BackgroundMaternal alcohol consumption is known to adversely affect fetal neurodevelopment. While it is known that alcohol dose and timing play a role in the cognitive and behavioral changes associated with prenatal alcohol exposure, it is unclear what developmental processes are disrupted that may lead to these phenotypes.MethodsMice (n=6 per treatment per developmental time) were exposed to two acute doses of alcohol (5 g/kg) at neurodevelopmental times representing the human first, second, or third trimester equivalent. Mice were reared to adulthood and changes to their adult brain transcriptome were assessed using expression arrays. These were then categorized based on Gene Ontology annotations, canonical pathway associations, and relationships to interacting molecules.ResultsThe results suggest that ethanol disrupts biological processes that are actively occurring at the time of exposure. These include cell proliferation during trimester one, cell migration and differentiation during trimester two, and cellular communication and neurotransmission during trimester three. Further, although ethanol altered a distinct set of genes depending on developmental timing, many of these show interrelatedness and can be associated with one another via ‘hub’ molecules and pathways such as those related to huntingtin and brain-derived neurotrophic factor.ConclusionsThese changes to brain gene expression represent a ‘molecular footprint’ of neurodevelopmental alcohol exposure that is long-lasting and correlates with active processes disrupted at the time of exposure. This study provides further support that there is no neurodevelopmental time when alcohol cannot adversely affect the developing brain.

Both gender and BCR-ABL transcript, but not age, were significantly associated with the molecular response. Men with b2a2 represent a less favorable group in their response to imatinib treatment and may need alternative therapy regimen and closer monitoring.

Background Inuit are considered to be vulnerable to cardiovascular disease (CVD) as their lifestyles become more Westernized. During sequence analysis of Inuit individuals at extremes of lipid traits, we identified two nonsynonymous variants in LDLR encoding the low-density lipoprotein (LDL) receptor, namely p.G116S and p.R730W. Methods and Results Genotyping these variants in 3,324 Inuit from Alaska, Canada and Greenland showed they were common, with allele frequencies 10–15%. Only p.G116S was associated with dyslipidemia: the increase in LDL cholesterol was 0.54 mmol/L (20.9 mg/dL) per allele (P = 5.6 × 10−49), which was >3-times larger than the largest effect sizes seen with common variants in other populations. Carriers of p.G116S had a 3.02-fold increased risk of hypercholesterolemia (CI 2.34 – 3.90, P = 1.7 × 10−17), but did not have classical familial hypercholesterolemia. In vitro, p.G116S showed 60% reduced ligand binding activity compared to wild-type receptor. In contrast, p.R730W was associated with neither LDL cholesterol nor altered in vitro activity. Conclusions LDLR p.G116S is thus unique: a common dysfunctional variant in Inuit whose large effect on LDL cholesterol may have public health implications.

BackgroundPrenatal alcohol exposure is known to result in fetal alcohol spectrum disorders, a continuum of physiological, behavioural, and cognitive phenotypes that include increased risk for anxiety and learning-associated disorders. Prenatal alcohol exposure results in life-long disorders that may manifest in part through the induction of long-term gene expression changes, potentially maintained through epigenetic mechanisms.FindingsHere we report a decrease in the expression of Canabinoid receptor 1 (Cnr1) and an increase in the expression of the regulatory microRNA miR-26b in the brains of adult mice exposed to ethanol during neurodevelopment. Furthermore, we show that miR-26b has significant complementarity to the 3’-UTR of the Cnr1 transcript, giving it the potential to bind and reduce the level of Cnr1 expression.ConclusionsThese findings elucidate a mechanism through which some genes show long-term altered expression following prenatal alcohol exposure, leading to persistent alterations to cognitive function and behavioural phenotypes observed in fetal alcohol spectrum disorders.

The developing brain is remarkably sensitive to alcohol exposure, resulting in the wide range of cognitive and neurobehavioral characteristics categorized under the term fetal alcohol spectrum disorders (FASD). The brain is particularly susceptible to alcohol during synaptogenesis, a process that occurs heavily during the third trimester and is characterized by the establishment and pruning of neural circuitry; however, the molecular response of the brain to ethanol during synaptogenesis has not been documented. To model a binge-like exposure during the third-trimester neurodevelopmental equivalent, neonate mice were given a high (5 g/kg over 2 h) dose of ethanol at postnatal day 7. Acute transcript changes within the brain were assessed using expression arrays and analyzed for associations with gene ontology functional categories, canonical pathways, and gene network interactions. The short-term effect of ethanol was characterized by an acute stress response and a downregulation of energetically costly cellular processes. Further, alterations to a number of genes with roles in synaptic transmission and hormonal signaling, particularly those associated with the neuroendocrine development and function, were evident. Ethanol exposure during synaptogenesis was also associated with altered histone deacetylase and microRNA transcript levels, suggesting that abnormal epigenetic patterning may maintain some of the persistent molecular consequences of developmental ethanol exposure. The results shed insight into the sensitivity of the brain to ethanol during the third-trimester equivalent and outline how ethanol-induced alterations to genes associated with neural connectivity may contribute to FASD phenotypes.

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Background Environmental exposures in utero which modify DNA methylation may have a long-lasting impact on health and disease in offspring. We aimed to identify and replicate previously published genomic loci where DNA methylation changes are attributable to in utero exposures in the NutriGen birth cohort studies Alliance. Methods We reviewed the literature to identify differentially methylated sites of newborn DNA which are associated with the following five traits of interest maternal diabetes, pre-pregnancy body mass index (BMI), diet during pregnancy, smoking, and gestational age. We then attempted to replicate these published associations in the Canadian Healthy Infant Longitudinal Development (CHILD) and the South Asian birth cohort (START) cord blood epigenome-wide data. Results We screened 68 full-text articles and identified a total of 17 cord blood epigenome-wide association studies (EWAS) of the traits of interest. Out of the 290 CpG sites reported, 19 were identified in more than one study; all of them associated with maternal smoking. In CHILD and START EWAS, thousands of sites associated with gestational age were identified and maintained significance after correction for multiple testing. In CHILD, there was differential methylation observed for 8 of the published maternal smoking sites. No other traits tested (i.e., folate levels, gestational diabetes, birthweight) replicated in the CHILD or START cohorts. Conclusions Maternal smoking during pregnancy and gestational age are strongly associated with differential methylation in offspring cord blood, as assessed in the EWAS literature and our birth cohorts. There are a limited number of reported methylation sites associated in more than two independent studies related to pregnancy. Additional large studies of diverse populations with fine phenotyping are needed to produce robust epigenome-wide data in order to further elucidate the effect of intrauterine exposures on the infants’ methylome.

Throughout a history of struggle the Métis have continually fought to be recognized as a distinct nation. An interesting perspective from which to examine the Métis nationhood is the use of Benedict Anderson’s theory of a nation as an ‘imagined community’. Anderson’s criteria state that a nation must be limited, have sovereignty, and provide a sense of community. An examination of Métis history demonstrates their right to nationhood under this theory. Through exclusionary terminology, a unique language, and conditional acceptance, the Métis identity remains separate from that of others. Military and political actions throughout their history demonstrate their constant quest for sovereignty. Finally, a set of inherited and invented cultural traditions brings the Métis together as a community. It is clear that under Anderson’s theory, the unity of the Métis throughout their turbulent past qualifies them as a distinct nation.