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Maternal obesity during pregnancy is associated with neurodevelopmental disorder (NDD) risk. We utilized integrative multi-omics to examine maternal obesity effects on offspring neurodevelopment in rhesus macaques by comparison to lean controls and two interventions. Differentially methylated regions (DMRs) from longitudinal maternal blood-derived cell-free fetal DNA (cffDNA) significantly overlapped with DMRs from infant brain. The DMRs were enriched for neurodevelopmental functions, methylation-sensitive developmental transcription factor motifs, and human NDD DMRs identified from brain and placenta. Brain and cffDNA methylation levels from a large region overlapping mir-663 correlated with maternal obesity, metabolic and immune markers, and infant behavior. A DUX4 hippocampal co-methylation network correlated with maternal obesity, infant behavior, infant hippocampal lipidomic and metabolomic profiles, and maternal blood measurements of DUX4 cffDNA methylation, cytokines, and metabolites. Ultimately, maternal obesity altered infant brain and behavior, and these differences were detectable in pregnancy through integrative analyses of cffDNA methylation with immune and metabolic biomarkers.

BackgroundPolychlorinated biphenyls (PCBs) are developmental neurotoxicants implicated as environmental risk factors for neurodevelopmental disorders (NDD), including autism spectrum disorders (ASD).ObjectiveWe examined the effects of prenatal exposure to a human-relevant mixture of PCBs on the DNA methylome of fetal mouse brain and placenta to determine if there was a shared subset of differentially methylated regions (DMRs).MethodsA PCB mixture formulated to model the 12 most abundant congeners detected in the serum of pregnant women from a prospective high-risk ASD cohort was administered to female mice prior to and during pregnancy. Whole-genome bisulfite sequencing (WGBS) was performed to assess genome-wide DNA methylation profiles of placenta and brain on gestational day 18.ResultsWe found thousands of significant (empiricalp< 0.05) DMRs distinguishing placentas and brains from PCB-exposed embryos from sex-matched vehicle controls. In both placenta and brain, PCB-associated DMRs were significantly (p< 0.005) enriched for functions related to neurodevelopment, cellular adhesion, and cellular signaling, and significantly (Odds Ratio > 2.4,q< 0.003) enriched for bivalent chromatin marks. The placenta and brain PCB DMRs overlapped significantly (Z-score = 4.5,p= 0.0001) by genomic coordinate and mapped to a shared subset of genes significantly (q< 0.05) enriched for Wnt signaling, Slit/Robo signaling, and genes differentially expressed in multiple NDD/ASD models. The placenta and brain DMRs also significantly (q< 0.05) overlapped by genomic coordinate with brain samples from humans with Rett syndrome and Dup15q syndrome.DiscussionThese results demonstrate that placenta can be used as a surrogate for embryonic brain DNA methylation changes over genes relevant to NDD/ASD in a mouse model of prenatal PCB exposure.

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental disorder with complex heritability and higher prevalence in males. Since the neonatal epigenome has the potential to reflect past interactions between genetic and environmental factors during early development, we performed whole-genome bisulfite sequencing of 152 umbilical cord blood samples from the MARBLES and EARLI high-familial risk prospective cohorts to identify an epigenomic signature of ASD at birth.ResultsWe identified differentially-methylated regions (DMRs) stratified by sex that discriminated ASD from control cord blood samples in discovery and replication sets. At a region level, 7 DMRs in males and 31 DMRs in females replicated across two independent groups of subjects, while 537 DMR genes in males and 1762 DMR genes in females replicated by gene association. These DMR genes were significantly enriched for brain and embryonic expression, X chromosome location, and identification in prior epigenetic studies of ASD in post-mortem brain. In males and females, autosomal ASD DMRs were significantly enriched for promoter and bivalent chromatin states across most cell types, while sex differences were observed for X-linked ASD DMRs. Lastly, these DMRs identified in cord blood were significantly enriched for binding sites of methyl-sensitive transcription factors relevant to fetal brain development.ConclusionsAt birth, prior to the diagnosis of ASD, a distinct DNA methylation signature was detected in cord blood over regulatory regions and genes relevant to early fetal neurodevelopment. Differential cord methylation in ASD supports the developmental and sex-biased etiology of ASD, and provides novel insights for early diagnosis and therapy.

Rhythmic oscillations of physiological processes depend on integrating the circadian clock and diurnal environment. DNA methylation is epigenetically responsive to daily rhythms, as a subset of CpG dinucleotides in brain exhibit diurnal rhythmic methylation. A major genetic effect on rhythmic methylation was identified in a mouse Snordll6 deletion model of the imprinted disorder Prader-Willi syndrome (PWS). Of the >23,000 diurnally rhythmic CpGs identified in wild-type cortex, 97% lost rhythmic methylation in PWS cortex. Circadian dysregulation of a second imprinted Snord cluster at the Temple/Kagami-Ogata syndrome locus was observed at the level of methylation, transcription, and chromatin, providing mechanistic evidence of crosstalk. Genes identified by diurnal epigenetic changes in PWS mice overlapped rhythmic and PWS-specific genes in human brain and were enriched for PWS-relevant obesity phenotypes and pathways. These results support the proposed evolutionary relationship between imprinting and sleep, and suggest possible chronotherapy in the treatment of PWS and related disorders.