| Description |
Fetal outcomes after uteroplacental insufficiency (UPI) include growth restriction and sex-divergent increase in neonatal and adult-onset disease. Fetal acquisition of long-chain polyunsaturated fatty acids (LCPUFA) is 1) linked to disease outcomes, 2) mediated by the placenta, and 3) impaired in pregnancies complicated by UPI. Peroxisome proliferator activated receptor gamma (PPARγ) regulates placental LCPUFA transport via direct control of gene expression and by initiating chromatin modifications through Setd8. We previously showed in our rat model that UPI results in fetal growth restriction and development of sex-divergent neonatal and adult-onset disease. We hypothesize that UPI in the rat results in sex-divergent changes in the placental PPARγ-Setd8 axis and sex-divergent changes in fetal serum LCPUFA profiles. UPI was induced by bilateral uterine artery ligation at embryonic day 19 in pregnant Sprague Dawley rats. Male and female fetal rat serum and corresponding placenta were surgically collected at term (embryonic day 21). Serum LCPUFA profiles were measured using gas chromatography-mass spectrometry. mRNA was measured using real-time RT-PCR, protein was measured using western blotting, and PPARγ occupancy at the Setd8 promoter was measured using ChIP. Data are expressed as mean ± standard deviation (SD), *p<0.05. UPI did not affect PPARγ mRNA levels and protein abundance in male placenta or female placenta compared to sex-matched control. UPI increased Setd8 mRNA levels, protein abundance, and total PPARγ at the promoter of the Setd8 compared to sex-matched control in male placenta but not in female placenta. In male placenta, UPI increased global H4K20me compared to sex-matched control. No differences were observed in female placenta. In male fetuses, UPI increased the LCPUFA palmitic acid (PAL), linoleic acid (LA), and arachidonic acid (AA), while decreasing palmitoleic acid (PA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). In female fetuses, UPI increased AA with no change in other LCPUFA. In conclusion, UPI in the rat results in sex-divergent changes in the PPARγ-Setd8 axis in association with sex-divergent changes in fetal serum LCPUFA profiles. Given the role of Setd8 in chromatin maintenance, sex-divergent changes in PPARγ-driven Setd8 expression may influence UPI-induced sex-divergent changes in the placental transcriptome and subsequent placental transfer of LCPUFA. |
