Effect of maternal diabetes on the embryo, fetus, and children: Congenital anomalies, genetic and epigenetic changes and developmental outcomes

Ornoy, Asher; Reece, E. Albert; Pavlínková, Gabriela; Kappen, Claudia; Miller, Richard K.

doi:10.1002/bdrc.21090

Cited by 234 publications

(212 citation statements)

References 191 publications

(204 reference statements)

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“…Epidemiological studies have identified significant environmental risk factors for human CHD, including maternal exposures to alcohol, isotretinoin, thalidomide, antiseizure medications, antiretroviral medications, environmental teratogens and infectious agents. Embryo hypoxia is another well-recognized risk factor caused by smoking, living at high altitude, maternal diabetes, high body mass index, hypertension or prescription medications (Watkins et al, 2003;Jenkins et al, 2007;Zheng et al, 2013;Webster et al, 2014;Ornoy et al, 2015;Ramakrishnan et al, 2015;Sullivan et al, 2015). The specific effects of environment on embryonic development have been studied by exposing pregnant animals to a variety of conditions.…”

Section: Introductionmentioning

confidence: 99%

Gestational stress induces the unfolded protein response, resulting in heart defects

et al. 2016

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Congenital heart disease (CHD) is an enigma. It is the most common human birth defect and yet, even with the application of modern genetic and genomic technologies, only a minority of cases can be explained genetically. This is because environmental stressors also cause CHD. Here we propose a plausible non-genetic mechanism for induction of CHD by environmental stressors. We show that exposure of mouse embryos to short-term gestational hypoxia induces the most common types of heart defect. This is mediated by the rapid induction of the unfolded protein response (UPR), which profoundly reduces FGF signaling in cardiac progenitor cells of the second heart field. Thus, UPR activation during human pregnancy might be a common cause of CHD. Our findings have far-reaching consequences because the UPR is activated by a myriad of environmental or pathophysiological conditions. Ultimately, our discovery could lead to preventative strategies to reduce the incidence of human CHD.

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Section: Introductionmentioning

confidence: 99%

Gestational stress induces the unfolded protein response, resulting in heart defects

et al. 2016

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“…It is well known that gestational diabetes can lead to adverse metabolic outcomes for both the mother and the child [12,13,14]. Our previous report established that FFA2 is involved in maintaining gestational glucose homeostasis [11].…”

Section: Discussionmentioning

confidence: 99%

“…In the long-term, it increases the likelihood that the mother will develop type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and metabolic syndrome [13]. Similarly, maternal hyperglycemia during pregnancy places the offspring at increased risk for T2DM, obesity and metabolic syndrome [14]. Therefore, we first explore if maternal hyperglycemia during pregnancy due to Ffar2 deletion is sufficient to lead to aberrant metabolic health in their offspring.…”

Section: Introductionmentioning

confidence: 99%

FFA2 Contribution to Gestational Glucose Tolerance Is Not Disrupted by Antibiotics

Fuller

Fisch

et al. 2016

PLoS ONE

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During the insulin resistant phase of pregnancy, the mRNA expression of free fatty acid 2 receptor (Ffar2) is upregulated and as we recently reported, this receptor contributes to insulin secretion and pancreatic beta cell mass expansion in order to maintain normal glucose homeostasis during pregnancy. As impaired gestational glucose levels can affect metabolic health of offspring, we aimed to explore the role of maternal Ffar2 expression during pregnancy on the metabolic health of offspring and also the effects of antibiotics, which have been shown to disrupt gut microbiota fermentative activity (the source of the FFA2 ligands) on gestational glucose homeostasis. We found that maternal Ffar2 expression and impaired glucose tolerance during pregnancy had no effect on the growth rates, ad lib glucose and glucose tolerance in the offspring between 3 and 6 weeks of age. To disrupt short chain fatty acid production, we chronically treated WT mice and Ffar2-/- mice with broad range antibiotics and further compared their glucose tolerance prior to pregnancy and at gestational day 15, and also quantified cecum and plasma SCFAs. We found that during pregnancy antibiotic treatment reduced the levels of SCFAs in the cecum of the mice, but resulted in elevated levels of plasma SCFAs and altered concentrations of individual SCFAs. Along with these changes, gestational glucose tolerance in WT mice, but not Ffar2-/- mice improved while on antibiotics. Additional data showed that gestational glucose tolerance worsened in Ffar2-/- mice during a second pregnancy. Together, these results indicate that antibiotic treatment alone is inadequate to deplete plasma SCFA concentrations, and that modulation of gut microbiota by antibiotics does not disrupt the contribution of FFA2 to gestational glucose tolerance.

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“…The autism genes are also expressed and enriched in the pancreas and this is relevant to associations between maternal diabetes and autism (Ornoy et al, 2015). The autism genes are also expressed and enriched in the adrenals which secrete many steroid hormones (e.g.…”

Section: Glandular Expression and Enrichment Of The Autism Genesmentioning

confidence: 99%

The barrier, airway particle clearance, placental and detoxification functions of autism susceptibility genes

Carter

2016

Neurochemistry International

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Effect of maternal diabetes on the embryo, fetus, and children: Congenital anomalies, genetic and epigenetic changes and developmental outcomes

Abstract: Tight metabolic control, surveillance, and labor management remain the cornerstone of care for pregnant women with diabetes, but advances in the field indicate that new treatments to protect the mother and baby are not far from becoming clinical realities.

Cited by 234 publications

References 191 publications

Gestational stress induces the unfolded protein response, resulting in heart defects

Gestational stress induces the unfolded protein response, resulting in heart defects

FFA2 Contribution to Gestational Glucose Tolerance Is Not Disrupted by Antibiotics

The barrier, airway particle clearance, placental and detoxification functions of autism susceptibility genes

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