ResearchPad - birth-defects https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Ultrasound prediction of Zika virus-associated congenital injury using the profile of fetal growth]]> https://www.researchpad.co/article/elastic_article_13878 Zika virus (ZIKV) is a mosquito-transmitted flavivirus, recently linked to microcephaly and central nervous system anomalies following infection in pregnancy. Striking findings of disproportionate growth with a smaller than expected head relative to body length have been observed more commonly among fetuses with exposure to ZIKV in utero compared to pregnancies without ZIKV infection regardless of other signs of congenital infection including microcephaly. This study’s objective was to determine the diagnostic accuracy of femur-sparing profile of intrauterine growth restriction for the identification of ZIKV-associated congenital injuries on postnatal testing. A retrospective cohort study of pregnant women with possible or confirmed ZIKV infection between January 1, 2016 and December 31, 2017 were included. Subjects were excluded if no prenatal ultrasound was available. A femur-sparing profile of growth restriction determined using INTERGROWTH-21st sonographic standard for head circumference to femur length (HC: FL). Congenital injuries were determined postnatally by imaging, comprehensive eye exam and standard newborn hearing screen. A total of 111 pregnant women diagnosed with ZIKV infection underwent fetal ultrasound and 95 neonates had complete postnatal evaluation. Prenatal microcephaly was detected in 5% of fetuses (6/111). Postnatal testing detected ZIKV-associated congenital injuries in 25% of neonates (24/95). A HC: FL Z-score ≤ -1.3 had a 52% specificity (95% CI 41–63%), 82% negative predictive value (NPV, 95% CI 73–88%) for the detection of ZIKV-associated congenital injuries in the neonatal period. A more stringent threshold with a Z-score ≤ -2 was associated with a 90% specificity (95% CI 81–95%), 81% NPV (95% CI 77–85%). Excluding cases of fetal microcephaly, HC: FL (Z-score ≤ -2) demonstrated a similar specificity (89%, 95% CI 81–95%) with superior NPV (87%, 95% CI 84–90%). The sonographic recognition of a normally proportioned fetus may be useful prenatally to exclude a wider spectrum of ZIKV-associated congenital injuries detected postnatally.

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<![CDATA[New estimates of the Zika virus epidemic attack rate in Northeastern Brazil from 2015 to 2016: A modelling analysis based on Guillain-Barré Syndrome (GBS) surveillance data]]> https://www.researchpad.co/article/elastic_article_7754 The mandatory reporting of the Zika virus (ZIKV) disease began region-wide in February 2016, and it is believed that ZIKV cases could have been highly under-reported before that. Given the Guillain-Barré syndrome (GBS) is relatively well reported, the GBS surveillance data has the potential to act as a reasonably reliable proxy for inferring the true ZIKV epidemics. We developed a mathematical model incorporating weather effects to study the ZIKV-GBS epidemics and estimated the key epidemiological parameters. It was found that the attack rate of ZIKV was likely to be lower than 33% over the two epidemic waves. The risk rate from symptomatic ZIKV case to develop GBS was estimated to be approximately 0.0061%. The analysis suggests that it would be difficult for another ZIKV outbreak to appear in Northeastern Brazil in the near future.

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<![CDATA[Micro-RNA signatures in monozygotic twins discordant for congenital heart defects]]> https://www.researchpad.co/article/N5a7c737e-22cf-4de0-b5e8-861cb3f8f58f

Background

MicroRNAs (miRNAs) are small RNAs regulating gene expression post-transcriptionally. Recent studies demonstrated that miRNAs are involved in the development of congenital heart defects (CHD). In this study, we aimed at identifying the specific patterns of miRNAs in blood of monozygotic twin pairs discordant for CHD and to assess whether miRNAs might be involved in the development or reflect the consequences of CHD.

Methods

miRNA microarray analysis and Real-Time Quantitative PCR (RT-qPCR) were employed to determine the miRNA abundance level from 12 monozygotic twins discordant for CHD and their non-CHD co-twins (n = 12). Enrichment analyses of altered miRNAs were performed using bioinformatics tools.

Results

Compared with non-CHD co-twins, profiling analysis indicated 34 miRNAs with a significant difference in abundance level (p<0.05, fold change ≥ 1.3), of which 11 miRNAs were up-regulated and 23 miRNAs were down-regulated. Seven miRNAs were validated with RT-qPCR including miR-511-3p, miR-1306-5p, miR-421, miR-4707-3p, miR-4732-3p, miR-5189-3p, and miR-890, and the results were consistent with microarray analysis. Five miRNAs namely miR-511-3p, miR-1306-5p, miR-4732-3p, miR-5189-3p, and miR-890 were found to be significantly up-regulated in twins < 10 years old. Bioinformatics analysis showed that the 7 validated miRNAs were involved in phosphatidylinositol signaling, gap junction signaling, and adrenergic signaling in cardiomyocytes.

Conclusions

Our data show deregulated miRNA abundance levels in the peripheral blood of monozygotic twins discordant for CHD, and identify new candidates for further analysis, which may contribute to understanding the development of CHD in the future. Bioinformatics analysis indicated that the target genes of these miRNAs are likely involved in signaling and communication of cardiomyocytes.

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<![CDATA[Furin, a transcriptional target of NKX2-5, has an essential role in heart development and function]]> https://www.researchpad.co/article/5c897793d5eed0c4847d307a

The homeodomain transcription factor NKX2-5 is known to be essential for both normal heart development and for heart function. But little is yet known about the identities of its downstream effectors or their function during differentiation of cardiac progenitor cells (CPCs). We have used transgenic analysis and CRISPR-mediated ablation to identify a cardiac enhancer of the Furin gene. The Furin gene, encoding a proprotein convertase, is directly repressed by NKX2-5. Deletion of Furin in CPCs is embryonic lethal, with mutant hearts showing a range of abnormalities in the outflow tract. Those defects are associated with a reduction in proliferation and premature differentiation of the CPCs. Deletion of Furin in differentiated cardiomyocytes results in viable adult mutant mice showing an elongation of the PR interval, a phenotype that is consistent with the phenotype of mice and human mutant for Nkx2-5. Our results show that Furin mediate some aspects of Nkx2-5 function in the heart.

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<![CDATA[The association between Zika virus infection and microcephaly in Brazil 2015–2017: An observational analysis of over 4 million births]]> https://www.researchpad.co/article/5c882414d5eed0c484639707

Background

In 2015, high rates of microcephaly were reported in Northeast Brazil following the first South American Zika virus (ZIKV) outbreak. Reported microcephaly rates in other Zika-affected areas were significantly lower, suggesting alternate causes or the involvement of arboviral cofactors in exacerbating microcephaly rates.

Methods and findings

We merged data from multiple national reporting databases in Brazil to estimate exposure to 9 known or hypothesized causes of microcephaly for every pregnancy nationwide since the beginning of the ZIKV outbreak; this generated between 3.6 and 5.4 million cases (depending on analysis) over the time period 1 January 2015–23 May 2017. The association between ZIKV and microcephaly was statistically tested against models with alternative causes or with effect modifiers. We found no evidence for alternative non-ZIKV causes of the 2015–2017 microcephaly outbreak, nor that concurrent exposure to arbovirus infection or vaccination modified risk. We estimate an absolute risk of microcephaly of 40.8 (95% CI 34.2–49.3) per 10,000 births and a relative risk of 16.8 (95% CI 3.2–369.1) given ZIKV infection in the first or second trimester of pregnancy; however, because ZIKV infection rates were highly variable, most pregnant women in Brazil during the ZIKV outbreak will have been subject to lower risk levels. Statistically significant associations of ZIKV with other birth defects were also detected, but at lower relative risks than that of microcephaly (relative risk < 1.5). Our analysis was limited by missing data prior to the establishment of nationwide ZIKV surveillance, and its findings may be affected by unmeasured confounding causes of microcephaly not available in routinely collected surveillance data.

Conclusions

This study strengthens the evidence that congenital ZIKV infection, particularly in the first 2 trimesters of pregnancy, is associated with microcephaly and less frequently with other birth defects. The finding of no alternative causes for geographic differences in microcephaly rate leads us to hypothesize that the Northeast region was disproportionately affected by this Zika outbreak, with 94% of an estimated 8.5 million total cases occurring in this region, suggesting a need for seroprevalence surveys to determine the underlying reason.

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<![CDATA[Potential inconsistencies in Zika surveillance data and our understanding of risk during pregnancy]]> https://www.researchpad.co/article/5c1813a1d5eed0c48477565b

Background

A significant increase in microcephaly incidence was reported in Northeast Brazil at the end of 2015, which has since been attributed to an epidemic of Zika virus (ZIKV) infections earlier that year. Further incidence of congenital Zika syndrome (CZS) was expected following waves of ZIKV infection throughout Latin America; however, only modest increases in microcephaly and CZS incidence have since been observed. The quantitative relationship between ZIKV infection, gestational age and congenital outcome remains poorly understood.

Methodology/Principle findings

We characterised the gestational-age-varying risk of microcephaly given ZIKV infection using publicly available incidence data from multiple locations in Brazil and Colombia. We found that the relative timings and shapes of ZIKV infection and microcephaly incidence curves suggested different gestational risk profiles for different locations, varying in both the duration and magnitude of gestational risk. Data from Northeast Brazil suggested a narrow window of risk during the first trimester, whereas data from Colombia suggested persistent risk throughout pregnancy. We then used the model to estimate which combination of behavioural and reporting changes would have been sufficient to explain the absence of a second microcephaly incidence wave in Bahia, Brazil; a population for which we had two years of data. We found that a 18.9-fold increase in ZIKV infection reporting rate was consistent with observed patterns.

Conclusions

Our study illustrates how surveillance data may be used in principle to answer key questions in the absence of directed epidemiological studies. However, in this case, we suggest that currently available surveillance data are insufficient to accurately estimate the gestational-age-varying risk of microcephaly from ZIKV infection. The methods used here may be of use in future outbreaks and may help to inform improved surveillance and interpretation in countries yet to experience an outbreak of ZIKV infection.

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<![CDATA[Identification of candidate gene FAM183A and novel pathogenic variants in known genes: High genetic heterogeneity for autosomal recessive intellectual disability]]> https://www.researchpad.co/article/5c0ae474d5eed0c484589bc7

The etiology of intellectual disability (ID) is heterogeneous including a variety of genetic and environmental causes. Historically, most research has not focused on autosomal recessive ID (ARID), which is a significant cause of ID, particularly in areas where parental consanguinity is common. Identification of genetic causes allows for precision diagnosis and improved genetic counseling. We performed whole exome sequencing to 21 Turkish families, seven multiplex and 14 simplex, with nonsyndromic ID. Based on the presence of multiple affected siblings born to unaffected parents and/or shared ancestry, we consider all families as ARID. We revealed the underlying causative variants in seven families in MCPH1 (c.427dupA, p.T143Nfs*5), WDR62 (c.3406C>T, p.R1136*), ASPM (c.5219_5225delGAGGATA, p.R1740Tfs*7), RARS (c.1588A>G, p.T530A), CC2D1A (c.811delG, p.A271Pfs*30), TUSC3 (c.793C>T, p.Q265*) and ZNF335 (c.808C>T, p.R270C and c.3715C>A, p.Q1239K) previously linked with ARID. Besides ARID genes, in one family, affected male siblings were hemizygous for PQBP1 (c.459_462delAGAG, p.R153Sfs*41) and in one family the proband was female and heterozygous for X-chromosomal SLC9A6 (c.1631+1G>A) variant. Each of these variants, except for those in MCPH1 and PQBP1, have not been previously published. Additionally in one family, two affected children were homozygous for the c.377G>A (p.W126*) variant in the FAM183A, a gene not previously associated with ARID. No causative variants were found in the remaining 11 families. A wide variety of variants explain half of families with ARID. FAM183A is a promising novel candidate gene for ARID.

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<![CDATA[A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies]]> https://www.researchpad.co/article/5b079d4e463d7e75962e790f

Recent evidence suggests that the presence of more than one pathogenic mutation in a single patient is more common than previously anticipated. One of the challenges hereby is to dissect the contribution of each gene mutation, for which animal models such as Drosophila can provide a valuable aid. Here, we identified three families with mutations in ADD3, encoding for adducin-γ, with intellectual disability, microcephaly, cataracts and skeletal defects. In one of the families with additional cardiomyopathy and steroid-resistant nephrotic syndrome (SRNS), we found a homozygous variant in KAT2B, encoding the lysine acetyltransferase 2B, with impact on KAT2B protein levels in patient fibroblasts, suggesting that this second mutation might contribute to the increased disease spectrum. In order to define the contribution of ADD3 and KAT2B mutations for the patient phenotype, we performed functional experiments in the Drosophila model. We found that both mutations were unable to fully rescue the viability of the respective null mutants of the Drosophila homologs, hts and Gcn5, suggesting that they are indeed pathogenic in flies. While the KAT2B/Gcn5 mutation additionally showed a significantly reduced ability to rescue morphological and functional defects of cardiomyocytes and nephrocytes (podocyte-like cells), this was not the case for the ADD3 mutant rescue. Yet, the simultaneous knockdown of KAT2B and ADD3 synergistically impaired kidney and heart function in flies as well as the adhesion and migration capacity of cultured human podocytes, indicating that mutations in both genes may be required for the full clinical manifestation. Altogether, our studies describe the expansion of the phenotypic spectrum in ADD3 deficiency associated with a homozygous likely pathogenic KAT2B variant and thereby identify KAT2B as a susceptibility gene for kidney and heart disease in ADD3-associated disorders.

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<![CDATA[Perinatal Natural History of the Ts1Cje Mouse Model of Down Syndrome: Growth Restriction, Early Mortality, Heart Defects, and Delayed Development]]> https://www.researchpad.co/article/5989da27ab0ee8fa60b813d9

Background

The Ts1Cje model of Down syndrome is of particular interest for perinatal studies because affected males are fertile. This permits affected pups to be carried in wild-type females, which is similar to human pregnancies. Here we describe the early natural history and growth profiles of Ts1Cje embryos and neonates and determine if heart defects are present in this strain.

Methods

Pups were studied either on embryonic (E) day 15.5, or from postnatal (P) day 3 through weaning on P21. PCR amplification targeting the neomycin cassette (present in Ts1Cje) and Sry (present in males) was used to analyze pup genotypes and sex ratios. Body weights and lengths, as well as developmental milestones, were recorded in Ts1Cje mice and compared to their wild-type (WT) littermates. Histological evaluations were performed at E15.5 to investigate the presence or absence of heart defects. Pups were divided into two groups: Ts1Cje-I pups survived past weaning and Ts1Cje-II pups died at some point before P21.

Results

Ts1Cje mouse embryos showed expected Mendelian ratios (45.8%, n = 66 for Ts1Cje embryos; 54.2%, n = 78 for WT embryos). Histological analysis revealed the presence of ventricular septal defects (VSDs) in 21% of Ts1Cje E15.5 embryos. After weaning, only 28.2% of pups were Ts1Cje (185 Ts1Cje out of 656 total pups generated), with males predominating (male:female ratio of 1.4:1). Among the recovered dead pups (n = 207), Ts1Cje (63.3%, n = 131, p<0.01) genotype was found significantly more often than WT (36.7%, n = 76). Retrospective analysis of Ts1Cje-II (pre-weaning deceased) pups showed that they were growth restricted compared to Ts1Cje-I pups (post-weaning survivors). Growth restriction correlated with statistically significant delays in achieving several neonatal milestones between P3 and P21 compared to Ts1Cje-I (post-weaning survivors) neonates and WT littermates.

Conclusions

Ts1Cje genotype is not associated with increased early in utero mortality. Cardiac defects, specifically VSDs, are part of the phenotype in this strain. There is increased neonatal mortality in Ts1Cje pups, with sex differences observed. Ts1Cje mice that died in the neonatal period were more likely to be growth restricted and delayed in achieving neonatal developmental milestones.

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<![CDATA[An Intact Brachyury Function Is Necessary to Prevent Spurious Axial Development in Xenopus laevis]]> https://www.researchpad.co/article/5989daf2ab0ee8fa60bc1b3d

We have previously shown that the member of the HES family hairy2 induces the ectopic expression of dorsal markers when it is overexpressed in the ventral side of Xenopus embryos. Intriguingly, hairy2 represses the mesoderm transcription factor brachyury (bra) throughout its domain in the marginal zone. Here we show that in early gastrula, bra and hairy2 are expressed in complementary domains. Overexpression of bra repressed hairy2. Interference of bra function with a dominant-negative construct expanded the hairy2 domain and, like hairy2 overexpression, promoted ectopic expression of dorsal axial markers in the ventral side and induced secondary axes without head and notochord. Hairy2 depletion rescued the ectopic dorsal development induced by interference of bra function. We concluded that an intact bra function is necessary to exclude hairy2 expression from the non-organiser field, to impede the ectopic specification of dorsal axial fates and the appearance of incomplete secondary axes. This evidence supports a previously unrecognised role for bra in maintaining the dorsal fates inhibited in the ventral marginal zone, preventing the appearance of trunk duplications.

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<![CDATA[Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene]]> https://www.researchpad.co/article/5989da70ab0ee8fa60b94768

Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13×10−14 for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32–1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94–1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47–9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions.

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<![CDATA[Preventing Zika Virus Infection during Pregnancy Using a Seasonal Window of Opportunity for Conception]]> https://www.researchpad.co/article/5989dae4ab0ee8fa60bbcfa8

It has come to light that Zika virus (ZIKV) infection during pregnancy can result in trans-placental transmission to the fetus along with fetal death, congenital microcephaly, and/or Central Nervous System (CNS) malformations. There are projected to be >9,200,000 births annually in countries with ongoing ZIKV transmission. In response to the ZIKV threat, the World Health Organization (WHO) is strategically targeting prevention of infection in pregnant women and funding contraception in epidemic regions. I propose that the damaging effects of ZIKV can be reduced using a seasonal window of opportunity for conception that may minimize maternal exposure. Like other acute viral infections—including the related flavivirus, dengue virus (DENV)—the transmission of ZIKV is anticipated to be seasonal. By seasonally planning pregnancy, this aspect of pathogen ecology can be leveraged to align sensitive periods of gestation with the low-transmission season.

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<![CDATA[Compromised Dynamic Cerebral Autoregulation in Patients with a Right-to-Left Shunt: A Potential Mechanism of Migraine and Cryptogenic Stroke]]> https://www.researchpad.co/article/5989da2cab0ee8fa60b82ad8

Background and Purpose

The relationship between right-to-left shunts (RLS) and migraine and cryptogenic stroke is not well understood. In this study, we investigated whether RLS are associated with impairment of dynamic cerebral autoregulation (dCA), which may play a role in migraine and cryptogenic stroke.

Methods

Sixty-six migraineurs were enrolled in the study, including 36 non-RLS patients and 30 RLS patients. Non-invasive continuous cerebral blood flow velocity and arterial blood pressure were recorded simultaneously from each patient by using transcranial Doppler and servo-controlled plethysmograph, respectively. Transfer function analysis was applied to derive autoregulatory parameters of gain, phase difference (PD), and autoregulation index.

Results

The PD in migraineurs with RLS was 50.6±22.9 degrees, which was significantly lower than that observed in the non-RLS group (67.2±18.2 degrees, P<0.001). The PD in the large RLS group (45.4±22.6 degrees) was significantly lower than that of the small RLS group (64.9±17.1 degrees, P<0.01) and non-RLS group (P<0.001); however, the PD in the small RLS group was similar to that of the non-RLS group. The PD in the permanent group (48.8±19.9 degrees) was similar to that of the latent group (52.6±26.1 degrees), and both were significantly lower than that of the non-RLS group (P<0.05). The autoregulation index results were similar to the PD findings.

Conclusions

dCA is impaired in migraineurs with large RLS, and this may represent a potential mechanism linking RLS, migraine, and cryptogenic stroke.

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<![CDATA[Nipbl and Mediator Cooperatively Regulate Gene Expression to Control Limb Development]]> https://www.researchpad.co/article/5989da1fab0ee8fa60b7e32f

Haploinsufficiency for Nipbl, a cohesin loading protein, causes Cornelia de Lange Syndrome (CdLS), the most common “cohesinopathy”. It has been proposed that the effects of Nipbl-haploinsufficiency result from disruption of long-range communication between DNA elements. Here we use zebrafish and mouse models of CdLS to examine how transcriptional changes caused by Nipbl deficiency give rise to limb defects, a common condition in individuals with CdLS. In the zebrafish pectoral fin (forelimb), knockdown of Nipbl expression led to size reductions and patterning defects that were preceded by dysregulated expression of key early limb development genes, including fgfs, shha, hand2 and multiple hox genes. In limb buds of Nipbl-haploinsufficient mice, transcriptome analysis revealed many similar gene expression changes, as well as altered expression of additional classes of genes that play roles in limb development. In both species, the pattern of dysregulation of hox-gene expression depended on genomic location within the Hox clusters. In view of studies suggesting that Nipbl colocalizes with the mediator complex, which facilitates enhancer-promoter communication, we also examined zebrafish deficient for the Med12 Mediator subunit, and found they resembled Nipbl-deficient fish in both morphology and gene expression. Moreover, combined partial reduction of both Nipbl and Med12 had a strongly synergistic effect, consistent with both molecules acting in a common pathway. In addition, three-dimensional fluorescent in situ hybridization revealed that Nipbl and Med12 are required to bring regions containing long-range enhancers into close proximity with the zebrafish hoxda cluster. These data demonstrate a crucial role for Nipbl in limb development, and support the view that its actions on multiple gene pathways result from its influence, together with Mediator, on regulation of long-range chromosomal interactions.

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<![CDATA[Inhibition of Histone H3K9 Acetylation by Anacardic Acid Can Correct the Over-Expression of Gata4 in the Hearts of Fetal Mice Exposed to Alcohol during Pregnancy]]> https://www.researchpad.co/article/5989da1eab0ee8fa60b7dddc

Background

Cardiovascular malformations can be caused by abnormalities in Gata4 expression during fetal development. In a previous study, we demonstrated that ethanol exposure could lead to histone hyperacetylation and Gata4 over-expression in fetal mouse hearts. However, the potential mechanisms of histone hyperacetylation and Gata4 over-expression induced by ethanol remain unclear.

Methods and Results

Pregnant mice were gavaged with ethanol or saline. Fetal mouse hearts were collected for analysis. The results of ethanol fed groups showed that global HAT activity was unusually high in the hearts of fetal mice while global HDAC activity remained unchanged. Binding of P300, CBP, PCAF, SRC1, but not GCN5, were increased on the Gata4 promoter relative to the saline treated group. Increased acetylation of H3K9 and increased mRNA expression of Gata4, α-MHC, cTnT were observed in these hearts. Treatment with the pan-histone acetylase inhibitor, anacardic acid, reduced the binding of P300, PCAF to the Gata4 promoter and reversed H3K9 hyperacetylation in the presence of ethanol. Interestingly, anacardic acid attenuated over-expression of Gata4, α-MHC and cTnT in fetal mouse hearts exposed to ethanol.

Conclusions

Our results suggest that P300 and PCAF may be critical regulatory factors that mediate Gata4 over-expression induced by ethanol exposure. Alternatively, P300, PCAF and Gata4 may coordinate over-expression of cardiac downstream genes in mouse hearts exposed to ethanol. Anacardic acid may thus protect against ethanol-induced Gata4, α-MHC, cTnT over-expression by inhibiting the binding of P300 and PCAF to the promoter region of these genes.

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<![CDATA[Maternal Synchronization of Gestational Length and Lung Maturation]]> https://www.researchpad.co/article/5989da35ab0ee8fa60b8605b

Among all mammals, fetal growth and organ maturation must be precisely synchronized with gestational length to optimize survival at birth. Lack of pulmonary maturation is the major cause of infant mortality in preterm birth. Whether fetal or maternal genotypes influence the close relationship between the length of gestation and lung function at birth is unknown. Structural and biochemical indicators of pulmonary maturity were measured in two mouse strains whose gestational length differed by one day. Shorter gestation in C57BL/6J mice was associated with advanced morphological and biochemical pulmonary development and better perinatal survival when compared to A/J pups born prematurely. After ovarian transplantation, A/J pups were born early in C57BL/6J dams and survived after birth, consistent with maternal control gestational length. Expression of genes critical for perinatal lung function was assessed in A/J pups born after ovarian transfer. A subset of mRNAs important for perinatal respiratory adaptation was selectively induced in the A/J pups born after ovarian transfer. mRNAs precociously induced after ovarian transfer indicated an important role for the transcription factors C/EBPα and CREB in maternally induced lung maturation. We conclude that fetal lung maturation is determined by both fetal and maternal genotypes. Ovarian transfer experiments demonstrated that maternal genotype determines the timing of birth and can influence fetal lung growth and maturation to ensure perinatal survival.

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<![CDATA[The Hole and the Whole: Lessons from Manipulation of Nipbl Deficiency]]> https://www.researchpad.co/article/5989da1dab0ee8fa60b7d70e

Congenital heart defects (CHDs) affect 2%–3% of newborns and remain challenging clinically. There is an ongoing project to elucidate the causes of CHDs, focusing primarily on genetics as dictated by the epidemiology. In a paper published in this issue, Santos and colleagues describe studies of Cornelia de Lange syndrome-associated secundum atrial septal defects (ASDs) caused by NIPBL mutations, undertaken with a targeted trapping allele in mice. They show that Nipbl haploinsufficiency in either of two cell populations was sufficient to engender ASDs but that expression solely in either one of those populations was sufficient to rescue them. This work provides novel insights into incomplete penetrance and oligogenic effects underlying CHDs.

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<![CDATA[Inhibition of Fumonisin B1 Cytotoxicity by Nanosilicate Platelets during Mouse Embryo Development]]> https://www.researchpad.co/article/5989dadbab0ee8fa60bb9d4f

Nanosilicate platelets (NSP), the form of natural silicate clay that was exfoliated from montmorillonite (MMT), is widely used as a feed additive for its high non-specific binding capacity with mycotoxins such as fumonisin B1 (FB1), and has been evaluated its safety for biomedical use including cytotoxicity, genotoxicity, and lethal dosage (LD). In the study, we further examined its toxicity on the development of CD1 mouse embryos and its capacity to prevent teratogenesis-induced by FB1. In vitro cultures, NSP did not disturb the development and the quality of intact pre-implantation mouse embryos. Further, newborn mice from females consumed with NSP showed no abnormalities. NSP had an unexpected high adsorption capacity in vitro. In contrast to female mice consumed with FB1 only, a very low residual level of FB1 in the circulation, reduced incidence of neutral tube defects and significantly increased fetal weight were observed in the females consumed with FB1 and NSP, suggesting a high alleviation effect of NSP on FB1 in vivo. Furthermore, FB1 treatment disturbed the gene expression of sphingolipid metabolism enzymes (longevity assurance homolog 5, LASS 5; sphingosine kinase 1, Sphk1; sphingosine kinase 2, Sphk2; sphingosine 1- phosphate lyase, Sgpl1; sphingosine 1-phosphate phosphatase, Sgpp1) in the maternal liver, uterus, fetus, and placenta, but NSP administration reversed the perturbations. Based on these findings, we conclude that NSP is a feasible and effective agent for supplementary use in reducing the toxicity of FB1 to animals.

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<![CDATA[Uncertain Inheritance: Transgenerational Effects of Environmental Exposures]]> https://www.researchpad.co/article/5ace437b463d7e05926494be ]]> <![CDATA[Magnitude of Birth Defects in Central and Northwest Ethiopia from 2010-2014: A Descriptive Retrospective Study]]> https://www.researchpad.co/article/5989da12ab0ee8fa60b79e6e

Background

Birth defects are defined as structural and functional defects that develop during the organogenesis period and present at birth or detected later in life. They are one of the leading causes of infant and child mortality, morbidity, and long term disability. The magnitude of birth defects varies from country to country and from race/ethnicity to race/ethnicity, and about 40–60% of their causes are unknown. The known causes of birth defects are genetic and environmental factors which may be prevented. For various reasons, there is lack of data and research on birth defects in Ethiopia.

Objective

The major objective of this study is to estimate the magnitude of birth defects in Ethiopia.

Subject and Methods

A hospital based, retrospective, cross sectional, descriptive study was conducted. The subjects were babies/children aged 0–17years who visited selected hospitals between 2010 and 2014. Fourteen hospitals (8 in Addis Ababa, 6 in Amhara Region) were selected purposively based on case load. A data retrieving form was developed to extract relevant information from record books.

Results

In the hospitals mentioned, 319,776 various medical records of children aged 0–17years were found. Of these, 6,076 (1.9% with 95% CI: 1.85%–1.95%) children were diagnosed as having birth defects. The majority (58.5%) of the children were male and 41.5% female. A slightly more than half (51.1%) of the children were urban dwellers, while 48.9% were from rural areas. Among the participants of the study the proportion of birth defects ranged as follows: orofacial (34.2%), neural tube (30.8%), upper and lower limb (12.8%), cardiovascular system (10.3%), digestive system and abdominal wall (4.8%), unspecified congenital malformations (2.5%), Down syndrome (2%), genitourinary system (2%), head, face, and neck defects (0.4%), and others (0.3%). The trend of birth defects increased linearly over time [Extended Mantel-Haenszel chi square for linear trend = 356.7 (P<0.0001)]. About 275 (4.5%) of the cases had multiple (associated) birth defects and 5,801 (95.5%) isolated (single) birth defects. Out of the total birth defects, 6,018 (99%) were major and 58 (1%) minor.

Conclusion

The magnitude of birth defects increased from 2010–2014. Orofacial and neural tube defects contributed about two thirds of the birth defects. There is an urgent need for registry and surveillance system strategies for intervention and control of birth defects in Ethiopia.

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