborn. The central autonomic nervous system has multiple roles in supporting transition of the fetus. Future studies should aim to improve real-time monitoring of fetal autonomic nervous system function and in supporting typical autonomic nervous system development even under complicated conditions.

ВЛИЯНИЕ ЦИТОМЕГАЛОВИРУСНОЙ ИНФЕКЦИИ НА ПРЕОБРАЗОВАНИЕ ПРОГЕСТЕРОНА В МЕТАБОЛИТ 5α-ПРЕГНАН-3,20-ДИОН В ПЛАЦЕНТЕ РАННИХ СРОКОВ БЕРЕМЕННОСТИ

The aim was to study the activity of progesterone and 5α-pregnan-3.20-dione conversion in the placenta at the exacerbation of cytomegalovirus infection (CMVI) during the first trimester of pregnancy. The study material included 50 villous chorions taken during medical abortions in the period of 8-10 weeks from women with exacerbation of chronic CMVI during pregnancy. The control group had 35 villous chorions of pregnant women of the same gestation period with chronic CMVI in the latent stage. Diagnosis of CMVI was performed taking into account the activity of CMVI with the immune-enzyme method by the level of antibodies of IgM and antibody titers of IgG in the paired serums in dynamics in 10 days. The progesterone content was determined at the “Stat Fax-2100ˮ spectrophotometer. The activity of 4-pregnene-3.20-dione dehydrogenase and 5α-pregnane-3.20-dione dehydrogenase was assessed by the histochemical method. Quantitative evaluation of the reaction products was carried out on sections under the microscope “Meiji Technoˮ connected to the software-hardware complex “SCION Corporationˮ. It was found out that progesterone content in villous chorions of women with reactivation of CMVI during pregnancy was reduced to 21.5±2.73 nmol/L in comparison with the control group (53.4±3.70 nmol/L, p&lt;0.001). The disturbance of progesterone inversion intensiveness in placenta was proved by the decrease of enzyme activity: of 4-pregnene-3.20-dione dehydrogenase till 15.9±0.47 standard units (in control it was 28.6±0.58 standard units, p&lt;0.001) and of 5α-pregnan-3.20-dione till 16.2±1.11 standard units (in control it was 25.0±1.91 standard units, p&lt;0.001). Reduction in the intensity of progesterone conversion into 5α-dihydroprogesterone (5α-pregnan-3.20-dione) in the placenta with the exacerbation of CMVI can negatively affect the formation and functioning of the fetal nervous system.

Highly segregated localization of the functionally related vps10p receptors sortilin and SorCS2 during neurodevelopment.

Nervous system development is a precisely orchestrated series of events requiring a multitude of intrinsic and extrinsic cues. Sortilin and SorCS2 are members of the Vps10p receptor family with complementary influence on some of these cues including the neurotrophins (NTs). However, the developmental time points where sortilin and SorCS2 exert their activities in conjunction or independently still remain unclear. In this study we present the characterization of the spatiotemporal expression pattern of sortilin and SorCS2 in the developing murine nervous system. Sortilin is highly expressed in the fetal nervous system with expression localized to distinct cell populations. Expression was high in neurons of the cortical plate and developing allocortex, as well as subpallial structures. Furthermore, the neuroepithelium lining the ventricles and the choroid plexus showed high expression of sortilin, together with the developing retina, spinal ganglia, and sympathetic ganglia. In contrast, SorCS2 was confined in a marked degree to the thalamus and, at E13.5, the floor plate from midbrain rostrally to spinal cord caudally. SorCS2 was also found in the ventricular zones of the ventral hippocampus and nucleus accumbens areas, in the meninges and in Schwann cells. Hence, sortilin and SorCS2 are extensively present in several distinct anatomical areas in the developing nervous system and are rarely co-expressed. Possible functions of sortilin and SorCS2 pertain to NT signaling, axon guidance and beyond. The present data will form the basis for hypotheses and study designs for unravelling the functions of sortilin and SorCS2 during the establishment of neuronal structures and connections.

Assessment of squalene eligibility in bettering some maternal and fetal disorders instigated by gamma irradiation of rats at mid gestation

Purpose: Squalene is an eminent vital part of the synthesis of steroid hormones in the body as well as the first specific intermediate in cholesterol biosynthesis that plays an essential role in normal embryogenesis. The present work was designed to test the maternal and embryonic response to the modulating capacity of squalene (0.4 ml/kg/d), when supplemented to rats from days 1 to 18 of pregnancy, against the damaging consequences induced by maternal subjection to 3 Gy gamma irradiation on day 10 post-conception.Materials and methods: The experimental protocol comprised of four different pregnant groups, namely: (1) control, (2) squalene supplemented, (3) irradiated and (4) squalene supplemented + irradiated.Results: It has been detected that radiation has increased the maternal blood lactate dehydrogenase (as a marker of tissue injury), cholesterol, triglycerides, estradiol and progesterone and has also provoked the oxidative stress that has been demonstrated by the increased malondialdehyde (MDA) and the decreased glutathione (GSH) and superoxide dismutase (SOD). These maternal changes were associated with high embryonic lethality, growth retardation, severe developmental abnormalities and defective neural tube closure expressed by exencephaly. However, squalene treatment has significantly improved the radiation imposed maternal variations and reduced the embryonic mortality, although it has not been able to attenuate the embryonic neural tube defects.Conclusions: It has been presumed that the maternal mid-gestational irradiation (day 10) has affected the fetal nervous system development with concomitant maternal oxidative stress, hyperlipidemia, and increased progesterone and estradiol levels. Squalene uptake has improved the maternal variations and reduced the embryonic mortality while could not stop or improve the embryonic neural tube defects imposed by radiation at this exact radiation timing.

Amniotic fluid oxidant-antioxidant status in foetal congenital nervous system anomalies.

ObjectiveThis study aimed to evaluate the oxidant–antioxidant status of amniotic fluid in pregnant women with foetal congenital malformations of the central nervous system.MethodsWe studied pregnant women with foetal congenital nervous system anomalies at 16–22 weeks’ gestation (n = 36). The control group (n = 30) consisted of pregnant women at the same gestational age who underwent amniocentesis, resulting in a normal karyotype. We analysed glutathione, catalase, and malondialdehyde levels in amniotic fluid. Enzyme activation was measured by spectrophotometry.ResultsThe demographic features of the groups were similar in terms of age, parity, body mass index, and gestational weeks. We detected lower glutathione and catalase levels in the foetal congenital anomaly group than in the control group. We detected higher malondialdehyde levels in the foetal congenital anomaly group than in the control group.ConclusionIn the organism, the rate of formation of free radicals and their rate of removal are balanced, and this is called oxidative balance. As long as oxidative stability is achieved, the organism is not affected by free radicals. This fact should be kept in mind to avoid any type of teratogenic agent that could lead to congenital disorders.

Hidrocefalia congênita canina seguida de hiperadrenocorticismo iatrogênico

A hidrocefalia congênita é caracterizada em animais pelo acúmulo excessivo de líquidocefalorraquidiano (LCR) no crânio, decorrente principalmente de infecção viral do sistemanervoso do feto no ambiente uterino; por predisposição genética ou ainda por quadros dedistocia. No presente relato abordam-se os principais aspectos clínicos, diagnósticos eterapêuticos desta patologia em cães, e apresenta-se um caso clínico de hidrocefalia congênitaem cão sem raça definida, que foi acompanhado clinicamente e laboratorialmente durante 12meses, e recebeu tratamento alopático convencional e acupuntura, evoluindo para quadro dehiperadrenocorticismo secundário.

Typical lesions in the fetal nervous system: correlations between fetal magnetic resonance imaging and obstetric ultrasonography findings.

Central nervous system (CNS) malformations play a role in all fetal malformations. Ultrasonography (US) is the best screening method for identifying fetal CNS malformations. A good echographic study depends on several factors, such as positioning, fetal mobility and growth, the volume of amniotic fluid, the position of the placenta, the maternal wall, the quality of the apparatus, and the sonographer’s experience. Although US is the modality of choice for routine prenatal follow-up because of its low cost, wide availability, safety, good sensitivity, and real-time capability, magnetic resonance imaging (MRI) is promising for the morphological evaluation of fetuses that otherwise would not be appropriately evaluated using US. The aim of this article is to present correlations of fetal MRI findings with US findings for the major CNS malformations.

Evolution of linear and nonlinear fetal heart rate indices throughout pregnancy in appropriate, small for gestational age and preterm fetuses: A cohort study

Background and objectivesTo assess the evolution of linear and nonlinear fetal heart rate (FHR) analysis throughout pregnancy in appropriate (AGA), small for gestational age (SGA) and preterm (PTB) fetuses. MethodsA prospective cohort study was carried out in 171 singleton pregnancies divided in three groups: AGA (n = 147), SGA (n = 13) fetuses and spontaneous PTB (n = 11). FHR was recorded with an external sensor from the 24th to the 40th week of gestation. Linear time- and frequency-domain and nonlinear FHR indices were computed on 10-min segments. Longitudinal analysis of indices throughout pregnancy was performed with generalized estimating equations, and receiver operating characteristic (ROC) curves were calculated for the prediction of SGA and PTB fetuses. ResultsIncreasing gestational age significantly affected most FHR indices, with a general increase in variability and entropy indices, and a decrease in mean FHR. The PTB group exhibited a significantly lower short-term variation, and no monotonic increase in the sympatho-vagal balance as observed in the AGA group. The SGA group exhibited higher long-term irregularity and lower short-term irregularity than the AGA group throughout gestation. In prediction of SGA and PTB, the largest areas under the ROC curves obtained were 0.76 and 0.78, respectively. ConclusionsLinear and nonlinear FHR analysis provides useful information on the evolution of fetal autonomic nervous and complexity control systems throughout pregnancy, in relation with AGA, SGA and PTB fetuses, which may be helpful in clinical practice.

The pathogenesis of microcephaly resulting from congenital infections: why is my baby's head so small?

The emergence of Zika-virus-associated congenital microcephaly has engendered renewed interest in the pathogenesis of microcephaly induced by infectious agents. Three of the original "TORCH" agents are associated with an appreciable incidence of congenital microcephaly: cytomegalovirus, rubella virus, and Toxoplasma gondii. The pathology of congenital microcephaly is characterized by neurotropic infectious agents that involve the fetal nervous system, leading to brain destruction with calcifications, microcephaly, sensorineural hearing loss, and ophthalmologic abnormalities. The inflammatory reaction induced by these four agents has an important role in pathogenesis. The potential role of "strain differences" in pathogenesis of microcephaly by these four pathogens is examined. Specific epidemiologic factors, such as first and early second trimester maternal infection, and the manifestations of congenital infection in the infant, shed some light on the pathogenesis. Immune aspects of normal pregnancy and their role in congenital infections is examined. In this review, we integrate all these findings to create a unified hypothesis of the pathogenesis of congenital microcephaly induced by these infectious agents.

Cannabis use during pregnancy: Pharmacokinetics and effects on child development.

The broad-based legalization of cannabis use has created a strong need to understand its impact on human health and behavior. The risks that may be associated with cannabis use, particularly for sensitive subgroups such as pregnant women, are difficult to define because of a paucity of dose-response data and the recent increase in cannabis potency. Although there is a large body of evidence detailing the mode of action of Δ9-tetrahydrocannabinol (THC) in adults, little work has focused on understanding how cannabis use during pregnancy may impact the development of the fetal nervous system and whether additional plant-derived cannabinoids might participate. This manuscript presents an overview of the historical and contemporary literature focused on the mode of action of THC in the developing brain, comparative pharmacokinetics in both pregnant and nonpregnant model systems and neurodevelopmental outcomes in exposed offspring. Despite growing public health significance, pharmacokinetic studies of THC have focused on nonpregnant adult subjects and there are few published reports on disposition parameters during pregnancy. Data from preclinical species show that THC readily crosses the placenta although fetal exposures appear lower than maternal exposures. The neurodevelopmental data in humans and animals suggest that prenatal exposure to THC may lead to subtle, persistent changes in targeted aspects of higher-level cognition and psychological well-being. There is an urgent need for well-controlled studies in humans and preclinical models on THC as a developmental neurotoxicant. Until more information is available, pregnant women should not assume that using cannabis during pregnancy is safe.

Maternal Antiviral Immunoglobulin Accumulates in Neural Tissue of Neonates To Prevent HSV Neurological Disease.

ABSTRACTWhile antibody responses to neurovirulent pathogens are critical for clearance, the extent to which antibodies access the nervous system to ameliorate infection is poorly understood. In this study on herpes simplex virus 1 (HSV-1), we demonstrate that HSV-specific antibodies are present during HSV-1 latency in the nervous systems of both mice and humans. We show that antibody-secreting cells entered the trigeminal ganglion (TG), a key site of HSV infection, and persisted long after the establishment of latent infection. We also demonstrate the ability of passively administered IgG to enter the TG independently of infection, showing that the naive TG is accessible to antibodies. The translational implication of this finding is that human fetal neural tissue could contain HSV-specific maternally derived antibodies. Exploring this possibility, we observed HSV-specific IgG in HSV DNA-negative human fetal TG, suggesting passive transfer of maternal immunity into the prenatal nervous system. To further investigate the role of maternal antibodies in the neonatal nervous system, we established a murine model to demonstrate that maternal IgG can access and persist in neonatal TG. This maternal antibody not only prevented disseminated infection but also completely protected the neonate from neurological disease and death following HSV challenge. Maternal antibodies therefore have a potent protective role in the neonatal nervous system against HSV infection. These findings strongly support the concept that prevention of prenatal and neonatal neurotropic infections can be achieved through maternal immunization.

DNA methylation and copy number variation analyses of human embryonic stem cell-derived neuroprogenitors after low-dose decabromodiphenyl ether and/or bisphenol A exposure.

The polybrominated diphenyl ether flame retardants decabromodiphenyl ether (BDE-209) and bisphenol A (BPA) are environmental contaminants that can cross the placenta and exert toxicity in the developing fetal nervous system. Copy number variants (CNVs) play a role in a number of genetic disorders and may be implicated in BDE-209/BPA teratogenicity. In this study, we found that BDE-209 and/or BPA exposure decreased neural differentiation efficiency of human embryonic stem cells (hESCs), although there was a >90% induction of neuronal progenitor cells (NPCs) from exposed hESCs. However, the mean of CNV numbers in the NPCs with BDE-209 + BPA treatment was significantly higher compared to the other groups, whereas DNA methylation was lower and DNA methyltransferase(DNMT1 and DNMT3A) expression were significantly decreased in all of the BDE-209 and/or BPA treatment groups compared with the control groups. The number of CNVs in chromosomes 3, 4, 11, 22, and X in NPCs with BDE-209 and/or BPA exposure was higher compared to the control group. In addition, CNVs in chromosomes 7, 8, 14, and 16 were stable in hESCs and hESCs-derived NPCs irrespective of BDE-209/BPA exposure, and CNVs in chromosomes 20 q11.21 and 16 p13.11 might be induced by neural differentiation. Thus, BDE-209/BPA exposure emerges as a potential source of CNVs distinct from neural differentiation by itself. BDE-209 and/or BPA exposure may cause genomic instability in cultured stem cells via reduced activity of DNA methyltransferase, suggesting a new mechanism of human embryonic neurodevelopmental toxicity caused by this class of environmental toxins.