Effects of intrauterine growth restriction and a maternal high fat diet on epigenetic determinants in rat lung

Intrauterine growth restriction (IUGR) complicates up to 15% of pregnancies and often occurs in conjunction with exposure to a maternal diet high in saturated fats (HFD). IUGR is associated with alterations to the structure and development of the lung. Lung development depends upon the precise and coordinate expression of genetic and epigenetic determinants. Methylation of lysine 20 on histone 4 (H4K20Me) is an epigenetic histone modification of interest in lung development. The enzyme Setd8 places the H4K20Me mark along target genes, including the PPARγ gene. The H4K20Me mark increases transcription of PPARγ mRNA and production of the translated product, PPARγ protein. By way of a feedback loop, PPARγ is also the transcription factor that regulates transcription of Setd8. PPARγ is critical in alveolarization, or the final stage in lung development. We previously showed that a diet high in unsaturated fat can reverse effects of IUGR on lung molecular changes, however, the effects of a diet high in saturated fats is unknown. In this study we hypothesized that maternal HFD in combination with IUGR will decrease PPARγ2 and Setd8 mRNA and protein expression beyond that of IUGR alone. We hypothesize that H4K20Me in whole rat lung and at Exon 4 of the PPARγ gene will also be decreased by HFD and IUGR. Sprague-Dawley rats were studied before and after alveolarization (prealveolarization and postalveolarization). Dams either underwent uteroplacental insufficiency to induce IUGR or anesthesia only for control rats. Half of each group (IUGR and control) were fed a regular diet while the other half were fed a HFD from preconception to the end of the study. Our study demonstrated that, HFD in combination with IUGR (HFD-IUGR) affects the PPARγ-Setd8 feedback loop in rat lung in a sex-specific manner. In male rat lung, HFD-IUGR resulted in disconnects in the PPARγ-Setd8 feedback loop. Furthermore, disconnects in the PPARγ-Setd8 feedback loop persisted beyond alveolarization. These novel findings suggest that male rat lungs are more susceptible to diet induced changes in the PPARγ-Setd8 feedback loop than female rat lungs. Further, these changes may make male IUGR rat lungs susceptible to lung injury over the longterm.