Abstract
Maternal obesity during pregnancy increases risk for neurodevelopmental disorders in offspring, although the underlying mechanisms remain unclear. Epigenetic deregulation associates with many neurodevelopmental disorders, and recent evidence indicates that maternal nutritional status can alter chromatin marks in the offspring brain. Thus, maternal obesity may disrupt epigenetic regulation of gene expression during offspring neurodevelopment. Using a C57BL/6 mouse model, we investigated whether maternal high fat diet (mHFD)-induced obesity alters the expression of genes previously implicated in the etiology of neurodevelopmental disorders within the Gestational Day 17.5 (GD 17.5) offspring hippocampus. We found significant two-fold upregulation of oxytocin receptor (Oxtr) mRNA in the hippocampus of male, but not female, GD 17.5 offspring from mHFD-induced obese dams (p < 0.05). To determine whether altered histone binding at the Oxtr gene promoter may underpin these transcriptional changes, we then performed chromatin immunoprecipitation (ChIP). Consistent with the Oxtr transcriptional changes, we observed increased binding of active histone mark H3K9Ac at the Oxtr transcriptional start site (TSS) in the hippocampus of mHFD male (p < 0.05), but not female, offspring. Together, these data indicate an increased vulnerability of male offspring to maternal obesity-induced changes in chromatin remodeling processes that regulate gene expression in the developing hippocampus, and contributes to our understanding of how early life nutrition affects the offspring brain epigenome.
Highlights
The correct establishment of the epigenome is critical for driving the complex gene expression patterns that underpin normal brain development
We provide evidence that in utero exposure to maternal high fat diet (mHFD)-induced obesity alters oxytocin receptor (Oxtr) gene expression and histone binding at the Oxtr promoter in offspring hippocampus in a sexually dimorphic manner
In response to mHFD, Oxtr transcription increased and H3K9Ac binding was enriched at the Oxtr promoter in male offspring hippocampus
Summary
The correct establishment of the epigenome is critical for driving the complex gene expression patterns that underpin normal brain development. Increasing evidence suggests that these epigenetic mechanisms have a high degree of plasticity during development, and can be modulated by external factors in the in utero environment, including maternal nutrition [1,2]. In this way, the maternal environment may contribute to the programming of offspring disease risk. Animal models of maternal obesity can reliably reproduce the offspring phenotype of elevated obesity risk [4], and recent work from both animal models and human studies indicate that maternal obesity can alter epigenetic regulation of genes related to metabolism and food-seeking behaviors in the brain of offspring [5,6]
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