scholarly journals Secondary Zinc Deficiency via Exposure to the Environmental Toxicant Di-2-ethylhexyl phthalate Affects Neurogenesis at Embryonic Day 19

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1220-1220
Author(s):  
Xiuzhen Liu ◽  
Patricia Oteiza
Keyword(s):  
Brain Development ◽  
Zinc Deficiency ◽  
Zinc Concentration ◽  
Fetal Brain ◽  
Adult Brain ◽  
Acid Decarboxylase ◽  
Environmental Toxicants ◽  
Gestational Exposure ◽  
Marginal Zinc Deficiency ◽  
Ethylhexyl Phthalate

Abstract Objectives Zinc deficiency can affect early brain development. We previously found that developmental marginal zinc deficiency affected neurogenesis leading to a lower number of neurons and altered neural specification in the adult rat brain. Zinc deficiency can occur as low dietary zinc intake and secondary to diseases, infections, and exposure to environmental toxicants such as phthalates. This work investigated if gestational exposure to toxicant Di-2-ethylhexyl phthalate (DEHP) could decrease zinc availability to the fetus and altered neurogenesis. Methods Rats were fed an adequate (25 µg zinc/g diet) (C) or a marginal zinc deficient (MZD) (10 µg zinc/g diet), without or with DEHP (300 mg/kg BW) (C + DEHP, MZD + DEHP) from gestational day zero until embryonic day 19 (E19). Zinc concentration was analyzed by atomic absorption spectrometry (AAS). Neurogenesis was evaluated in the offspring at E19 measuring parameters of neural progenitor cells (NPC) proliferation and differentiation by Western blot and/or immunofluorescence. Results Fetal brain zinc concentration was significantly decreased in MZD, C + DEHP and MZD + DEHP than in C. Protein Markers of neurogenesis (NeuN, PAX6, SOX2, TBR2) were lower in MZD and C + DEHP than C, and lowest in MZD + DEHP. The excitatory neuron marker vesicular glutamate transporter 1 (VGLUT1) was lower in C + DEHP, MZD and MZD + DEHP than in C, while the marker of inhibitory neurons glutamic acid decarboxylase (GAD65) level were similar among groups. The ERK1/2 pathway, crucial to neurogenesis, was affected by MZD and DEHP. ERK1/2 activation was lower, and at a similar extent in C + DEHP and MZD groups than in C, while it was markedly lower in the MZD + DEHP group compared to all other groups. Lower ERK1/2 activation could be due to activation of the ERK1/2 phosphatase 2A (PP2A). We found that PP2A activation was higher, in MZD and DEHP than in C, being highest in the MZD + DEHP group. Conclusions Gestational exposure to DEHP in rats causes a secondary zinc deficiency in the fetal brain and altered neurogenesis. This can be due to the inhibition of the ERK1/2 signaling pathway. DEHP exposure can adversely affect the offspring's brain development and result in irreversible consequences to adult brain structure and function. Funding Sources Supported by grants from NIFA CA-D-XXX-7244-H, Packer-Wentz foundation, NIEHS T 32 training grant (T32 ES 0,07059).

scholarly journals Marginal Zinc Deficiency and Environmentally Relevant Concentrations of Arsenic Elicit Combined Effects on the Gut Microbiome

mSphere ◽  
2018 ◽  
Vol 3 (6) ◽  
Author(s):  
Christopher A. Gaulke ◽  
John Rolshoven ◽  
Carmen P. Wong ◽  
Laurie G. Hudson ◽  
Emily Ho ◽  
...  
Keyword(s):  
Dna Damage ◽  
Zinc Deficiency ◽  
Relative Abundance ◽  
Gut Microbiome ◽  
Zinc Concentration ◽  
Arsenic Exposure ◽  
Physiological Changes ◽  
Plasma Zinc ◽  
Marginal Zinc Deficiency ◽  
Dietary Variation

ABSTRACT Extensive research shows that dietary variation and toxicant exposure impact the gut microbiome, yielding effects on host physiology. However, prior work has mostly considered such exposure-microbiome interactions through the lens of single-factor exposures. In practice, humans exposed to toxicants vary in their dietary nutritional status, and this variation may impact subsequent exposure of the gut microbiome. For example, chronic arsenic exposure affects 200 million people globally and is often comorbid with zinc deficiency. Zinc deficiency can enhance arsenic toxicity, but it remains unknown how zinc status impacts the gut microbiome’s response to arsenic exposure and whether this response links to host toxicity. Using 16S amplicon sequencing, we examined the combinatorial effects of exposure to environmentally relevant concentrations of arsenic on the composition of the microbiome in C57BL/6 mice fed diets varying in zinc concentration. Arsenic exposure and marginal zinc deficiency independently altered microbiome diversity. When combined, their effects on microbiome community structure were amplified. Generalized linear models identified microbial taxa whose relative abundance in the gut was perturbed by zinc deficiency, arsenic, or their interaction. Further, we correlated taxonomic abundances with host DNA damage, adiponectin expression, and plasma zinc concentration to identify taxa that may mediate host physiological responses to arsenic exposure or zinc deficiency. Arsenic exposure and zinc restriction also result in increased DNA damage and decreased plasma zinc. These physiological changes are associated with the relative abundance of several gut taxa. These data indicate that marginal zinc deficiency sensitizes the microbiome to arsenic exposure and that the microbiome associates with some toxicological effects of arsenic. IMPORTANCE Xenobiotic compounds, such as arsenic, have the potential to alter the composition and functioning of the gut microbiome. The gut microbiome may also interact with these compounds to mediate their impact on the host. However, little is known about how dietary variation may reshape how the microbiome responds to xenobiotic exposures or how these modified responses may in turn impact host physiology. Here, we investigated the combinatorial effects of marginal zinc deficiency and physiologically relevant concentrations of arsenic on the microbiome. Both zinc deficiency and arsenic exposure were individually associated with altered microbial diversity and when combined elicited synergistic effects. Microbial abundance also covaried with host physiological changes, indicating that the microbiome may contribute to or be influenced by these pathologies. Collectively, this work demonstrates that dietary zinc intake influences the sensitivity of the microbiome to subsequent arsenic exposure.

scholarly journals Global Epigenomic Reconfiguration During Mammalian Brain Development

Science ◽  
2013 ◽  
Vol 341 (6146) ◽  
pp. 1237905 ◽  
Author(s):  
Ryan Lister ◽  
Eran A. Mukamel ◽  
Joseph R. Nery ◽  
Mark Urich ◽  
Clare A. Puddifoot ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brain Development ◽  
Adult Development ◽  
Fetal Brain ◽  
Brain Cell ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Dominant Form ◽  
Single Base ◽  
Single Base Resolution

DNA methylation is implicated in mammalian brain development and plasticity underlying learning and memory. We report the genome-wide composition, patterning, cell specificity, and dynamics of DNA methylation at single-base resolution in human and mouse frontal cortex throughout their lifespan. Widespread methylome reconfiguration occurs during fetal to young adult development, coincident with synaptogenesis. During this period, highly conserved non-CG methylation (mCH) accumulates in neurons, but not glia, to become the dominant form of methylation in the human neuronal genome. Moreover, we found an mCH signature that identifies genes escaping X-chromosome inactivation. Last, whole-genome single-base resolution 5-hydroxymethylcytosine (hmC) maps revealed that hmC marks fetal brain cell genomes at putative regulatory regions that are CG-demethylated and activated in the adult brain and that CG demethylation at these hmC-poised loci depends on Tet2 activity.

scholarly journals Nucleolin is expressed in human fetal brain development and reactivated in human glial brain tumors regulating angiogenesis and vascular metabolism

2020 ◽  
Author(s):  
Marc Schwab ◽  
Ignazio de Trizio ◽  
Jau-Ye Shiu ◽  
Moheb Ghobrial ◽  
Oguzkan Sürücü ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Brain Development ◽  
Umbilical Vein ◽  
Neurovascular Unit ◽  
Fetal Brain ◽  
Adult Brain ◽  
Sprouting Angiogenesis ◽  
Brain Vasculature

ABSTRACTGlioblastoma (GBM) is amongst the deadliest human cancers and is characterized by high levels of vascularisation. Angiogenesis is highly dynamic during brain development and almost quiescent in the adult brain, but is reactivated in vascular-dependent CNS pathologies such as brain tumors. Nucleolin (NCL) is a known regulator of cell proliferation and angiogenesis, but its roles on physiological and pathological brain vasculature remain unknown. Here, we studied the expression of Nucleolin in the neurovascular unit (NVU) in human fetal brains and human gliomas in vivo as well as its effects on sprouting angiogenesis and endothelial metabolism in vitro. Nucleolin is highly expressed in endothelial- and perivascular cells during brain development, downregulated in the adult brain, and upregulated in glioma. Moreover, Nucleolin expression in tumor- and blood vessel cells correlated with glioma malignancy in vivo. In culture, siRNA-mediated NCL knockdown reduced human umbilical vein endothelial cell (HUVEC) sprouting angiogenesis, proliferation and filopodia extension, and reduced glucose metabolism. Mechanistically, RNA sequencing of Nucleolin knockdown in HUVECs revealed a putative p53-TIGAR-HK2 regulation of endothelial glycolysis. These findings identify Nucleolin as a neurodevelopmental factor reactivated in glioma that positively regulates sprouting angiogenesis and endothelial metabolism. Our findings have important implications in therapeutic targeting of glioma.

A Case of Acquired Zinc Deficiency due to Low Zinc Concentration in Maternal Breast Milk

2008 ◽  
Vol 70 (4) ◽  
pp. 402-405 ◽  
Author(s):  
Chie HIRABE ◽  
Chisato HOSOKAWA ◽  
Masakazu TAKAHARA ◽  
Satoko SHIBATA ◽  
Satoshi TAKEUCHI ◽  
...  
Keyword(s):  
Breast Milk ◽  
Zinc Deficiency ◽  
Zinc Concentration

New normal range of fetal cavum septum pellucidum in the second trimester of gestation

2020 ◽  
Author(s):  
M.V. Medvedev, O.I. Kozlova, À.Yu. Romanova
Keyword(s):  
Brain Development ◽  
Reference Range ◽  
Fetal Brain ◽  
Septum Pellucidum ◽  
Second Trimester ◽  
Normal Range ◽  
Cavum Septum Pellucidum ◽  
New Normal ◽  
Biparietal Diameter ◽  
Fetal Brain Development

Fetal brain was retrospectively evaluated in 418 normal fetuses at 16–28 weeks of gestation. The multiplanar mode to obtain the axial cerebral plane and measured the width of the cavum septum pellucidum (CSP) and biparietal diameter (BD). All measurements of CSP were done from as the widest diameter across both borders in an inter-to inter fashion. The CSP width is increasing at second trimester of gestation. Normal range plotted on the reference range (mean, 5th and 95th percentiles) of fetal width CSP by measuring of its size may be useful for assessment of fetal brain development in the second trimester of gestation.

scholarly journals CB1 antagonism increases excitatory synaptogenesis in a cortical spheroid model of fetal brain development

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexis Papariello ◽  
David Taylor ◽  
Ken Soderstrom ◽  
Karen Litwa
Keyword(s):  
Brain Development ◽  
Spontaneous Activity ◽  
Microelectrode Array ◽  
Cannabinoid Receptor ◽  
Fetal Brain ◽  
Endocannabinoid System ◽  
Autism Spectrum ◽  
Nervous System Development ◽  
Inhibitory Synapses ◽  
Fetal Brain Development

AbstractThe endocannabinoid system (ECS) plays a complex role in the development of neural circuitry during fetal brain development. The cannabinoid receptor type 1 (CB1) controls synaptic strength at both excitatory and inhibitory synapses and thus contributes to the balance of excitatory and inhibitory signaling. Imbalances in the ratio of excitatory to inhibitory synapses have been implicated in various neuropsychiatric disorders associated with dysregulated central nervous system development including autism spectrum disorder, epilepsy, and schizophrenia. The role of CB1 in human brain development has been difficult to study but advances in induced pluripotent stem cell technology have allowed us to model the fetal brain environment. Cortical spheroids resemble the cortex of the dorsal telencephalon during mid-fetal gestation and possess functional synapses, spontaneous activity, an astrocyte population, and pseudo-laminar organization. We first characterized the ECS using STORM microscopy and observed synaptic localization of components similar to that which is observed in the fetal brain. Next, using the CB1-selective antagonist SR141716A, we observed an increase in excitatory, and to a lesser extent, inhibitory synaptogenesis as measured by confocal image analysis. Further, CB1 antagonism increased the variability of spontaneous activity within developing neural networks, as measured by microelectrode array. Overall, we have established that cortical spheroids express ECS components and are thus a useful model for exploring endocannabinoid mediation of childhood neuropsychiatric disease.

scholarly journals Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 470
Author(s):  
Jeremy W. Prokop ◽  
Caleb P. Bupp ◽  
Austin Frisch ◽  
Stephanie M. Bilinovich ◽  
Daniel B. Campbell ◽  
...  
Keyword(s):  
Brain Development ◽  
Neural Progenitor Cells ◽  
Neurodevelopmental Disorder ◽  
Fetal Brain ◽  
Missense Variant ◽  
Neural Progenitor ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Systematic Analysis ◽  
Function Expression

Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.

scholarly journals Neuroplacentology in congenital heart disease: placental connections to neurodevelopmental outcomes

2021 ◽  
Author(s):  
Rachel L. Leon ◽  
Imran N. Mir ◽  
Christina L. Herrera ◽  
Kavita Sharma ◽  
Catherine Y. Spong ◽  
...  
Keyword(s):  
Brain Development ◽  
Congenital Heart ◽  
Fetal Brain ◽  
In Utero ◽  
Structure And Function ◽  
Brain Growth ◽  
Neurodevelopmental Outcomes ◽  
Fetal Brain Development ◽  
And Function

Abstract Children with congenital heart disease (CHD) are living longer due to effective medical and surgical management. However, the majority have neurodevelopmental delays or disorders. The role of the placenta in fetal brain development is unclear and is the focus of an emerging field known as neuroplacentology. In this review, we summarize neurodevelopmental outcomes in CHD and their brain imaging correlates both in utero and postnatally. We review differences in the structure and function of the placenta in pregnancies complicated by fetal CHD and introduce the concept of a placental inefficiency phenotype that occurs in severe forms of fetal CHD, characterized by a myriad of pathologies. We propose that in CHD placental dysfunction contributes to decreased fetal cerebral oxygen delivery resulting in poor brain growth, brain abnormalities, and impaired neurodevelopment. We conclude the review with key areas for future research in neuroplacentology in the fetal CHD population, including (1) differences in structure and function of the CHD placenta, (2) modifiable and nonmodifiable factors that impact the hemodynamic balance between placental and cerebral circulations, (3) interventions to improve placental function and protect brain development in utero, and (4) the role of genetic and epigenetic influences on the placenta–heart–brain connection. Impact Neuroplacentology seeks to understand placental connections to fetal brain development. In fetuses with CHD, brain growth abnormalities begin in utero. Placental microstructure as well as perfusion and function are abnormal in fetal CHD.

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