Meta-Analysis of Gene Expression Patterns in Animal Models of Prenatal Alcohol Exposure Suggests Role for Protein Synthesis Inhibition and Chromatin Remodeling

Fetal Alcohol Spectrum Disorders (FASD) are a serious public health concern, affecting approximately 5% of live births in the US. The more severe craniofacial and central nervous system malformations characteristic of FASD are caused by alcohol exposure during gastrulation (embryonic day 7 in mice; 3rd week of human pregnancy). Genetics are a known contributor to differences in alcohol sensitivity in humans and in animal models of FASD. Our study profiled gene expression in gastrulation-stage embryos from two commonly used, genetically similar mouse substrains, C57BL/6J and C57BL/6NHsd, that differ in alcohol sensitivity. First, we established normal gene expression patterns at three finely resolved timepoints during gastrulation and developed a web-based interactive tool. Baseline transcriptional differences across strains were associated with immune signaling, indicative of their molecular divergence. Second, we examined the gene networks impacted by alcohol in each strain. Alcohol was associated with a more pronounced transcriptional effect in the 6J's vs. 6N's, matching the 6J's increased susceptibility. The 6J strain exhibited down-regulation of cell proliferation and morphogenic signaling pathways and up-regulation of pathways related to cell death and craniofacial defects, while 6N's show enrichment of hypoxia (up) and cellular metabolism (down) pathways. Collectively, these datasets 1) provide insight into the changing transcriptional landscape across gastrulation in two commonly used mouse strains, 2) establish a valuable resource that enables the discovery of candidate genes that may modify susceptibility to prenatal alcohol exposure that can be validated in humans, and 3) identify novel pathogenic mechanisms potentially involved in alcohol's impact on development.

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Global gene expression patterns in response to white patch syndrome: Disentangling symbiont loss from the thermal stress response in reef-building coral

10.1101/2019.12.13.875989 ◽

2019 ◽

Author(s):

Carly D. Kenkel ◽

Veronique J.L. Mocellin ◽

Line K. Bay

Keyword(s):

Gene Expression ◽

Abiotic Stress ◽

Thermal Stress ◽

Stress Response ◽

Meta Analysis ◽

Expression Patterns ◽

Global Gene Expression ◽

Host Protein ◽

Gene Expression Patterns ◽

White Patch

AbstractThe mechanisms resulting in the breakdown of the coral symbiosis once the process of bleaching has been initiated remain unclear. Distinguishing symbiont loss from the abiotic stress response may shed light on the cellular and molecular pathways involved in each process. This study examined physiological changes and global gene expression patterns associated with white patch syndrome (WPS) in P. lobata, which manifests in localized bleaching independent of thermal stress. In addition, a meta-analysis of global gene expression studies in other corals and anemones was used to contrast differential regulation as a result of abiotic stress from expression patterns correlated with symbiotic state. Symbiont density, chlorophyll a content, holobiont productivity, instant calcification rate, and total host protein content were uniformly reduced in WPS relative to healthy tissue. While expression patterns associated with WPS were secondary to fixed effects of source colony, specific functional enrichments suggest that the viral infection putatively giving rise to this condition affects symbiont rather than host cells. The meta-analysis revealed that expression patterns in WPS-affected tissues were significantly correlated with prior studies examining short-term thermal stress responses. This correlation was independent of symbiotic state, as the strongest correlations were found between WPS adults and both symbiotic adult and aposymbiotic coral larvae experiencing thermal stress, suggesting that the majority of expression changes reflect a non-specific stress response. Across studies, the magnitude and direction of expression change among particular functional enrichments suggests unique responses to stressor duration, and highlights unique responses to bleaching in an anemone model which engages in a non-obligate symbiosis.

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Risk for Childhood Internalizing and Externalizing Behavior Problems in the Context of Prenatal Alcohol Exposure: A Meta-Analysis and Comprehensive Examination of Moderators

Alcoholism Clinical and Experimental Research ◽

10.1111/acer.13805 ◽

2018 ◽

Vol 42 (8) ◽

pp. 1358-1377 ◽

Cited By ~ 11

Author(s):

Jennifer E. Khoury ◽

Brittany Jamieson ◽

Karen Milligan

Keyword(s):

Behavior Problems ◽

Externalizing Behavior ◽

Prenatal Alcohol Exposure ◽

Meta Analysis ◽

Alcohol Exposure ◽

Externalizing Behavior Problems ◽

Comprehensive Examination ◽

Prenatal Alcohol ◽

Internalizing And Externalizing

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Prenatal Alcohol Exposure in Rats Diminishes Postnatal Cxcl16 Chemokine Ligand Brain Expression

Brain Sciences ◽

10.3390/brainsci10120987 ◽

2020 ◽

Vol 10 (12) ◽

pp. 987

Author(s):

Pedro Juárez-Rodríguez ◽

Marisol Godínez-Rubí ◽

Carolina Guzmán-Brambila ◽

Edgar Padilla-Velarde ◽

Arturo Orozco-Barocio ◽

...

Keyword(s):

Gene Expression ◽

Prenatal Alcohol Exposure ◽

Quantitative Polymerase Chain Reaction ◽

Alcohol Exposure ◽

Microarray Gene Expression ◽

Chemokine Ligand ◽

Inflammatory Processes ◽

Prenatal Alcohol ◽

Rat Nucleus Accumbens ◽

The Brain

Maternal ethanol consumption during pregnancy is one of the main causes of Neurodevelopmental disorders (NDD). Prenatal alcohol exposure (PAE) produces several adverse manifestations. Even low or moderate intake has been associated with long-lasting behavioral and cognitive impairment in offspring. In this study we examined the gene expression profile in the rat nucleus accumbens using microarrays, comparing animals exposed prenatally to ethanol and controls. Microarray gene expression showed an overall downward regulatory effect of PAE. Gene cluster analysis reveals that the gene groups most affected are related to transcription regulation, transcription factors and homeobox genes. We focus on the expression of the C-X-C motif chemokine ligand 16 (Cxcl16) which was differentially expressed. There is a significant reduction in the expression of this chemokine throughout the brain under PAE conditions, evidenced here by quantitative polymerase chain reaction qPCR and immunohistochemistry. Chemokines are involved in neuroprotection and implicated in alcohol-induced brain damage and neuroinflammation in the developing central nervous system (CNS), therefore, the significance of the overall decrease in Cxcl16 expression in the brain as a consequence of PAE may reflect a reduced ability in neuroprotection against subsequent conditions, such as excitotoxic damage, inflammatory processes or even hypoxic-ischemic insult.

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Prenatal Alcohol Exposure and Congenital Heart Defects: A Meta-Analysis

PLoS ONE ◽

10.1371/journal.pone.0130681 ◽

2015 ◽

Vol 10 (6) ◽

pp. e0130681 ◽

Cited By ~ 28

Author(s):

Jiaomei Yang ◽

Huizhen Qiu ◽

Pengfei Qu ◽

Ruo Zhang ◽

Lingxia Zeng ◽

...

Keyword(s):

Congenital Heart Defects ◽

Congenital Heart ◽

Prenatal Alcohol Exposure ◽

Heart Defects ◽

Meta Analysis ◽

Alcohol Exposure ◽

Prenatal Alcohol

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68 GENE EXPRESSION COMPARISONS BETWEEN BOVINE IN VIVO AND CLONED EMBRYOS PRODUCED BY THREE DIFFERENT METHODS

Reproduction Fertility and Development ◽

10.1071/rdv18n2ab68 ◽

2006 ◽

Vol 18 (2) ◽

pp. 142

Author(s):

N. Ruddock ◽

K. Wilson ◽

M. Cooney ◽

R. Tecirlioglu ◽

V. Hall ◽

...

Keyword(s):

Gene Expression ◽

Chromatin Remodeling ◽

Nuclear Transfer ◽

Expression Patterns ◽

Experimental Models ◽

Gene Expression Patterns ◽

Imprinted Genes ◽

Mammalian Embryo

Developmental pathways in the mammalian embryo are profoundly influenced by the epigenetic interaction of the environment and the genome. Loss of epigenetic control has been implicated in aberrant gene expression and altered imprinting patterns with consequence to the physiology and viability of the conceptus. Bovine somatic cell nuclear transfer (SCNT) is contingent on in vitro culture, and both SCNT and culture conditions are known to induce changes in embryonic gene expression patterns. Using these experimental models, this study compared gene expression of Day 7 cloned blastocysts created from three different SCNT protocols using the same cell line, with Day 7 in vivo blastocysts to elucidate mechanisms responsible for variations in phenotypic outcomes. SCNT methods included: (1) traditional SCNT by subzonal injection (SI); (2) handmade cloning (HMC); and (3) modified serial nuclear transfer (SNT), developed within the group. Four imprinted genes (Grb10, Ndn, Nnat, and Ube3a), four chromatin remodeling genes (Cbx1, Cbx3, Smarca4, and Smarcb1) and two genes implicated in polycystic liver disease (Prkcsh and Sec63) were analyzed in single blastocysts from each treatment (n = 5). All blastocysts expressed Actin, Oct-4 and Ifn-tau. All genes were sequence verified. Several genes were expressed ubiquitously across all groups, including Ndn, Ube3a, Cbx1, Cbx3, and Smarcb1. Interestingly, Grb10 was not expressed in two HMCs and one SNT blastocyst. Nnat was weakly expressed in one in vivo blastocyst and in the majority of cloned blastocysts in all groups. Prkcsh and Sec63 were expressed in all but one HMC blastocyst. While gene expression patterns were mostly maintained following SCNT, the imprinted genes Nnat and Grb10 showed instances of differential or abnormal expression in SCNT embryos. The chromatin remodeling genes were maintained in all SCNT treatments. Prkcsh and Sec63 were both absent in one HMC blastocyst, with implications for liver dysfunction, a condition previously reported in abnormal cloned offspring. The variable mRNA expression following SCNT provides an insight into genetic and environmental factors controlling implantation, placentation, organ formation, and fetal growth.

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