The rate of obesity amongst men of reproductive age has tripled in the last 30 years. Previously, we have shown that paternal obesity (modelled in the mouse) causes poor embryo development and leads to significantly reduced fetal and placental weights. Fetal growth restriction (FGR) is a major obstetric complication, stemming from poor placental development. We hypothesised that the FGR observed in our paternal obesity model is due to alterations in metabolic, cell signalling and stress pathways.
Sperm was collected from normal and obese C57BL/6 mice and used for IVF with normal oocytes. Blastocysts were transferred to recipient females, and placentas derived from normal and obese fathers were collected at E14. RNA, DNA and protein were extracted from placentas and assessed for: 1) mRNA expression using custom RT-qPCR arrays, 2) DNA methylation analysis, 3) immunohistochemistry and western blot. In addition, human placental tissue was obtained from pregnancies complicated by severe FGR and gestationally-matched controls, to assess altered gene expression in the human.
PPARα and Casp12 expression was significantly altered in male placentas from obese fathers compared to normal (p<0.05), but not female placentas. PPARα and Casp12 immunoreactive protein was localised within the placenta to both trophoblast and vasculature, and antibody specificity confirmed by western blot analysis. Global DNA methylation was significantly increased in female placentas from obese fathers compared to normal (p<0.05), but not male placenta. Given these results, we examined PPARα and Casp12 expression in placentas from human FGR. PPARα expression was significantly altered in male placentas complicated with severe FGR (p<0.05); in contrast to the mouse, Casp12 was not detected in human placental tissue.
These findings expand our previous work, showing paternal obesity negatively impacts the resultant offspring. Here we clearly demonstrate altered molecular pathways in the placenta and identify PPARα as a key molecule in placental function.