Abstract
Fetal growth restriction (FGR) is a major obstetric complication stemming from poor placental development. We have previously demonstrated that paternal obesity in mice is associated with impaired embryo development and significantly reduced fetal and placental weights. We hypothesised that the FGR observed in our rodent model of paternal diet-induced obesity is associated with alterations in metabolic, cell signalling and stress pathways. Male C57BL/6 mice were fed either a normal or high-fat diet for 10 weeks before sperm collection for IVF and subsequent embryo transfer. On embryonic day 14, placentas were collected and RNA extracted from both male and female placentas to assess mRNA expression of 24 target genes using custom RT-qPCR arrays. Peroxisome proliferator-activated receptor alpha (Ppara) and caspase-12 (Casp12) expression were significantly altered in male placentas from obese fathers compared with normal (P<0.05), but not female placentas. PPARA and CASP12 proteins were localised within the placenta to trophoblast giant cells by immunohistochemistry, and relative protein abundance was determined by western blot analysis. DNA was also extracted from the same placentas to determine methylation status. Global DNA methylation was significantly increased in female placentas from obese fathers compared with normal (P<0.05), but not male placentas. In this study, we demonstrate for the first time that paternal obesity is associated with changes in gene expression and methylation status of extraembryonic tissue in a sex-specific manner. These findings reinforce the negative consequences of paternal obesity before conception, and emphasise the need for more lifestyle advice for prospective fathers.