| Description |
Fetal outcomes from pregnancies complicated by uteroplacental insufficiency (UPI) include growth restriction and an increase in neonatal and adult-onset disease. These outcomes are often sex-divergent, with males having worse outcomes than females. Fetal acquisition of long-chain polyunsaturated fatty acids (LCPUFA) is impaired in pregnancies complicated by UPI and is linked to disease outcomes. Fetal acquisition of LCPUFA is mediated by the placenta. PPARγ regulates placental LCPUFA transport through direct control of gene expression, and indirectly by initiating chromatin modifications through Setd8. We have previously shown in our rat model of UPI that the PPARγ-Setd8 axis is present in the placenta and UPI results in sex-divergent changes in fetal serum LCPUFA profiles. Docosahexaenoic acid (DHA) is an LCPUFA ligand of PPARγ and is critical for normal fetal development. We hypothesize that UPI and DHA supplementation will cause sex divergent changes in mRNA levels of Setd8, as well as fatty acid transport and handling genes in association with altered H4k20me along one representative gene. UPI was induced by bilateral uterine artery ligation at embryonic day 19 in pregnant Sprague Dawley rats. Male and female placenta were surgically collected at term (embryonic day 21). mRNA was measured using real-time RT-PCR, and H4K20me on the SLC27A2 gene was measured using ChIP. Oil-Red-O staining was used as an additional qualitative measure of lipid accumulation in the placenta. iv Data are expressed as mean ± standard deviation (SD), *P < .05. In male placenta UPI increases Setd8 and alters mRNA levels of transport, binding, and handling genes. We also performed pilot experiments examining H4K20me along the fatty-acid transport protein 2 gene (gene name SLC27A2). In males, UPI caused a significant increase in H4k20me at the exon 3 region of SLC27A2 (FATP2), but not the promoter, possibly influenced by our small sample size. In contrast, in female placenta, UPI did not affect Setd8 or FATP2 mRNA, or H4K20me along the SLC27A2 (FATP2) gene. The combination of UPI and DHA supplementation, on the other hand, increased Setd8 and FATP2 mRNA, and H4K20me along the SLC27A2 (FATP2) gene in both male and female placenta. Oil-Red-O staining indicates increased lipid droplet formation in the basal zone of the male and female placenta when supplemented with DHA. In conclusion, UPI and DHA supplementation in the rat results in sex-divergent changes in Setd8 and mRNA levels of fatty acid transport and handling genes, as well as H4K20me along the SLC27A2 (FATP2) gene. Given the role of these genes in LCPUFA metabolism in the placenta, sex-divergent changes in gene expression resulting from changes to the PPARγ-Setd8 axis may influence placental handling and transfer of LCPUFA to the fetus. |
