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Disruption of Zinc homeostasis can impair maternal glucocorticoid metabolism: consequences on the developing fetus

ABSTRACT: Steroids play a broad and vital role in regulation of gene expression, secondary sexual characteristics, maturation, reproduction, and neurological functions; but an imbalance in steroid metabolism is also linked to development and progression of many diseases including autism. Prenatal stress of different nature has been demonstrated to affect both the mother and the offspring. Adverse nutritional conditions during gestation can impair the maternal hypothalamic-pituitary-adrenal axis (HPA) and expose the fetus to high levels of glucocorticoids (GC). Evenwhen GC are required for normal brain development; an increased exposure of the fetus to GC as a consequence of prenatal stress can affect fetal hypothalamic-pituitary-gonad axis (HPG) development, impair neurogenesis, and have a long term impact on the offsprings mental health. Decreased zinc availability can occur during pregnancy as a consequence of different conditions (nutritional deficiency, infections, diabetes, alcohol consumption, and exposure to certain toxicants). Importantly, several of these gestational conditions have been linked to autism. In fact, alterations in maternal zinc homeostasis upon exposure to select environmental stressors (e.g. the phthalate plasticizer bis-2-ethylhexyl phthalate (DEHP)) that have become increasingly common since the industrial revolution may underlie the recent rise in the incidence of autism.Alterations in maternal zinc homeostasis could expose the fetus to high GC concentrations secondary to a high maternal GC production and/or to a decreased capacity of the placenta to metabolize GC to inactive metabolites. The overall goal of this proposal is to investigate if alterations in zinc homeostasis during gestation triggered by either a marginal zinc nutrition or exposure to an environmental pollutant (the phthalate plasticizer bis-2-ethylhexyl phthalate (DEHP)) can impair maternal and fetal endocrine signaling leading to impaired fetal brain development.

ORGANISM(S): Rat Rattus Norvegicus

TISSUE(S): Brain, Placenta, Amniotic Fluid, Liver, Adrenal Gland, Blood

SUBMITTER: Heidi Kucera

PROVIDER: ST000120 | MetabolomicsWorkbench | Tue Sep 30 00:00:00 BST 2014

REPOSITORIES: MetabolomicsWorkbench

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Project description:Activation of the maternal immune system during pregnancy can fetal development, which can lead to postnatal susceptibility to a wide range of diseases, including cardiovascular, metabolic and psychiatric disorders. During maternal immune activation (MIA), the maternal body must balance its ressources between mounting an immune response and investing resources into continued metabolism and growth : both essential for survival of the fetus and a successful pregnancy. How the placenta responds to MIA over time and how it can protect the fetus is not well understood, and neither are the fetal consequences of MIA. Here, we characterised the response to an induced acute inflammation in maternal lungs over time across maternal and fetal organs, using a combination of omics-methods, imaging and integrative computational analysis. We found that the placenta, unlike other maternal organs, did not react by inducing a typical inflammatory response, but instead initially induced genes associated to strengthen tissue integrity and simultaneously reduced growth to prevent exposure to potential infections. Afterwards, a return to homeostasis was observed, with heightened biosynthesis and expression of endoplasmic reticulum (ER) stress genes. This mechanism likely protects the fetus from inflammation, as we observed no immune response in the fetal liver transcriptome. Instead, we observed metabolic adaptations in the fetus, including a release of docosahexaenoic acid (DHA) Notably, DHA has a crucial function for fetal brain development , and levels of triglyceride and phosphatidylcholine lipids that are necessary for transportation of DHA to the brain were also increased. This metabolic response is likely a combination of the placental MIA response and temporary maternal fasting, caused by MIA-induced fever and lack of nutrient intake. Our study shows, for the first time, the temporal and systemic response to MIA in lungs across maternal and fetal organs.

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Disruption of Zinc homeostasis can impair maternal glucocorticoid metabolism: consequences on the developing fetus

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