Durbin-Johnson, B. P. | bioRxiv Science

bioRxiv2024

Placental-brain axis in females detected within broadly impacted metabolic gene networks protects against prenatal PCB exposure

BackgroundNeurodevelopmental disorders have a strong male bias that is poorly understood. Placenta is a rich source of molecular information about environmental interactions with genetics (including biological sex), that affect the developing brain. We investigated placental-brain transcriptional responses in an established mouse model of prenatal exposure to a human-relevant mixture of polychlorinated biphenyls (PCBs). ResultsTo understand sex, tissue, and dosage effects in embryonic (E18) brain and placenta by RNAseq, we used weighted gene correlation network analysis (WGCNA) to create correlated gene networks that could be compared across sex or tissue. WGCNA revealed that expression within most correlated gene networks was significantly and strongly associated with PCB exposures, but frequently in opposite directions between male-female and placenta-brain comparisons. In both WGCNA and differentially expressed gene analyses, male brain showed more PCB-induced transcriptional changes than male placenta, but the reverse pattern was seen in females. Furthermore, non-monotonic dose responses to PCBs were observed in most gene networks but were most prominent in male brain. The transcriptomic effects of low dose PCB exposure were significantly reversed by dietary folic acid supplementation across both sexes, but these effects were strongest in female placenta. PCB-dysregulated and folic acid-reversed gene networks were commonly enriched in functions in metabolic pathways involved in energy usage and translation, with female-specific protective effects enriched in PPAR, thermogenesis, glycerolipids, and O-glycan biosynthesis, as opposed to toxicant responses in male brain. ConclusionsThe female protective effect in prenatal PCB exposures appears to be mediated by dose-dependent sex differences in transcriptional modulation of metabolism in placenta. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/603326v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@14d4936org.highwire.dtl.DTLVardef@101b87eorg.highwire.dtl.DTLVardef@1f787e6org.highwire.dtl.DTLVardef@1fb1b62_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2020

Expression changes in immune and epigenetic gene pathways associated with nutritional metabolites in maternal blood from pregnancies resulting in autism and atypical neurodevelopment

BackgroundThe prenatal period is a critical window to study factors involved in the development of autism spectrum disorder (ASD). Environmental factors, especially in utero nutrition, can interact with genetic risk for ASD, but how specific prenatal nutrients in mothers of children later diagnosed with ASD or non-typical development (Non-TD) associate with gestational gene expression is poorly understood. Maternal blood collected prospectively during pregnancy provides a new opportunity to gain insights into nutrition, particularly one-carbon metabolites, on gene pathways and neurodevelopment. MethodsGenome-wide transcriptomes were measured using microarrays in 300 maternal blood samples from all three trimesters in the Markers of Autism Risk in Babies - Learning Early Signs (MARBLES) study. Sixteen different one-carbon metabolites, including folic acid, betaine, 5-methyltretrahydrofolate (5-MeTHF), and dimethylglycine (DMG) were measured. Differential expression analysis and weighted gene correlation network analysis (WGCNA) were used to compare gene expression between children later diagnosed as typical development (TD), Non-TD and ASD, and to nutrient metabolites. ResultsUsing differential gene expression analysis, six transcripts associated with four genes (TGR-AS1, SQSTM1, HLA-C and RFESD) showed genome-wide significance (FDR q < 0.05) with child outcomes. Genes nominally differentially expressed compared to TD specifically in ASD, but not Non-TD, significantly overlapped with seven high confidence ASD genes. 218 transcripts in common to ASD and Non-TD differential expression compared to TD were significantly enriched for functions in immune response to interferon-gamma, apoptosis, and metal ion transport. WGCNA identified co-expressed gene modules significantly correlated with 5-MeTHF, folic acid, DMG, and betaine. A module enriched in DNA methylation functions showed a protective association with folic acid/5-MeTHF concentrations and ASD risk. Independent of child outcome, maternal plasma betaine and DMG concentrations associated with a block of co-expressed genes enriched for adaptive immune, histone modification, and RNA processing functions. LimitationsBlood contains a heterogeneous mixture of cell types, and many WGCNA modules correlated with cell type and/or nutrient concentrations, but not child outcome. Gestational age correlated with some co-expressed gene modules in addition to nutrients. ConclusionsThese results support the premise that the prenatal maternal blood transcriptome is a sensitive indicator of gestational nutrition and childrens later neurodevelopmental outcomes.

bioinformatics↗