Development Of Fetal Central Nervous System Research Articles

In Vitro and In Vivo Analysis of the Effects of 3,5-DMA and Its Metabolites in Neural Oxidative Stress and Neurodevelopmental Toxicity.

3,5-Dimethylaniline (3,5-DMA), a monocyclic aromatic amine, is widely present in a spectrum of sources including tobacco, dyes, combustion products, and suspended particulates. 3,5-DMA and its metabolites form superoxides, resulting in apoptosis or oncogenesis. Data of a direct effect of 3,5-DMA on the nervous system, especially the developing brain, are lacking. Therefore, we investigated the effects of 3,5-DMA and its metabolites on fetal neurite growth and brain development using in vitro cell cultures of primary cortical neurons to observe whether these compounds caused neuronal cytotoxicity and affected neurite structural development. With increasing concentrations of 3,5-DMA (10, 50, 100, 500, 1000 μM) and its major metabolite 5-dimethylaminophenol (3,5-DMAP) (10, 50, 100, 500, 1000 μM), reactive oxygen species (ROS), cytotoxicity, and DNA damage increased significantly in the cells and dendritic arborization decreased. The addition of 5 mM N-acetylcysteine, an ROS scavenger, reduced ROS in the cells and alleviated the neuronal damage. In vivo studies in Sprague Dawley pregnant rats suggested that exposure to 3,5-DMA (10, 30, 60, 100 mg/kg/day) subcutaneously from GD15 to GD17 led to fetal cerebral cortex thinning. BrdU labeling showed that 3,5-DMA reduced the number and generation of cortical cells. To detect the laminar position of newly generated neurons, cortex layer markers such as Satb2, Ctip2, and Tbr1 were used. 3,5-DMA perturbed the cortical layer distribution in developing fetal rats. In summary, this is the first study to provide evidence for 3,5-DMA and its metabolites causing anomalies of the fetal central nervous system development through ROS production.

A metabolomics-based approach for non-invasive diagnosis of chromosomal anomalies

Chromosomal anomalies (CA) are the most frequent fetal anomalies. To evaluate the diagnostic performance of a machine learning ensemble model based on the maternal serum metabolomic fingerprint of fetal aneuploidies during the second trimester . This is a case-control pilot study. Metabolomic profiles have been obtained on serum of 328 mothers (220 controls and 108 cases), using gas chromatography coupled to mass spectrometry. Eight machines learning and classification models were built and optimized. An ensemble model was built using a voting scheme. All samples were randomly divided into two sets. One was used as training set, the other one for diagnostic performance assessment. Ensemble machine learning model correctly classified all cases and controls. The accuracy was the same for trisomy 21 and 18; also, the other CA were correctly detected. Elaidic, stearic, linolenic, myristic, benzoic, citric and glyceric acid, mannose, 2-hydroxy butyrate, phenylalanine, proline, alanine and 3-methyl histidine were selected as the most relevant metabolites in class separation. The proposed model, based on the maternal serum metabolomic fingerprint of fetal aneuploidies during the second trimester, correctly identifies all the cases of chromosomal abnormalities. Overall, this preliminary analysis appeared suggestive of a metabolic environment conductive to increased oxidative stress and a disturbance in the fetal central nervous system development. Maternal serum metabolomics can be a promising tool in the screening of chromosomal defects. Moreover, metabolomics allows to extend our knowledge about biochemical alterations caused by aneuploidies and responsible for the observed phenotypes.

Decabrominated diphenyl ether and methylmercury impair fetal nervous system development in mice at documented human exposure levels.

The central nervous system (CNS) is extremely vulnerable to the toxic effects of environmental pollutants during development. Polybrominated diphenyl ethers (PBDEs) are persistent contaminants, increasingly present in the environment and in human tissues. Recent investigations identified a correlation between maternal exposure to PBDEs and impairment in fetal neurobehavioral development, suggesting that these contaminants pose a potential risk for children. We investigated on the potential effects of environmental decabrominated diphenyl ether (decaBDE, the fully brominated congener) on key neurodevelopmental molecules (e.g., synaptic proteins and immature neuron markers) in fetal mouse neurons. Methylmercury was used as reference neurotoxic contaminant and to evaluate its possible synergism with decaBDE. The neurotoxic effects of decaBDE and methylmercury were determined in developing cultured neurons from mouse fetal hippocampus and cerebellum. Neuron death, dendritic branching, synaptic protein expression, markers of immature neurons, and microglia activation were evaluated by immunocytochemistry. Brain samples from prenatally treated embryos were also examined for neurotoxicity signs by immunoblotting and histochemistry. DecaBDE significantly affected (down to 0.4 nM) the number of dendritic branches, and the levels of synaptic proteins and doublecortin in cultured neurons. Prenatal exposure to decaBDE decreased the synaptic proteins and increased the expression of the immature neuron and microglial markers in mouse fetuses. In conclusion, prenatal exposure to realistic (relevant for human exposure) concentrations of decaBDE induces impairment of fetal CNS development in mice, suggesting a potential risk of fetotoxicity in humans.

A new treatment for cognitive disorders related to in utero exposure to alcohol.

Maternal alcohol consumption during pregnancy has detrimental effects on fetal central nervous system development. Maternal alcohol consumption prior to and during pregnancy significantly affects cognitive functions in offspring, which may be related to changes in cyclin-dependent kinase 5 because it is associated with modulation of synaptic plasticity and impaired learning and memory. In this study, we examined adult offspring in a maternal alcohol consumption model in rats. Y-maze test results showed that in utero exposure to alcohol impairs learning and memory capacities. Cyclin-dependent kinase 5 mRNA and protein expressions in the hippocampus of the offspring were significantly elevated, as assayed by quantitative real-time PCR and reverse transcription-PCR, immunofluorescence, and immuno-precipitation. Our experimental findings strongly suggest that altered cyclin-dependent kinase 5 may mediate impaired learning and memory in adult rats that were exposed to alcohol by maternal consumption while in utero.

Cross-hemispheric functional connectivity in the human fetal brain.

Compelling evidence indicates that psychiatric and developmental disorders are generally caused by disruptions in the functional connectivity (FC) of brain networks. Events occurring during development, and in particular during fetal life, have been implicated in the genesis of such disorders. However, the developmental timetable for the emergence of neural FC during human fetal life is unknown. We present the results of resting-state functional magnetic resonance imaging performed in 25 healthy human fetuses in the second and third trimesters of pregnancy (24 to 38 weeks of gestation). We report the presence of bilateral fetal brain FC and regional and age-related variation in FC. Significant bilateral connectivity was evident in half of the 42 areas tested, and the strength of FC between homologous cortical brain regions increased with advancing gestational age. We also observed medial to lateral gradients in fetal functional brain connectivity. These findings improve understanding of human fetal central nervous system development and provide a basis for examining the role of insults during fetal life in the subsequent development of disorders in neural FC.

Sonographic study of the development of fetal corpus callosum in a Chinese population

The observation of fetal corpus callosum (CC) is important for the prenatal sonographic assessment of fetal central nervous system development. The aim of this study was to investigate the development of normal Chinese fetal CC. CC measurements were performed using high-resolution transabdominal sonography on 622 Chinese fetuses between 16 and 39 weeks' gestation. The correlation between CC size and gestational age was investigated. The fetal CC length increased in a linear fashion during pregnancy. The length of the CC as a function of gestational age was expressed by the following regression equation: length (mm) = -9.567 + 1.495 x gestational age (weeks) (r = 0.932, p < 0.001). Knowledge of normal CC appearance may help identify developmental anomalies and enable accurate prenatal counseling.

DEHP, bis(2)-ethylhexyl phthalate, alters gene expression in human cells: possible correlation with initiation of fetal developmental abnormalities

Diethylhexylphthalate (DEHP) is a widely distributed phthalate, to which humans are exposed to due to its variety of commercial and manufacturing uses. As a plasticiser, it is found in a wide number of products, and metabolites of DEHP have been detected in urine samples from a high percentage of the people screened for phthalates. We utilised DNA microarray analysis to evaluate DEHP for gene expression disrupting activity using the human cell line MCF-7, and found that DEHP significantly dysregulated approximately 34% of the 2400 genes spotted on the NEN2400 chip we used. The results suggest that DEHP, a known estrogen agonist and probable androgen antagonist, alters the expression of a number of genes, many of which are critical for fetal development. Down-regulation of two genes, FGD1 and PAFAH1B1, related in that both are essential for fetal brain development, was corroborated using quantitative real time PCR. These studies show DEHP to be a highly effective human gene expression-altering chemical, and that, at appropriate concentrations, it has the possibility of altering fetal central nervous system development, resulting in the birth defects lissencephaly and/or faciodigitogenital dysplasia.

New data about embryonic and fetal neurodevelopment and behavior obtained by 3D and 4D sonography

The development of the human central nervous system (CNS) begins in the early embryonic period and proceeds through a sequence of very complicated processes long after delivery. Although the neurodevelopmental processes are genetically determined, their complexity and intensity implicates the vulnerability of the CNS to number of environmental factors. There is substantial evidence to show that many neurological problems, from minor cerebral dysfunction to the cerebral palsy, originate form the prenatal, rather than perinatal or postnatal periods of life. A variety of neurological and neuropsychiatric diseases is nowadays considered to originate, at least partly, from the prenatal incidents. In most of these conditions, there is no reliable parameter for detection or prediction of cerebral lesions and there is an urgent need to develop strategies that would enable the early detection of cerebral lesions or indications that such lesions might occur. The new, advanced, imaging techniques such as 3-dimensional and 4-dimensional sonography, opened a new perspective for the investigation of structural and functional development of fetal CNS. The application of these techniques might improve our understanding of the prenatal neurodevelopmental events and possibly facilitate the development of diagnostic strategies for early detection or prevention of brain dysfunctions and damage.

Fetal magnetoencephalography in intrauterine growth retarded pregnancies.

To investigate the fetal brain activity in pre-eclamptic and normal pregnancies. Biomagnetic measurements were performed by means of a superconducting quantum interference device (SQUID) in an electrically shielded room of low magnetic noise. The study population included 28 pre-eclamptic (34-37 weeks' gestation) and 19 normal pregnancies (34-37 weeks' gestation). The pre-eclamptic group consisted of 11 cases with birth weight below the 10th percentile (1969 +/- 129 g) and 17 cases above the 10th percentile (2496 +/- 257 g). Biomagnetic signals (waveforms) recorded from fetal brains were expressed in terms of magnetic power spectral amplitudes. The total corresponding spectral amplitudes in the frequency range 2-7 Hz were high (719 +/- 69 Ft/ radical Hz in neonates <10th percentile and 537 +/- 105 Ft/ radical Hz in neonates >10th percentile) in most (82%) pre-eclamptic pregnancies and low (382 +/- 35 Ft/ radical Hz) in most normal pregnancies (95%). The difference between normal and all pre-eclamptic pregnancies was highly significant (Student's t-test: p < 0.0001). Comparing the two groups of pre-eclampsia we found also a highly significant difference (Student's t-test: p < 0.0001). Biomagnetic measurements of fetal brain activity could be useful in the assessment of fetal central nervous system development.

The Role of Erythropoietin in the Mother and Fetus

Erythropoietin is one of the main regulators of haematopoiesis in the human and is being used more and more widely in the treatment of such clinical conditions as anaemia of chronic renal disease which would otherwise require transfusion. Recently, this approach has been extended to pregnant patients and the results have been encouraging. Fetal erythropoietin levels appear to be good indicators of anaemia and hypoxia which, if detected, allow for the identification of compromised fetuses. More data are emerging pointing to erythropoietin’s role in fetal central nervous system development and its potential protective role against hypoxia. This carries important implications for the obstetrician/gynaecologist, as erythropoietin is likely to play a major part in the diagnosis and treatment of certain maternal and fetal conditions.

Geographic and Seasonal Variations in Births

IN previous investigations we have attempte,d to demonstrate the relationship of climatic variations during the first trimester of pregnancy to the b,irth of mentally deficient children. In the most recent study we tested the hypothesis that above-average summer temperatures during the third month of pregnancy, the critical period of fetal central nervous system development, are associated with an increased risk of being born mentally defective. This hypothesis was substantiated for the period of 1913-48 based on the date of birth, and therefore of conception, of mentally defective children admitted to the Columbus State