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206: Sex-specific effects of maternal obesity on embryo size and fetal brain oxidative stress

      Objective

      Maternal obesity (MATOB) is associated with adverse neurodevelopmental outcomes in children, including autism spectrum disorder, developmental delay, and ADHD. Underlying mechanisms remain unclear. In amniotic fluid of obese women, we previously identified gene expression patterns consistent with dysregulated fetal brain development and significant upregulation of APOD, a CNS-specific gene implicated in response to oxidative stress,. Here, we directly examined fetal brains in a mouse model of maternal diet-induced obesity.

      Study Design

      Female (F) C57BL/6J mice were fed a 60% fat high-fat diet (HFD) or a 10% fat control diet (CD) for 10-12 weeks prior to mating. In pregnancy, obese dams continued on the HFD (HFD/HFD), or transitioned to a CD (HFD/CD). Lean dams stayed on the CD (CD/CD). On embryonic day 17.5, fetal brains were snap frozen. RNA and protein were extracted from 25-35 embryonic brains/diet group. Quantitative RT-PCR was performed for apod. Fetal brain maldionaldehyde (MDA), a marker of oxidative stress, was quantified using HPLC. Kruskal-Wallis and Mann-Whitney testing determined significant differences between groups (p<0.05).

      Results

      Embryos of HFD/HFD dams were significantly smaller than controls, with males (M) more severely affected than Fs (p<0.001, Fig 1A). Brain apod expression was significantly decreased in F embryos of HFD/HFD dams compared to controls (p=0.003, Fig 1B). When obese dams were switched to a CD in pregnancy, brain apod expression in Fs increased to levels similar to controls (p=0.04). These changes were not observed in M brains. F brains exposed to MATOB (HFD/HFD and HFD/CD) had significantly higher MDA levels than Ms (p=0.02, Fig 1C).

      Conclusion

      MATOB had a more significant effect on M embryo size. However, MATOB had more significant effects on F brain apod expression and MDA levels, two parameters related to brain oxidative stress. Maternal diet in pregnancy also impacted fetal brain gene expression of apod in Fs only. MATOB and diet in pregnancy appear to have sex-specific influences on embryo size and on the fetal brain. Future evaluation of the effects of MATOB on fetal neurodevelopment should consider fetal sex and maternal diet.
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