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Significant Effects of Maternal Diet During Pregnancy on the Murine Fetal Brain Transcriptome and Offspring Behavior.

ABSTRACT: Background:Maternal over- and undernutrition in pregnancy plays a critical role in fetal brain development and function. The effects of different maternal diet compositions on intrauterine programing of the fetal brain is a lesser-explored area. The goal of this study was to investigate the impact of two chowmaternal diets on fetal brain gene expression signatures, fetal/neonatal growth, and neonatal and adult behavior in a mouse model. Methods:Throughout pregnancy and lactation, female C57Bl/6J mice were fed one of two standard, commercially available chow diets (pellet versus powder). The powdered chow diet was relatively deficient in micronutrients and enriched for carbohydrates and n-3 long-chain polyunsaturated fatty acids compared to the pelleted chow. RNA was extracted from embryonic day 15.5 forebrains and hybridized to whole genome expression microarrays (N = 5/maternal diet group). Functional analyses of significantly differentially expressed fetal brain genes were performed using Ingenuity Pathways Analysis and Gene Set Enrichment Analysis. Neonatal behavior was assessed using a validated scale (N = 62 pellet-exposed and 31 powder-exposed). Hippocampal learning, locomotor behavior, and motor coordination were assessed in a subset of adults using fear conditioning, open field testing, and Rotarod tests (N = 16 pellet-exposed, 14 powder-exposed). Results:Comparing powdered to pelleted chow diets, neither maternal weight trajectory in pregnancy nor embryo size differed. Maternal powdered chow diet was associated with 1647 differentially expressed fetal brain genes. Functional analyses identified significant upregulation of canonical pathways and upstream regulators involved in cell cycle regulation, synaptic plasticity, and sensory nervous system development in the fetal brain, and significant downregulation of pathways related to cell and embryo death. Pathways related to DNA damage response, brain immune response, amino acid and fatty acid transport, and dopaminergic signaling were significantly dysregulated. Powdered chow-exposed neonates were significantly longer but not heavier than pelleted chow-exposed counterparts. On neonatal behavioral testing, powdered chow-exposed neonates achieved coordination- and strength-related milestones significantly earlier, but sensory maturation reflexes significantly later. On adult behavioral testing, powdered chow-exposed offspring exhibited hyperactivity and hippocampal learning deficits. Conclusion:In wild-type offspring, two diets that differed primarily with respect to micronutrient composition had significant effects on the fetal brain transcriptome, neonatal and adult behavior. These effects did not appear to be mediated by alterations in gross maternal nutritional status nor fetal/neonatal weight. Maternal dietary content is an important variable to consider for investigators evaluating fetal brain development and offspring behavior.

SUBMITTER: Edlow AG

PROVIDER: S-EPMC6928003 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Significant Effects of Maternal Diet During Pregnancy on the Murine Fetal Brain Transcriptome and Offspring Behavior.

Edlow Andrea G AG Guedj Faycal F Sverdlov Deanna D Pennings Jeroen L A JLA Bianchi Diana W DW

Frontiers in neuroscience 20191217

<h4>Background</h4>Maternal over- and undernutrition in pregnancy plays a critical role in fetal brain development and function. The effects of different maternal diet compositions on intrauterine programing of the fetal brain is a lesser-explored area. The goal of this study was to investigate the impact of two chowmaternal diets on fetal brain gene expression signatures, fetal/neonatal growth, and neonatal and adult behavior in a mouse model.<h4>Methods</h4>Throughout pregnancy and lactation, ...[more]

PMID: 31920502

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Project description:Suboptimal nutrition during pregnancy is recognised as a significant modifiable determinant in the development of chronic disease in offspring in later life. The current study aimed: (i) to assess the dietary intakes of pregnant Indigenous Australian women against national recommendations and (ii) to investigate the associations between maternal nutrition during pregnancy and the growth of the offspring, including kidney development in late gestation in the Gomeroi gaaynggal cohort (n = 103). Maternal dietary intake in the third trimester was assessed using the Australian Eating Survey Food Frequency Questionnaire. Estimated fetal weight (EFW) and kidney size were obtained by ultrasound. Birth weight was retrieved from hospital birth records. Of the five key nutrients for optimal reproductive health (folate, iron, calcium, zinc and fibre), the nutrients with the highest percentage of pregnant women achieving the nutrient reference values (NRVs) were zinc (75.7%) and folate (57.3%), whereas iron was the lowest. Only four people achieved all NRVs (folate, iron, calcium, zinc and fibre) important in pregnancy. Sodium and saturated fat intake exceeded recommended levels and diet quality was low, with a median score of 28 out of 73 points. After adjusting for smoking and pre-pregnancy body mass index, only maternal intake of retinol equivalents and the proportion of energy from nutrient-dense or energy-dense, nutrient-poor (EDNP) foods were associated with fetal growth. EFW decreased by 0.13 g and birth weight decreased by 0.24 g for every µg increase in maternal dietary retinol intake. Interestingly, EFW, but not actual birth weight, was positively associated with percentage energy from nutrient dense foods and negatively associated with percentage energy from EDNP foods. Dietary supplement usage was associated with increased birthweight, most significantly iron and folate supplementation. Current dietary intakes of pregnant Australian women from this cohort do not align with national guidelines. Furthermore, current findings show that maternal retinol intake and diet composition during pregnancy can influence fetal growth, but not fetal kidney growth in late gestation. Strategies that aim to support and optimise nutrient intakes of Indigenous pregnant women are urgently needed. Future studies with long-term follow-up of the children in the current cohort to assess renal damage and blood pressure are imperative.

Project description:“Dysbiosis" of the maternal gut microbiome, in response to environmental challenges such as infection, altered diet and stress during pregnancy, has been increasingly associated with abnormalities in offspring brain function and behavior. However, whether the maternal gut microbiome regulates neurodevelopment in the absence of environmental challenge remains unclear. In addition, whether the maternal microbiome exerts such influences during critical periods of embryonic brain development is poorly understood. Here we investigate how depletion, and selective reconstitution, of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibit widespread transcriptomic alterations in the fetal brain relative to conventionally-colonized controls, with reduced expression of several genes involved in axonogenesis. In addition, embryos from microbiome-depleted mothers exhibit deficient thalamocortical axons and impaired thalamic axon outgrowth in response to cell-extrinsic guidance cues and growth factors. Consistent with the importance of fetal thalamocortical axonogenesis for shaping neural circuits for sensory processing, restricted depletion of the maternal microbiome from pre-conception through mid-gestation yields offspring that exhibit tactile hyposensitivity in select sensorimotor behavioral tasks. Gnotobiotic colonization of antibiotic-treated dams with a limited consortium of spore-forming bacteria indigenous to the gut microbiome prevents abnormalities in fetal brain gene expression, fetal thalamocortical axonogenesis and adult tactile sensory behavior associated with maternal microbiome depletion. Metabolomic profiling reveals that the maternal microbiota regulates levels of numerous small molecules in the maternal serum as well as the brains of fetal offspring. Select microbiota-dependent metabolites – trimethylamine N-oxide, 5-aminovalerate, imidazole propionate, and hippurate – sufficiently promote axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with the metabolites during early gestation abrogates deficiencies in fetal thalamocortical axons and prevents abnormalities in tactile sensory behavior in offspring from microbiome-depleted dams. Altogether, these findings reveal that the maternal gut microbiome promotes fetal thalamocortical axonogenesis and select tactile sensory behaviors in mice, likely by signaling of microbially modulated metabolites to neurons in the developing brain.

Dataset Information

Significant Effects of Maternal Diet During Pregnancy on the Murine Fetal Brain Transcriptome and Offspring Behavior.

Publications

Significant Effects of Maternal Diet During Pregnancy on the Murine Fetal Brain Transcriptome and Offspring Behavior.

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