Periods Of Fetal Brain Development Research Articles

Sex-specific associations between placental corticotropin releasing hormone and problem behaviors in childhood

Placental corticotropin-releasing hormone (pCRH) is a neuroactive peptide produced in high concentrations in mid-late pregnancy, during key periods of fetal brain development. Some evidence suggests that higher pCRH exposure during gestation is associated with adverse neurodevelopment, particularly in female offspring. In 858 mother-child dyads from the sociodemographically diverse CANDLE cohort (Memphis, TN), we examined: (1) the slope of pCRH rise in mid-late pregnancy and (2) estimated pCRH at delivery as a measure of cumulative prenatal exposure. When children were 4 years-old, mothers reported on problem behaviors using the Child Behavior Checklist (CBCL) and cognitive performance was assessed by trained psychologists using the Stanford-Binet Intelligence Scales. We fitted linear regression models examining pCRH in relation to behavioral and cognitive performance measures, adjusting for covariates. Using interaction models, we evaluated whether associations differed by fetal sex, breastfeeding, and postnatal neighborhood opportunity. In the full cohort, log-transformed pCRH measures were not associated with outcomes; however, we observed sex differences in some models (interaction p-values≤0.01). In male offspring, an interquartile (IQR) increase in pCRH slope (but not estimated pCRH at delivery), was positively associated with raw Total (β=3.06, 95%CI: 0.40, 5.72), Internalizing (β=0.89, 95%CI: 0.03, 1.76), and Externalizing (β=1.25, 95%CI: 0.27, 2.22) Problem scores, whereas, in females, all associations were negative (Total Problems: β=−1.99, 95%CI: −3.89, −0.09; Internalizing: β=−0.82, 95%CI: −1.42, −0.23; Externalizing: β=−0.56, 95%CI: −1.34, 0.22). No associations with cognitive performance were observed nor did we observe moderation by breastfeeding or postnatal neighborhood opportunity. Our results provide further evidence that prenatal pCRH exposure may impact subsequent child behavior in sex-specific ways, however in contrast to prior studies suggesting adverse impacts in females, steeper mid-gestation pCRH rise was associated with more problem behaviors in males, but fewer in females.

Prenatal exposure to sand and dust storms and children's cognitive function in China: a quasi-experimental study

While there is evidence that sand and dust storms can have adverse health effects, the effects of such storms on children's cognitive function has not been explored. We examined whether prenatal exposure to sand and dust storms affects children's cognitive function and, if so, whether harmful effects of sand and dust storms vary by the trimester of exposure. This study used nationally representative data from the China Family Panel Studies between 2010 and 2014 and data on sand and dust storms from the national Sand and Dust Weather Almanac. We selected four indicators of children's cognitive function: mathematics test scores, word-recognition test scores, the age the child began speaking in whole sentences, and the age the child began counting from one to ten. Since the annual incidence of sand and dust storms is highly variable and is largely unpredictable, we used a region-and-year fixed-effect model to compare the cognitive function of children born in the same region and year but with varying amounts of prenatal exposure to sand and dust storms. We also investigated whether the effect of sand and dust storms varied by the specific month of prenatal exposure. We included 1236 observations for the analysis of mathematics and word-recognition test scores, 2693 observations in the analysis of the age the child began speaking in whole sentences, and 1951 observations for the analysis of the age the child began counting from one to ten. Every 10 additional days of prenatal exposure to sand and dust storms was associated with a 0·20 SD (95% CI 0·06 to 0·35, p=0·009) reduction in word test scores, 0·04 (-0·00 to 0·09, p=0·089) additional months to begin speaking in sentences, and 0·14 (0·03 to 0·25, p=0·021) additional months to begin counting, but was not significantly associated with mathematics test scores (reduction of 0·02 SD, -0·19 to 0·15). 10 additional days of prenatal exposure to sand and dust storms in the seventh gestational month was associated with a 0·18 SD (0·10 to 0·25) reduction in mathematics test scores, a 0·34 SD (0·18 to 0·50) reduction in word test scores, an additional 0·33 months (0·07 to 0·59) to begin speaking in sentences, and an additional 0·20 months (0·04 to 0·35) to begin counting. Our results suggest that protecting pregnant women from the effects of sand and dust storms in the critical periods of fetal brain development could generate benefits for the cognitive function of the next generation. None.

Maternal LC-PUFA status during pregnancy and child problem behavior: the Generation R Study.

Omega 3 (n-3) and 6 (n-6) long-chain polyunsaturated fatty acids (LC-PUFAs) and the n-3:n-6 ratio are important for brain development. Whether maternal LC-PUFA status during pregnancy affects risk of problem behavior in later childhood is unclear. Within a population-based cohort, we measured maternal plasma docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) concentrations and n-3:n-6-ratio in mid-pregnancy. Child emotional and behavioral problems at 6 y of age were assessed by parents (child behavior checklist), teachers (teacher report form), and combined parent/teacher report. Higher maternal DHA and n-3:n-6 ratio were associated with fewer child emotional problems using parent (odds ratio (OR)DHA = 0.82; 95% confidence interval (CI): 0.70, 0.96; P = 0.02 and OR(n-3:n-6) = 0.83; 95% CI: 0.71, 0.96; P = 0.01; n = 5,307) and combined parent/teacher scores (ORDHA = 0.79; 95% CI: 0.66, 0.95; P = 0.01 and OR(n-3:n-6) = 0.77; 95% CI: 0.65, 0.92; P < 0.01; n = 2,828). Higher AA was associated with more child behavioral problems using teacher (OR = 1.10; 95% CI: 1.00, 1.20; P = 0.04; n = 3,365) and combined parent/teacher scores (OR = 1.12; 95% CI: 1.02, 1.22; P = 0.02; n = 2,827). Maternal EPA was not associated with child problem behavior. Indications of associations of maternal LC-PUFA status with child emotional and behavioral problems were found. Future research is needed to identify LC-PUFA-sensitive periods of fetal brain development by including multiple assessments of prenatal LC-PUFA status.

Influence of Panax ginseng on the offspring of adult rats exposed to prenatal stress.

The exposure of pregnant females to stress during a critical period of fetal brain development is an environmental risk factor for the development of schizophrenia in adult offspring. Schizophrenia is a group of common mental disorders of unclear origin, affecting approximately 1% of the global population, showing a generally young age at onset. In the present study, a repeated variable stress paradigm was applied to pregnant rats during the final week of gestation. The effects of an extract of Panax ginseng C.A. Meyer (PG) on rats exposed to prenatal stress (PNS) were investigated in terms of behavioral activity and protein expression analyses. In the behavioral tests, grooming behavior in a social interaction test, line-crossing behavior in an open-field test and swimming activity in a forced-swim test were decreased in the rats exposed to PNS compared with the non-stressed offspring; the changes in behavioral activity were reversed upon oral treatment with PG (300 mg/kg). Subsequently, western blot analysis and immunohistochemical analyses of the prefrontal cortex and hippocampus revealed that the downregulation of several neurodevelopmental genes which occurred following exposure to PNS was reversed upon treatment with PG. The current findings demonstrate that the downregulation of several genes following exposure to PNS may affect subsequent behavioral changes, and that these phenomena are reversed following treatment with PG during pregnancy. Our results suggest that oral treatment with PG reduces the incidence of psychiatric disorders, such as schizophrenia.

Maternal Stress Induces Epigenetic Signatures of Psychiatric and Neurological Diseases in the Offspring

The gestational state is a period of particular vulnerability to diseases that affect maternal and fetal health. Stress during gestation may represent a powerful influence on maternal mental health and offspring brain plasticity and development. Here we show that the fetal transcriptome, through microRNA (miRNA) regulation, responds to prenatal stress in association with epigenetic signatures of psychiatric and neurological diseases. Pregnant Long-Evans rats were assigned to stress from gestational days 12 to 18 while others served as handled controls. Gestational stress in the dam disrupted parturient maternal behaviour and was accompanied by characteristic brain miRNA profiles in the mother and her offspring, and altered transcriptomic brain profiles in the offspring. In the offspring brains, prenatal stress upregulated miR-103, which is involved in brain pathologies, and downregulated its potential gene target Ptplb. Prenatal stress downregulated miR-145, a marker of multiple sclerosis in humans. Prenatal stress also upregulated miR-323 and miR-98, which may alter inflammatory responses in the brain. Furthermore, prenatal stress upregulated miR-219, which targets the gene Dazap1. Both miR-219 and Dazap1 are putative markers of schizophrenia and bipolar affective disorder in humans. Offspring transcriptomic changes included genes related to development, axonal guidance and neuropathology. These findings indicate that prenatal stress modifies epigenetic signatures linked to disease during critical periods of fetal brain development. These observations provide a new mechanistic association between environmental and genetic risk factors in psychiatric and neurological disease.

Lack of Action of Exogenously Administered T3 on the Fetal Rat Brain Despite Expression of the Monocarboxylate Transporter 8

Mutations of the monocarboxylate transporter 8 gene (MCT8, SLC16A2) cause the Allan-Herndon-Dudley syndrome, an X-linked syndrome of severe intellectual deficit and neurological impairment. Mct8 transports thyroid hormones (T4 and T3), and the Allan-Herndon-Dudley syndrome is likely caused by lack of T3 transport to neurons during critical periods of fetal brain development. To evaluate the role of Mct8 in thyroid hormone action in the fetal brain we administered T4 or T3 to thyroidectomized pregnant dams treated with methyl-mercapto-imidazol to produce maternal and fetal hypothyroidism. Gene expression was then measured in the fetal cerebral cortex. T4 increased Camk4, Sema3c, and Slc7a3 expression, but T3 was without effect. To investigate the cause for the lack of T3 action we analyzed the expression of organic anion transport polypeptide (Oatp14, Slco1c1), a T4 transporter, and Mct8 (Slc16a2), a T4 and T3 transporter, by confocal microscopy. Both proteins were present in the brain capillaries forming the blood-brain barrier and in the epithelial cells of the choroid plexus forming the blood-cerebrospinal fluid barrier. It is concluded that T4 from the maternal compartment influences gene expression in the fetal cerebral cortex, possibly after transport via organic anion transporter polypeptide and/or Mct8, and conversion to T3 in the astrocytes. On the other hand, T3 does not reach the target neurons despite the presence of Mct8. The data indicate that T4, through local deiodination, provides most T3 in the fetal rat brain. The role of Mct8 as a T3 transporter in the fetal rat brain is therefore uncertain.

Binge-pattern alcohol exposure during puberty induces sexually dimorphic changes in genes regulating the HPA axis

Maternal alcohol consumption during critical periods of fetal brain development leads to devastating long-term consequences on adult reproductive physiology, cognitive function, and social behaviors. However, very little is known about the long-term consequences of alcohol consumption during puberty, which is perhaps an equally dynamic and critical period of brain development. Alcohol abuse during adulthood has been linked with an increase in clinically diagnosed anxiety disorders, yet the etiology and neurochemical mechanisms of alcohol-induced anxiety behavior is unknown. In this study, we determined the effects of binge ethanol exposure during puberty on two critical central regulators of stress and anxiety behavior: corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP). Our results showed that ethanol increased plasma corticosterone (CORT) levels in both sexes, yet binge-treated animals had significantly lower CORT levels than animals exposed to a single dose, suggesting that the hypothalamo-pituitary-adrenal (HPA) axis habituated to the repeated stressful stimuli of ethanol. Binge ethanol exposure also significantly increased CRH and AVP gene expression in the paraventricular nucleus of males, but not females. Overall, our results demonstrate that binge ethanol exposure during puberty changes the central expression of stress-related genes in a sex-specific manner, potentially leading to permanent dysregulation of the HPA axis and long-term behavioral consequences.

Antenatal and postnatal evidence of periventricular leukomalacia as a further indication of vascular disruption in Adams–Oliver syndrome

We describe a new family with Adams-Oliver syndrome (AOS). The propositus is a 14-month-old boy presenting with aplasia cutis congenita, distal limb transverse defects, growth retardation, and a wide atrial septal defect. Central nervous system abnormalities included central hypotonia, and magnetic resonance imaging (MRI) findings consistent with periventricular leukomalacia (PVL). Fetal MRI at 26 weeks' gestation had shown bilateral dilatation of lateral ventricles and periventricular cysts at the site of postnatal lesions. The patient's father and paternal grandfather also had manifestations indicative of AOS. Antenatal and postnatal MRI findings suggest that our patient's PVL represents an unusual congenital feature of AOS, possibly due to vascular disruption and decreased perfusion during critical periods of fetal brain development.

Relationships between sex hormones assessed in amniotic fluid, and maternal and umbilical cord serum: What is the best source of information to investigate the effects of fetal hormonal exposure?

Levels of testosterone (T) (total and free), androstenedione (A4), dehydroepiandrosterone sulphate (DHEAS), sex hormone-binding globulin (SHBG), and estradiol (E2) were measured by radioimmunoassay (RIA) in 156 normal pregnancies (77 male and 79 female fetuses). Samples were obtained from amniotic fluid, 2nd and 3rd trimester maternal serum, and umbilical cord serum at birth . During the critical period of brain differentiation, at the beginning of the second trimester of pregnancy, sex differences in T and A4 were found in amniotic fluid and not in maternal serum. This finding adds to the fact that mostly low and nonsignificant correlations were found for the different androgenic hormones between levels assessed in amniotic fluid and maternal plasma at this particular and very sensitive period of fetal brain development. On the other hand, high correlations were found for the same hormones between the samples of maternal serum in the 2nd and the 3rd trimester. Our data show that, of all available sources, amniotic fluid seems to be the best candidate to investigate the effects of early fetal androgen exposure.

Repeated variable prenatal stress alters pre- and postsynaptic gene expression in the rat frontal pole.

Exposure of pregnant women to stress during a critical period of fetal brain development is an environmental risk factor for developing schizophrenia in the adult offspring. We have applied a repeated variable stress paradigm to pregnant Sprague-Dawley rats during the last week of gestation coinciding with the second trimester in human brain development. Here we report our findings from a microarray analysis of the frontal pole of the prenatally stressed adult offspring and non-stressed adult controls complemented with measurement of plasma corticosterone levels following exposure to an acute stress. The direction of change of selected genes was confirmed by real time quantitative fluorescence PCR and in situ hybridization. The analysis revealed significant changes in genes associated with the NMDA receptor/postsynaptic density complex and the vesicle exocytosis machinery including NMDA receptor NR1 and NR2A subunits, densin-180, brain enriched guanylate kinase-associated protein, synaptosome-associated protein of 25 kDa, synaphin/complexin and vesicle-associated membrane protein 2/synaptobrevin 2. Interestingly, some of the changes in this animal preparation are analogous to changes observed in schizophrenic and bipolar patients. Our results suggest that application of a repeated variable prenatal stress paradigm during a critical period of fetal brain development reprograms the response of the hypothalamo-pituitary-adrenal axis to acute stress and results in gene expression changes that may have enduring effects on synaptic function in the offspring during adulthood.