scholarly journals An enriched biosignature of gut microbiota-dependent metabolites characterizes maternal plasma in a mouse model of fetal alcohol spectrum disorder

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Manjot S. Virdee ◽  
Nipun Saini ◽  
Colin D. Kay ◽  
Andrew P. Neilson ◽  
Sze Ting Cecilia Kwan ◽  
...  
Keyword(s):  
Phenolic Acids ◽  
Fetal Liver ◽  
Prenatal Alcohol Exposure ◽  
Fetal Brain ◽  
Principal Component ◽  
Alcohol Exposure ◽  
Maternal Plasma ◽  
Cognitive Disability ◽  
Fetal Alcohol ◽  
Network Analyses

AbstractPrenatal alcohol exposure (PAE) causes permanent cognitive disability. The enteric microbiome generates microbial-dependent products (MDPs) that may contribute to disorders including autism, depression, and anxiety; it is unknown whether similar alterations occur in PAE. Using a mouse PAE model, we performed untargeted metabolome analyses upon the maternal–fetal dyad at gestational day 17.5. Hierarchical clustering by principal component analysis and Pearson’s correlation of maternal plasma (813 metabolites) both identified MDPs as significant predictors for PAE. The majority were phenolic acids enriched in PAE. Correlational network analyses revealed that alcohol altered plasma MDP-metabolite relationships, and alcohol-exposed maternal plasma was characterized by a subnetwork dominated by phenolic acids. Twenty-nine MDPs were detected in fetal liver and sixteen in fetal brain, where their impact is unknown. Several of these, including 4-ethylphenylsulfate, oxindole, indolepropionate, p-cresol sulfate, catechol sulfate, and salicylate, are implicated in other neurological disorders. We conclude that MDPs constitute a characteristic biosignature that distinguishes PAE. These MDPs are abundant in human plasma, where they influence physiology and disease. Their altered abundance here may reflect alcohol’s known effects on microbiota composition and gut permeability. We propose that the maternal microbiome and its MDPs are a previously unrecognized influence upon the pathologies that typify PAE.

scholarly journals Untargeted Metabolomics Analysis of Maternal Plasma from Pregnant C57Bl/6J Mice Identifies Significant Metabolic Changes in Response to Gestational Alcohol Exposure (OR26-01-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Nipun Saini ◽  
Kaylee Helfrich ◽  
Sze-Ting Cecilia Kwan ◽  
Susan Smith
Keyword(s):  
Fetal Alcohol Spectrum Disorders ◽  
Prenatal Alcohol Exposure ◽  
Redox Homeostasis ◽  
Principal Component ◽  
Hierarchical Cluster ◽  
Methionine Sulfoxide ◽  
Alcohol Exposure ◽  
Maternal Plasma ◽  
Ethyl Glucuronide ◽  
Untargeted Metabolomics

Abstract Objectives Prenatal alcohol exposure (PAE) affects 8% of U.S. pregnancies and causes persistent growth and neurodevelopmental deficits diagnosed as fetal alcohol spectrum disorders. Clinical trials using prenatal nutritional interventions can mitigate these neurobehavioral deficits. However, these studies are haphazard, because we do not understand how PAE alters nutrient needs and metabolite flux in the mother-child dyad. To address this knowledge gap, we used untargeted metabolomics to identify biochemical features that are significantly altered by PAE. Methods C57Bl/6J female mice fed AIN93G diet were randomly assigned to receive 3 g/Kg body weight alcohol or isocaloric maltodextrin (MD) by daily gavage from embryonic day (E) E8.5 to E17.5. Metabolite analysis of E17.7 maternal plasma was performed at Metabolon using UPLC-MS/MS. Results We detected 813 metabolites in PAE plasma, 713 known and 100 named metabolites. Of these, 218 metabolites were significantly increased and 25 were decreased compared with control dams (p ≤ 0.05; Welch's two-sample t-test). An additional 63 metabolites trended to increase (43) or decrease (20) in response to PAE (0.05 < p < 0.10). Both Principal Component and hierarchical cluster analyses successfully segregated the plasma samples by treatment, affirming these metabolite profiles could predict PAE. PAE altered multiple pathway signatures. PAE elevated multiple indicators of oxidative stress, such as methionine sulfoxide, S-methylcysteine, and S-methylcysteine sulfoxide, along with metabolites involved in redox homeostasis (cysteine-glutathione disulfide, 2-aminobutyrate, 2-hydroxybutyrate/2-hydroxyisobutyrate and cysteinylglycine disulfide). Conjugated metabolites indicative of enhanced Phase I and Phase II hepatic metabolism including 4-methylcatechol sulfate, 4-acetylphenol sulfate, methyl-4-hydroxybenzoate sulfate, 4-allylphenol sulfate, ethyl glucuronide and 4-ethylphenol glucuronide were also significantly increased. Conclusions The oxidative metabolite signatures identified here are consistent with alcohol's known actions. They may have predictive power as a biomarker signature to identify at-risk pregnancies. Funding Sources NIAAA & UNC-NRI.

scholarly journals Exploring the experiences of social workers in working with children suspected to have fetal alcohol spectrum disorders

2021 ◽  
Vol 45 (2) ◽  
pp. 155-172
Author(s):  
David J Gilbert ◽  
Raja AS Mukherjee ◽  
Nisha Kassam ◽  
Penny A Cook
Keyword(s):  
Social Workers ◽  
Social Services ◽  
Child Protection ◽  
Prenatal Alcohol Exposure ◽  
Alcohol Exposure ◽  
Fetal Alcohol ◽  
The Social ◽  
Prenatal Alcohol ◽  
Fetal Alcohol Spectrum ◽  
Lack Of Knowledge

Fetal alcohol spectrum disorder (FASD) is one outcome from prenatal alcohol exposure. Social workers are likely to encounter children with the condition, due to the greater likelihood of prenatal alcohol exposure among children in social services settings. This study explores the experiences of social workers in working with children suspected of having FASD and the support offered to social workers, the children and their families. Semi-structured interviews followed by qualitative framework analysis were conducted with seven child and family social workers along with one child protection solicitor who had experience of handling FASD cases. The two main themes that emerged from the data were a lack of knowledge about FASD and the paucity of diagnosis. Lack of knowledge among the social workers was linked to difficulty in managing children suspected to have the condition, feelings of frustration and normalisation of challenging behaviours. The paucity of diagnosis led to an under-emphasis of FASD in assessments, a dearth of specialist services and confusion about its specific effects in contexts of multiple substance misuse and harmful socio-environmental factors. The need for increased FASD awareness within social services and the development of FASD-targeted support for children and families is highlighted. Social workers would benefit from the inclusion of FASD-focused training in their curricula and professional development plans. Improving the diagnostic capacities of health institutions would address the paucity of diagnosis and raise the profile of FASD, especially in the social services setting.

scholarly journals Suicidality and Associated Factors Among Individuals Assessed for Fetal Alcohol Spectrum Disorder Across the Lifespan in Canada

2021 ◽  
pp. 070674372110532
Author(s):  
Katherine Flannigan ◽  
Carly McMorris ◽  
Amanda Ewasiuk ◽  
Dorothy Badry ◽  
Mansfield Mela ◽  
...  
Keyword(s):  
Suicidal Ideation ◽  
Affect Regulation ◽  
Fetal Alcohol Spectrum Disorder ◽  
Prenatal Alcohol Exposure ◽  
Secondary Analysis ◽  
Clinical Information ◽  
Alcohol Exposure ◽  
Spectrum Disorder ◽  
Fetal Alcohol ◽  
Fetal Alcohol Spectrum

Objective Individuals with fetal alcohol spectrum disorder (FASD) experience a range of complex neurodevelopmental, psychological, and socioenvironmental vulnerabilities. There is growing evidence that suicidal ideation, attempts, and death by suicide are significant concerns within this population. In this study, we (1) determined the rate of suicidal ideation/attempts in a large group of individuals with prenatal alcohol exposure (PAE) who were assessed for FASD in Canada and (2) investigated the associations between suicidal ideation/attempts and select demographic and biopsychosocial factors in this group. Method A secondary analysis of data from Canada's National FASD Database, a national repository of clinical information gathered through FASD assessment and diagnostic clinics across the country, was conducted. Descriptive analyses, chi-square/Fisher's exact tests, and binary logistic regression were used to examine demographic and biopsychosocial variables and their associations with suicidality. Results In our sample of 796 participants ( Mage = 17.7 years, range = 6–59; 57.6% male) assessed for FASD, 25.9% were reported to experience suicidal ideation/attempts. Numerous demographic and biopsychosocial factors were found to be significantly associated with suicidal ideation/attempts. The strongest associations with suicidal ideation/attempts were substance use, history of trauma/abuse, and impaired affect regulation. Conclusions With this study, we contribute to the emerging evidence of elevated risk of suicidality among individuals with PAE/FASD and improve our understanding of factors that may exacerbate this risk. Findings have relevance for improving screening, prevention, and proactive treatment approaches for individuals with PAE and FASD, their families, and wider support systems.

Synthesizing Animal and Human Studies of Prenatal Alcohol Exposure

2001 ◽  
Vol 7 (5) ◽  
pp. 648-649 ◽  
Author(s):  
Paul D. Connor
Keyword(s):  
Fetal Alcohol Syndrome ◽  
Prenatal Alcohol Exposure ◽  
Alcohol Exposure ◽  
Fetal Alcohol ◽  
Behavioral Disturbances ◽  
Quarter Century ◽  
Prenatal Alcohol ◽  
Primary Focus ◽  
Maternal Alcohol Abuse ◽  
The Impact

The primary focus of this volume is on the impact of alcohol on brain development. It is a perfect example of how research on both animals and humans can interact to produce very important findings. In the case of prenatal alcohol exposure, dialogue between animal and human researchers has proved to be very profitable for both lines of research. Initial observations by human researchers identified a syndrome of facial stigmata, physical malformations, and early behavioral disturbances that was related to maternal alcohol abuse during pregnancy. They gave this syndrome the name Fetal Alcohol Syndrome. However, human researchers were unable to state unequivocally that prenatal alcohol exposure was teratogenic to the fetus. Thus, they turned to animal researchers who were able to model Fetal Alcohol Syndrome in a variety of animals and to confirm the teratogenicity of alcohol on the developing fetus. The quarter century of studies of the damage caused by prenatal alcohol exposure is replete with such interactions between these two groups of researchers. Without the input and pioneering studies of animal researchers on the effects of prenatal alcohol exposure, human researchers would have much less understanding of the damage caused by alcohol exposure in utero or insights into possible treatment or remediation strategies for those damaged by alcohol exposure.

scholarly journals Fetal and Maternal Hepcidin Respond Inversely to Prenatal Alcohol Exposure in a C57BL/6J Mouse Model (P09-010-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Kaylee Helfrich ◽  
Nipun Saini ◽  
Sze Ting (Cecilia) Kwan ◽  
Susan Smith
Keyword(s):  
Rat Model ◽  
Fetal Liver ◽  
Prenatal Alcohol Exposure ◽  
Iron Status ◽  
Alcohol Exposure ◽  
Higher Alcohol ◽  
Regulatory Pathways ◽  
Hepcidin Expression ◽  
Funding Sources ◽  
Prenatal Alcohol

Abstract Objectives Prenatal alcohol exposure (PAE) dysregulates iron metabolism and causes fetal iron deficiency in rats, even when mothers consume sufficient iron. This dysregulation is partly due to PAE-mediated induction of hepcidin, which routes iron to hepatic storage, where it is unavailable for fetal use. It is unclear how PAE upregulates hepcidin; our rat model suggests dysregulation may be via the IL6/STAT3 pathway. The objective of this study is to quantify hepcidin in a mouse PAE model and ascertain via which pathway(s) PAE disrupts hepcidin. Methods C57BL/6J female mice consumed AIN93G diet prior to and throughout pregnancy. Pregnant females received 3g/Kg alcohol or isocaloric maltodextrin (MD) by gavage from gestational day (GD) 8.5-17.5. We analyzed mothers and fetuses at GD17.5. Results Although PAE fetuses had an increased incidence of malformations, fetal weight at GD17.5 did not differ from MD controls (p = 0.800). As in our rat model, PAE upregulated fetal hepatic hepcidin expression (191% increase, p = 0.010). Supporting other studies of chronic alcohol consumption in mice, PAE reduced maternal hepcidin expression, although not significantly (45% decrease, p = 0.055). At a higher alcohol dose (4.5g/Kg, GD13.5-17.5), maternal hepcidin expression was significantly lower than MD controls (59% decrease, p = 0.044). Potential sources of this hepcidin dysregulation include PAE-induced reductions in fetal (24% decrease, p = 0.035) and maternal (61% decrease, p = 0.0004) hepatic Bmp6 expression and elevated fetal hepatic erythropoietin expression (61% increase, p = 0.033). Although decreased BMP6 may contribute to the reduced maternal hepcidin, decreased BMP6 is inconsistent with the elevated fetal hepcidin, and, along with the elevated Epo, may reflect an attempt to increase iron availability in response to PAE. We quantified pro-inflammatory cytokines and found unaltered (Il-6, Ifn-gamma) or decreased (Tnf-alpha) expression in maternal and fetal liver, suggesting a lack of generalized hepatic inflammation in this model. Conclusions PAE exerts different effects on maternal and fetal hepcidin, which may reflect differences in iron status, time of development, or ethanol processing. PAE also dysregulates hepcidin regulatory pathways. Funding Sources T32-DK, R01-AA.

Neuroimaging effects of prenatal alcohol exposure on the developing human brain: a magnetic resonance imaging review

2015 ◽  
Vol 27 (5) ◽  
pp. 251-269 ◽  
Author(s):  
Kirsten Ann Donald ◽  
Emma Eastman ◽  
Fleur Margaret Howells ◽  
Colleen Adnams ◽  
Edward Patrick Riley ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Corpus Callosum ◽  
Human Brain ◽  
Grey Matter ◽  
Prenatal Alcohol Exposure ◽  
Alcohol Exposure ◽  
Resonance Imaging ◽  
Fetal Alcohol ◽  
Prenatal Alcohol

ObjectiveThis paper reviews the magnetic resonance imaging (MRI) literature on the effects of prenatal alcohol exposure on the developing human brain.MethodA literature search was conducted through the following databases: PubMed, PsycINFO and Google Scholar. Combinations of the following search terms and keywords were used to identify relevant studies: ‘alcohol’, ‘fetal alcohol spectrum disorders’, ‘fetal alcohol syndrome’, ‘FAS’, ‘FASD’, ‘MRI’, ‘DTI’, ‘MRS’, ‘neuroimaging’, ‘children’ and ‘infants’.ResultsA total of 64 relevant articles were identified across all modalities. Overall, studies reported smaller total brain volume as well as smaller volume of both the white and grey matter in specific cortical regions. The most consistently reported structural MRI findings were alterations in the shape and volume of the corpus callosum, as well as smaller volume in the basal ganglia and hippocampi. The most consistent finding from diffusion tensor imaging studies was lower fractional anisotropy in the corpus callosum. Proton magnetic resonance spectroscopy studies are few to date, but showed altered neurometabolic profiles in the frontal and parietal cortex, thalamus and dentate nuclei. Resting-state functional MRI studies reported reduced functional connectivity between cortical and deep grey matter structures.DiscussionThere is a critical gap in the literature of MRI studies in alcohol-exposed children under 5 years of age across all MRI modalities. The dynamic nature of brain maturation and appreciation of the effects of alcohol exposure on the developing trajectory of the structural and functional network argue for the prioritisation of studies that include a longitudinal approach to understanding this spectrum of effects and potential therapeutic time points.

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