Prenatal exposure to gestational diabetes mellitus as an independent risk factor for long-term neuropsychiatric morbidity of the offspring

Sacks, Kira Nahum; Friger, Michael; Shoham‐Vardi, Ilana; Abokaf, Hanaa; Spiegel, Efrat; Sergienko, Ruslan; Landau, Daniella; Sheiner, Eyal

doi:10.1016/j.ajog.2016.03.030

Cited by 114 publications

(68 citation statements)

References 65 publications

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“…These data suggest that altered gut microbiota are uniquely and intrinsically able to disrupt neurologic function in offspring. These findings are in agreement with the extensive body of literature documenting the adverse effects of maternal obesity and high fat diet consumption on body weight and neuronal function in offspring in both human and animal models [49],[50],[51],[52],[53]. For example, maternal high fat diet, obesity, and metabolic syndrome have all been shown to adversely impact the behavior and physiology of children [49, 51], [7],[31],[32].…”

Section: Discussionsupporting

confidence: 90%

Maternal obese-type gut microbiota differentially impact cognition, anxiety and compulsive behavior in male and female offspring in mice

et al. 2017

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Maternal obesity is known to predispose offspring to metabolic and neurodevelopmental abnormalities. While the mechanisms underlying these phenomena are unclear, high fat diets dramatically alter intestinal microbiota, and gut microbiota can impact physiological function. To determine if maternal diet-induced gut dysbiosis can disrupt offspring neurobehavioral function, we transplanted high fat diet- (HFD) or control low fat diet-associated (CD) gut microbiota to conventionally-housed female mice. Recipient mice were then bred and the behavioral phenotype of male and female offspring was tracked. While maternal behavior was unaffected, neonatal offspring from HFD dams vocalized less upon maternal separation than pups from CD dams. Furthermore, weaned male offspring from HFD dams had significant and selective disruptions in exploratory, cognitive, and stereotypical/compulsive behavior compared to male offspring from CD dams; while female offspring from HFD dams had increases in body weight and adiposity. 16S metagenomic analyses confirmed establishment of divergent microbiota in CD and HFD dams, with alterations in diversity and taxonomic distribution throughout pregnancy and lactation. Likewise, significant alterations in gut microbial diversity and distribution were noted in offspring from HFD dams compared to CD dams, and in males compared to females. Regression analyses of behavioral performance against differentially represented taxa suggest that decreased representation of specific members of the Firmicutes phylum predict behavioral decline in male offspring. Collectively, these data establish that high fat diet-induced maternal dysbiosis is sufficient to disrupt behavioral function in murine offspring in a sex-specific manner. Thus these data reinforce the essential link between maternal diet and neurologic programming in offspring and suggest that intestinal dysbiosis could link unhealthy modern diets to the increased prevalence of neurodevelopmental and childhood disorders.

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Section: Discussionsupporting

confidence: 90%

Maternal obese-type gut microbiota differentially impact cognition, anxiety and compulsive behavior in male and female offspring in mice

et al. 2017

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“…The prevalence of GDM and maternal obesity is constantly increasing worldwide and gives rise to a vicious cycle in which babies exposed to GDM in utero are more likely to develop metabolic (and other) disorders later in life [12–16]. The mechanisms increasing the risk for long-term morbidity in the offspring are still poorly understood, but epigenetics is thought to be a key player in this process [18–20].…”

Section: Discussionmentioning

confidence: 99%

“…The offspring of GDM mothers have increased risks of developing obesity, type 2 diabetes, and cardiovasular disease [12–15]. Moreover, GDM exposure has been associated with autism spectrum disorder and long-term neuropsychiatric morbidity [16]. Studies of Pima Indian siblings discordant for exposure to GDM indicate that in addition to shared risk alleles, the increased lifelong disease risk is at least partially mediated by the hyperglycemic intrauterine environment [17].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic signatures of gestational diabetes mellitus on cord blood methylation

et al. 2017

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BackgroundIntrauterine exposure to gestational diabetes mellitus (GDM) confers a lifelong increased risk for metabolic and other complex disorders to the offspring. GDM-induced epigenetic modifications modulating gene regulation and persisting into later life are generally assumed to mediate these elevated disease susceptibilities. To identify candidate genes for fetal programming, we compared genome-wide methylation patterns of fetal cord bloods (FCBs) from GDM and control pregnancies.Methods and resultsUsing Illumina’s 450K methylation arrays and following correction for multiple testing, 65 CpG sites (52 associated with genes) displayed significant methylation differences between GDM and control samples. Four candidate genes, ATP5A1, MFAP4, PRKCH, and SLC17A4, from our methylation screen and one, HIF3A, from the literature were validated by bisulfite pyrosequencing. The effects remained significant after adjustment for the confounding factors maternal BMI, gestational week, and fetal sex in a multivariate regression model. In general, GDM effects on FCB methylation were more pronounced in women with insulin-dependent GDM who had a more severe metabolic phenotype than women with dietetically treated GDM.ConclusionsOur study supports an association between maternal GDM and the epigenetic status of the exposed offspring. Consistent with a multifactorial disease model, the observed FCB methylation changes are of small effect size but affect multiple genes/loci. The identified genes are primary candidates for transmitting GDM effects to the next generation. They also may provide useful biomarkers for the diagnosis, prognosis, and treatment of adverse prenatal exposures.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0329-3) contains supplementary material, which is available to authorized users.

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“…GD, a glucose intolerance first recognized during pregnancy, is an independent risk factor of disease in both offspring and mother [60,61]. The hyperglycemia occurring during pregnancy induces long-term phenotypic alterations in fetal endothelial cells, changes in miR-101 expression levels, as well as in those of Enhancer of Zester Homolog 2 (EZH2), its target [24].…”

Section: Mirna-associated Pregnancy Complicationsmentioning

confidence: 99%

Roles of MicroRNA across Prenatal and Postnatal Periods

Floris

Kraft

Altosaar

2016

IJMS

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Communication between mother and offspring in mammals starts at implantation via the maternal–placental–fetal axis, and continues postpartum via milk targeted to the intestinal mucosa. MicroRNAs (miRNAs), short, noncoding single-stranded RNAs, of about 22 nucleotides in length, are actively involved in many developmental and physiological processes. Here we highlight the role of miRNA in the dynamic signaling that guides infant development, starting from implantation of conceptus and persisting through the prenatal and postnatal periods. miRNAs in body fluids, particularly in amniotic fluid, umbilical cord blood, and breast milk may offer new opportunities to investigate physiological and/or pathological molecular mechanisms that portend to open novel research avenues for the identification of noninvasive biomarkers.

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Prenatal exposure to gestational diabetes mellitus as an independent risk factor for long-term neuropsychiatric morbidity of the offspring

Cited by 114 publications

References 65 publications

Maternal obese-type gut microbiota differentially impact cognition, anxiety and compulsive behavior in male and female offspring in mice

Maternal obese-type gut microbiota differentially impact cognition, anxiety and compulsive behavior in male and female offspring in mice

Epigenetic signatures of gestational diabetes mellitus on cord blood methylation

Roles of MicroRNA across Prenatal and Postnatal Periods

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