Biology subjects

Regnault, T. R. H.

Publications and source records attributed to Regnault, T. R. H..

5 recordsLinked to original sources

bioRxiv2026

Maternal BMI and Placental Transcriptomic Changes: A Meta-Analysis of Gene Expression at the Maternal-Fetal Interface

ObjectiveMaternal body mass index (BMI) is often used as a measure of metabolic status and increased or decreased maternal BMI is associated with a heightened risk of cardiometabolic diseases across generations. The placenta mediates these maternal metabolic cues; however, its genome-wide transcriptional adaptations in response to maternal BMI remain incompletely defined. MethodsTo delineate placental genes, pathways, and interaction clusters whose transcript abundance varies with maternal pre-pregnancy BMI through a genome-wide meta-analysis of human placental RNA-sequencing datasets. Placental RNA-seq reads from four publicly available cohorts (n = 146) were mapped to the GRCh38 reference genome and differentially expressed genes were identified. An independent microarray cohort (n = 19) was re-analysed separately to facilitate cross-platform comparison. Functional enrichment employed GO, KEGG, and STRING protein-interaction resources. ResultsMeta-analysis of 146 RNA-seq samples identified eight genes with genome-wide significance in placentae from underweight pregnancies including inflammatory signaling gene MAP4K1 and metabolic enzyme PSPH, while overweight and obese categories revealed nominally significant differential expression. KEGG analysis demonstrated significant downregulation of oxidative phosphorylation with increasing maternal BMI, and protein-protein interaction networks revealed inflammatory mediators as central nodes in overweight and obese groups. Independent microarray validation corroborated key findings, including consistent downregulation of oxidative phosphorylation in obesity. ConclusionMaternal BMI is associated with placental transcriptomic signatures involving inflammatory, metabolic, and hormonal pathways, with consistent downregulation of oxidative phosphorylation across platforms. This genome-wide meta-analysis provides a reproducible catalogue of BMI-responsive placental transcripts that may contribute to developmental programming of offspring health. Article highlightsO_LIMeta-analysis of 146 RNA-seq samples across four cohorts spanning the BMI spectrum C_LIO_LIEight genes reached genome-wide significance in underweight placentae C_LIO_LIOxidative phosphorylation downregulated with increasing maternal BMI across platforms C_LIO_LIInflammatory mediators emerged as central nodes in obesity-associated PPI networks C_LIO_LIIndependent microarray validation corroborated RNA-seq pathway findings C_LI

bioinformatics↗

bioRxiv2024

White matter microglia morphological changes with aging in guinea pig offspring born growth restricted

Fetal growth restriction is implicated in the programming of later-life neurodegeneration. We hypothesized that growth restricted offspring would show accelerated changes to microglial white matter morphology, relative to controls. Control guinea pig sows were fed ad libitum, while maternal nutrient restriction sows received 70% of control diet switched to 90% from mid-gestation. Offspring were sacrificed at [~]26 days (neonate) or [~]110 days (adult) postpartum. Coronal brain sections from the frontal cortex were subject to IBA1-staining for microglial detection and analyzed by machine learning software. At birth, total body weight of growth restricted offspring was reduced relative to control (p<0.0001) with postnatal catch-up growth observed. Microglial density was reduced in the corpus callosum of control (p<0.05) and growth restricted (p=0.13) adults, relative to neonates. Adults from both groups showed greater IBA1-positive area in the cingulum and periventricular white matter (p<0.05) and increased microglial fractal dimension in the corpus callosum (p<0.10) and periventricular white matter (p<0.05), relative to neonates. At the timepoints studied, we report age-related changes in white matter microglial morphology. However, maternal nutrient restriction leading to fetal growth restriction in guinea pigs does not appear to exacerbate these white matter microglia morphological changes as a marker for later-life neurodegeneration.

developmental biology↗

bioRxiv2023

Quantifying Myelin Water Fraction in a Guinea Pig Model of Spontaneous Intrauterine Growth Restriction

Intrauterine growth restriction (IUGR) is an obstetrical outcome where a fetus has not achieved its genetic potential. A consequence of IUGR is a decrease in brain myelin content. Myelin water imaging (MWI) has previously assessed fetal myelin water fraction (MWF) and can potentially assess myelination changes associated with IUGR. Thus, this study aims to quantify and compare the MWF of non-IUGR and IUGR fetal guinea pigs (GPs) in late gestation. Our sample consisted of 22 pregnant Dunkin-Hartley GPs with 71 fetuses (34 male) [mean {+/-} standard deviation: 60 {+/-} 1.2 days gestation]. Eight SPGR volumes [flip angles (): 2{degrees} - 16{degrees}], and two sets of 8 bSSFP volumes (: 8{degrees} - 64{degrees}), at 0{degrees} and 180{degrees} phase increments were acquired at 3.0 T. MWF maps were generated for each fetal GP brain using multicomponent driven equilibrium single pulse observation of T1/T2 (mcDESPOT). Regions of interest (ROIs) were placed in the fetal corpus callosum (CC), fornix (FOR), and parasagittal white matter (PSW). Linear regression was performed between five fetal IUGR markers [body volume (BV), body-to-pregnancy volume ratio (BPrVR), brain-to-liver VR (BLVR), brain-to-placenta VR (BPlVR), and brain-to-BVR (BBVR)] and MWF for all regions (coefficient of determination, R2). A t-test with a linear mixed model compared the MWF of non-IUGR and IUGR fetal GPs for all three regions ( = 0.05). The MWF values are as follows: (mean {+/-} standard deviation): 0.23 {+/-} 0.02 (fetal CC), 0.19 {+/-} 0.02 (fetal CC - IUGR), 0.31 {+/-} 0.02 (fetal FOR), 0.27 {+/-} 0.01 (fetal FOR - IUGR), 0.28 {+/-} 0.02 (fetal PSW), and 0.24 {+/-} 0.03 (fetal PSW - IUGR). Significant differences in MWF were found between the non-IUGR and IUGR fetuses in every region. In conclusion, the mean MWF of IUGR fetal GPs is significantly lower than non-IUGR fetal GPs.

biophysics↗

bioRxiv2021

Differential and synergistic effects of low birth weight and Western diet on skeletal muscle vasculature, mitochondrial lipid metabolism and insulin signaling in male guinea pigs

Low birth weight (LBW) offspring are at increased risk for developing insulin resistance, a key precursor in metabolic syndrome and type 2 diabetes mellitus. Altered skeletal muscle vasculature, extracellular matrix, amino acid and mitochondrial lipid metabolism, and insulin signaling are implicated in this pathogenesis. Using uteroplacental insufficiency (UPI) to induce intrauterine growth restriction (IUGR) and LBW in the guinea pig, we investigated the relationship between UPI-induced IUGR/LBW and later life skeletal muscle arteriole density, fibrosis, amino acid and mitochondrial lipid metabolism, markers of insulin signaling and glucose uptake, and how a postnatal high-fat, high-sugar "Western" diet (WD) modulates these changes. Muscle of 145-day-old male LBW glucose tolerant offspring displayed diminished vessel density and altered acylcarnitine levels. Disrupted muscle insulin signaling despite maintained whole-body glucose homeostasis also occurred in both LBW and WD-fed male lean offspring. Additionally, postnatal WD unmasked LBW-induced impairment of mitochondrial lipid metabolism as reflected by increased acylcarnitine accumulation. This study provides evidence that early markers of skeletal muscle metabolic dysfunction appear to be influenced by the in utero environment and interact with a high fat-sugar postnatal environment to exacerbate altered mitochondrial lipid metabolism promoting mitochondrial overload.

physiology↗

bioRxiv2020

Sex-specific Alterations in Hepatic Cholesterol Metabolism in Young Uteroplacental Insufficiency-induced Low Birth Weight Adult Guinea Pig Offspring

BackgroundIntrauterine growth restriction (IUGR) and low birth weight (LBW) have been widely reported as an independent risk factor for hypercholesterolemia and increased hepatic cholesterol underlying liver dysfunction in adulthood. However, the specific impact of uteroplacental insufficiency (UPI), a leading cause of LBW in developed world, on hepatic cholesterol metabolism in later life, is ill defined and is clinically relevant in understanding later life liver metabolic health trajectories. MethodsHepatic cholesterol metabolism pathways were studied in uterine artery ablation-induced LBW and normal birth weight (NBW) male and female guinea pig offspring at postnatal day 150. ResultsHepatic free and total cholesterol were increased in LBW versus NBW males. Transcriptome analysis of LBW versus NBW livers revealed that "Cholesterol metabolism" was an enriched pathway in LBW males but not females. Microsomal triglyceride transfer protein and cytochrome P450 7A1 protein, involved in hepatic cholesterol efflux and catabolism, respectively, and catalase activity were decreased in LBW male livers. Superoxide dismutase activity was reduced in LBW males but increased in LBW females. ConclusionsUPI environment is associated with a later life programed hepatic cholesterol accumulation via impaired cholesterol elimination, in a sex-specific manner. These programmed alterations could underlie later life cholesterol-induced hepatic lipotoxicity in LBW male offspring. Impact StatementO_LILow birth weight (LBW) is a risk factor for adult hypercholesterolemia and increased hepatic cholesterol. C_LIO_LIUteroplacental insufficiency (UPI) resulting in LBW increased hepatic cholesterol content, altered hepatic expression of cholesterol metabolism-related genes in young adult guinea pigs. C_LIO_LIUPI-induced LBW was also associated with markers of a compromised hepatic cholesterol elimination process and failing antioxidant system in young adult guinea pigs. C_LIO_LIThese changes, at the current age studied, were sex-specific, only being observed in LBW males and not LBW females. C_LIO_LIThese programmed alterations could lead to further hepatic damage and greater predisposition to liver diseases in UPI-induced LBW male offspring as they age. C_LI

physiology↗