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8: Males are from Mars, females are from Venus: sex-specific fetal brain gene expression signatures in a mouse model of maternal diet-induced obesity

      Objective

      Maternal obesity (MATOB) is associated with adverse neurodevelopmental outcomes in children, including autism spectrum disorder, developmental delay, and ADHD. Underlying mechanisms remain unclear. We previously identified second trimester amniotic fluid gene expression patterns suggesting dysregulated brain development in fetuses of obese (OB) compared to lean (L) women. Here, we characterized fetal brain gene expression signatures and associated pathways in a mouse model of diet-induced obesity.

      Study Design

      Female (F) C57BL/6J mice were fed a 60% high-fat diet (HFD) or 10% fat control diet (CD) for 10-12 weeks prior to mating. In pregnancy, OB dams continued on the HFD (HFD/HFD), or transitioned to the CD (HFD/CD). L dams stayed on the CD (CD/CD). On embryonic day 17.5, fetal brains were snap frozen. RNA was extracted from male (M) and F brains (10/diet group/sex) and hybridized to whole genome expression arrays. Significantly differentially expressed genes (DEGs) were identified using Welch’s t-test with the Benjamini-Hochberg (BH) correction. False discovery rate of 20% was used as a significance cutoff. Functional analyses were performed using Ingenuity Pathways Analysis™ and Gene Set Enrichment Analysis.

      Results

      MATOB resulted in more dysregulated genes in M (386) vs F (66) fetal brains (p<0.001). MATOB was associated with unique brain gene expression signatures for each sex, with overlap of only one gene (Fig 1). Changing OB dams to a CD in pregnancy induced more DEGs in the fetal brain than MATOB alone. Functional analyses identified common dysregulated pathways in both sexes, but MATOB affected different aspects of brain development in Ms vs Fs (Fig 2).

      Conclusion

      MATOB is associated with sex-specific brain gene expression signatures in M and F embryos. Maternal diet in pregnancy significantly impacts the embryonic brain transcriptome. M brain gene expression may be more sensitive to environmental influences during pregnancy such as MATOB and/or maternal diet. It is important to consider both fetal sex and maternal diet when evaluating the effects of MATOB on fetal neurodevelopment.
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